Kampo Formula-Pattern Models: The Development of 13 New Clinically Useful Standard Abdominal Pattern Models in the Fukushin Simulator.

Aim: In Kampo medicine, there exists an important system of diagnosis called Fukushin, or abdominal diagnosis or palpation. By applying pressure to the abdomen of the patient, the physician can gain important information on the patient's physical state and use those indications to choose a suitable Kampo formulation. We have previously developed a Fukushin simulator, a teaching tool that reproduces the important abdominal patterns that doctors will encounter in clinical practice and that has received favourable feedback for students and practitioners. In order to make diagnosis and prescription easier, it is desirable to have matched formula-pattern pairings. The present study aims to develop such pairings. Methods: With the previously developed models as a foundation, in the present study the production team (two members) used materials such as urethane foam and silicone rubber to build an additional 13 standard abdominal pattern models matched to Kampo herbal formulas commonly used by practitioners in Japan. Subsequently, the evaluation team (the remaining 10 authors) investigated the viability of these models. Results: The evaluation team determined that abdominal pattern models matched to the following typical Kampo formulas were created successfully: Dai-saiko-To (), Dai-joki-To (), Shigyaku-San (), Saiko-ka-ryukotsu-borei-To (), Keishi-bukuryo-Gan (), Hachimi-jio-Gan (), Hange-shashin-To (), Sho-saiko-To (), Hochu-ekki-To (), Sho-kenchu-To (), Toki-shakuyaku-San (), Ninjin-To (), and Dai-kenchu-To (). Conclusion: We suggest that these new formula-pattern models can make an important contribution to the standardization of abdominal diagnosis and prescription and to Kampo education.

Adverse Effects of Kampo Medicines.

This review summarizes the adverse effects of Kampo medicines. These adverse effects in terms of immunoallergic reactions include interstitial pneumonia, liver injury, allergic cystitis, and drug eruption. Many cases of interstitial pneumonia, liver injury, and allergic cystitis associated with Kampo formulas have been reported to be caused by formulas containing Scutellariae Radix (Scutellaria root, ogon). The known adverse effects linked to overdose of Kampo formulas include pseudoaldosteronism [caused by Glycyrrhizae Radix (licorice, kanzo)], sympathomimetic symptoms [caused by Ephedrae Herba (ephedra, mao)], aconite poisoning [caused by Aconiti Tuber (processed aconite root, bushi and uzu)], and diarrhea [caused by Rhei Rhizoma (rhubarb, daio)]. In recent years, mesenteric phlebosclerosis caused by the long-term administration of Gardeniae Fructus (gardenia fruit, sanshishi) has also been reported. It is necessary to consider these potential adverse effects when prescribing Kampo medicines in clinical practice.

Discrimination of prediction models between cold-heat and deficiency-excess patterns.

OBJECTIVE: The purpose of this study was to extract important patient questionnaire items by creating random forest models for predicting pattern diagnosis considering an interaction between deficiency-excess and cold-heat patterns. DESIGN: A multi-centre prospective observational study. SETTING: Participants visiting six Kampo speciality clinics in Japan from 2012 to 2015. MAIN OUTCOME MEASURE: Deficiency-excess pattern diagnosis made by board-certified Kampo experts. METHODS: We used 153 items as independent variables including, age, sex, body mass index, systolic and diastolic blood pressures, and 148 subjective symptoms recorded through a questionnaire. We sampled training data with an equal number of the different patterns from a 2 × 2 factorial combination of deficiency-excess and cold-heat patterns. We constructed the prediction models of deficiency-excess and cold-heat patterns using the random forest algorithm, extracted the top 10 essential items, and calculated the discriminant ratio using this prediction model. RESULTS: BMI and blood pressure, and subjective symptoms of cold or heat sensations were the most important items in the prediction models of deficiency-excess pattern and of cold-heat patterns, respectively. The discriminant ratio was not inferior compared with the result ignoring the interaction between the diagnoses. CONCLUSIONS: We revised deficiency-excess and cold-heat pattern prediction models, based on balanced training sample data obtained from six Kampo speciality clinics in Japan. The revised important items for diagnosing a deficiency-excess pattern and cold-heat pattern were compatible with the definition in the 11th version of international classification of diseases.

Cistanche tubulosa (Schenk) Wight Extract Enhances Hindlimb Performance and Attenuates Myosin Heavy Chain IId/IIx Expression in Cast-Immobilized Mice.

Skeletal muscle atrophy is encountered in many clinical conditions, but a pharmacological treatment has not yet been established. Cistanche tubulosa (Schenk) Wight is an herbal medicine used in traditional Japanese and Chinese medicine. In the current study, we investigated the effect of C. tubulosa extract (CTE) on atrophied muscle in vivo. We also investigated hindlimb cast immobilization in mice and devised a novel type of hindlimb-immobilizing cast, consisting of sponge-like tape and a thin plastic tube. Using this method, 3 out of 4 groups of mice (n = 11 for each group) were cast-immobilized in the hindlimbs and administered CTE or vehicle for 13 days. A sham procedure was performed in the mice of the fourth group to which the vehicle was administered. Next, the triceps surae muscles (TS) were excised. To analyze the effect of the novel cast system and CTE administration on muscle atrophy, we evaluated TS wet weight and myofiber cross-sectional area (CSA). We also determined MyHC IId/IIx expression levels by western blotting, since their increase is a hallmark of disuse muscle atrophy, suggesting slow-to-fast myofiber type shift. Moreover, we performed two tests of hindlimb performance. The novel cast immobilization method significantly reduced TS wet weight and myofiber CSA. This was accompanied by deterioration of hindlimb function and an increase in MyHC IId/IIx expression. CTE administration did not alter TS wet weight or myofiber CSA; however, it showed a trend of amelioration of the loss of hindlimb function and of suppression of the increased MyHC IId/IIx expression in cast-immobilized mice. Our novel hindlimb cast immobilization method effectively induced muscle atrophy. CTE did not affect muscle mass, but suppressed the shift from slow to fast myofiber type in cast-immobilized mice, ameliorating hindlimb function deterioration.

Prediction of deficiency-excess pattern in Japanese Kampo medicine: Multi-centre data collection.

OBJECTIVE: The purpose of the present study was to compare important patient questionnaire items by creating a random forest model for predicting deficiency-excess pattern diagnosis in six Kampo specialty clinics. DESIGN: A multi-centre prospective observational study. SETTING: Participants who visited six Kampo specialty clinics in Japan from 2012 to 2015. MAIN OUTCOME MEASURE: Deficiency-excess pattern diagnosis made by board-certified Kampo experts. METHODS: To predict the deficiency-excess pattern diagnosis by Kampo experts, we used 153 items as independent variables, namely, age, sex, body mass index, systolic and diastolic blood pressures, and 148 subjective symptoms recorded through a questionnaire. We extracted the 30 most important items in each clinic's random forest model and selected items that were common among the clinics. We integrated participating clinics' data to construct a prediction model in the same manner. We calculated the discriminant ratio using this prediction model for the total six clinics' data and each clinic's independent data. RESULTS: Fifteen items were commonly listed in top 30 items in each random forest model. The discriminant ratio of the total six clinics' data was 82.3%; moreover, with the exception of one clinic, the independent discriminant ratio of each clinic was approximately 80% each. CONCLUSIONS: We identified common important items in diagnosing a deficiency-excess pattern among six Japanese Kampo clinics. We constructed the integrated prediction model of deficiency-excess pattern.

Kihito, a Traditional Japanese Kampo Medicine, Improves Cognitive Function in Alzheimer's Disease Patients.

BACKGROUND AND AIMS: We previously reported that the administration of traditional Japanese medicines, kihito (Gui-Pi-Tang in Chinese) and kamikihito (Jia-Wei-Gui-Pi-Tang in Chinese), to Alzheimer's disease (AD) model mice improved memory impairment. There are a few reports that show kihito and kamikihito have a beneficial effect on the cognitive function of AD patients in clinical studies. However, these studies are not comparative and are retrospective studies; thus, more evidence is needed. Therefore, we conducted an open-label, crossover designed clinical trial to investigate the effect of kihito on cognitive function of AD patients. METHODS: The inclusion criteria for eligible patients were as follows: (1) imaging diagnosis (magnetic resonance imaging and single-photon emission computed tomography) of AD, (2) a treatment regimen including acetylcholinesterase inhibitors (ChEIs), and (3) a Mini-Mental State Examination (MMSE) score ≥15. The exclusion criteria were as follows: (1) change in ChEI dosage, (2) memantine usage, and (3) MMSE score < 15. To prevent bias in age and baseline cognitive function, patients were divided into two groups: the first group received 2.5 g of kihito extract 3 times/day during the first half of the study (weeks 0-16) and the second group received the same dose of kihito during the second half of the study (weeks 17-32). ChEI dosage did not change during the study period. Patients underwent a cognitive function test during weeks 0, 16, and 32. Cognitive function was evaluated by Japanese versions of the Mini-Mental State Examination (MMSE-J) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS-J) test. RESULTS: Ten patients completed the clinical trial (4 males, 6 females, average age 71.7 years). MMSE-J scores significantly increased during the kihito intake period. RBANS-J test scores had a slight improvement during the kihito intake period compared with the ChEI alone treatment period, but no significant changes were observed. CONCLUSION: Kihito improves cognitive function in AD patients.

Adverse Events Associated with Ethical Kampo Formulations: Analysis of the Domestic Adverse-Event Data Reports of the Ministry of Health, Labor, and Welfare in Japan.

OBJECTIVES: Traditional Japanese Kampo medicines have been integrated into the Japanese national health-care system. In Japan, the Ministry of Health, Labor, and Welfare's website discloses adverse drug-event data that have been obtained from medical personnel reports investigated by the Pharmaceutical and Medical Devices Agency. Using these data, we investigated adverse events associated with ethical Kampo formulations. METHODS: Reports of adverse events associated with ethical Kampo formulations from the domestic adverse-event data were obtained from July 30, 2003, to March 31, 2018. Adverse events were then categorized, and the relationships between categories of adverse events and crude drugs were analyzed. RESULTS: There were 4,232 reported adverse events associated with ethical Kampo formulations. The numbers of events by category were as follows: events related to liver injury, 1,193; lung injury, 1,177; pseudoaldosteronism, 889; mesenteric phlebosclerosis, 223; drug eruption, 185; and others, 565. Among events related to both liver injury and lung injury, approximately 70% were suspected to be induced by Kampo formulations containing Scutellariae Radix. The pseudoaldosteronism-related events, which are induced by Glycyrrhizae Radix, included several events related to muscle injury, heart failure, and arrhythmia. Events related to mesenteric phlebosclerosis, believed to be induced by long-term use of Kampo formulas containing Gardeniae Fructus, increased remarkably during the study period. Among the events related to drug eruption, approximately 35% were suspected to be induced by Kampo formulations containing Ephedrae Herba. CONCLUSION: Kampo medicines may cause various adverse events. The present results provide valuable information regarding adverse events associated with Kampo medicines from the viewpoint of patient safety.

Recurrent Drug-induced Liver Injury Caused by the Incidental Readministration of a Kampo Formula Containing Scutellariae Radix.

A 67-year-old woman experiencing coughing visited a clinic and was prescribed drugs, including shosaikoto extract, for 4 days. She subsequently suffered from liver injury, but her condition improved after the discontinuation of all medications. Approximately 1 year later, she experienced fatigue, consulted another clinic, and received saikokeishikankyoto extract for 21 days. She subsequently suffered liver injury again. Both shosaikoto and saikokeishikankyoto contain Scutellariae Radix. This case is thought to be one of recurrent drug-induced liver injury caused by the incidental readministration of a Kampo formula containing Scutellariae Radix. An awareness of adverse drug events caused by Kampo formulas, especially those containing Scutellariae Radix, is essential.

Patient safety incident reports related to traditional Japanese Kampo medicines: medication errors and adverse drug events in a university hospital for a ten-year period.

BACKGROUND: Kampo medicine is traditional Japanese medicine, which originated in ancient traditional Chinese medicine, but was introduced and developed uniquely in Japan. Today, Kampo medicines are integrated into the Japanese national health care system. Incident reporting systems are currently being widely used to collect information about patient safety incidents that occur in hospitals. However, no investigations have been conducted regarding patient safety incident reports related to Kampo medicines. The aim of this study was to survey and analyse incident reports related to Kampo medicines in a Japanese university hospital to improve future patient safety. METHODS: We selected incident reports related to Kampo medicines filed in Toyama University Hospital from May 2007 to April 2017, and investigated them in terms of medication errors and adverse drug events. RESULTS: Out of 21,324 total incident reports filed in the 10-year survey period, we discovered 108 Kampo medicine-related incident reports. However, five cases were redundantly reported; thus, the number of actual incidents was 103. Of those, 99 incidents were classified as medication errors (77 administration errors, 15 dispensing errors, and 7 prescribing errors), and four were adverse drug events, namely Kampo medicine-induced interstitial pneumonia. The Kampo medicine (crude drug) that was thought to induce interstitial pneumonia in all four cases was Scutellariae Radix, which is consistent with past reports. According to the incident severity classification system recommended by the National University Hospital Council of Japan, of the 99 medication errors, 10 incidents were classified as level 0 (an error occurred, but the patient was not affected) and 89 incidents were level 1 (an error occurred that affected the patient, but did not cause harm). Of the four adverse drug events, two incidents were classified as level 2 (patient was transiently harmed, but required no treatment), and two incidents were level 3b (patient was transiently harmed and required substantial treatment). CONCLUSIONS: There are many patient safety issues related to Kampo medicines. Patient safety awareness should be raised to prevent medication errors, especially administration errors, and adverse drug events in Kampo medicine.

The renoprotective effect of shichimotsukokato on hypertension-induced renal dysfunction in spontaneously hypertensive rats.

Antihypertensive treatment is highly important to prevent the progression of chronic kidney disease. Shichimotsukokato (SKT), a traditional Japanese medicine (i.e., Kampo formula), lowered systolic blood pressure (SBP) in experimental animal models of hypertension. However, its mechanism of action has not been fully elucidated. We investigated the potential renoprotective mechanism of SKT in spontaneously hypertensive rats (SHRs). Ten-week-old SHRs were randomly divided into four groups (six rats per group). In the SHR control group, the SBP increased remarkably during the 8-week experimental period. In the SHRs, SKT extract administered orally at a daily dose of 0.45 or 0.15 g/kg significantly suppressed the increase in SBP to the same extent as telmisartan administered orally at a daily dose of 0.01 g/kg. At the end of the experiment, blood, urine, and kidney cortex tissue samples were examined. The SKT treatment significantly decreased urinary albumin excretion to nearly the same level as the telmisartan treatment. A notable loss of chloride channel 5 (ClC-5), a chloride channel in the proximal renal tubules, occurred in the SHR control group. Thus, we concluded that SKT administration significantly ameliorated this decrease. The mechanism of SKT in reducing urinary albumin excretion is mediated, at least partly, by prevention of the loss of ClC-5 in the renal cortex of SHRs.

Yokukansan Improves Mechanical Allodynia through the Regulation of Interleukin-6 Expression in the Spinal Cord in Mice with Neuropathic Pain.

Neuropathic pain is caused by nerve injury. Yokukansan (Yi-Gan San), a traditional Japanese (Kampo) medicine, has been widely used for neuropathic pain control. However, the analgesic mechanisms remain unknown. In this study, we investigated the analgesic mechanisms of yokukansan in a mouse model of neuropathic pain. Partial sciatic nerve ligation (PSL) induced mechanical allodynia in mice. Repetitive oral administration of the extracts of yokukansan and the constituent herbal medicine Atractylodis Lanceae Rhizoma, but not Glycyrrhizae Radix, relieved mechanical allodynia in the PSL mice and inhibited the PSL-induced expression of interleukin- (IL-) 6 mRNA in the spinal cord. Yokukansan did not attenuate intrathecal IL-6-induced mechanical allodynia. IL-6 immunoreactivity was detected in microglia and astrocytes in the spinal dorsal horn. These results suggest that yokukansan relieves mechanical allodynia in PSL mice by regulating the expression of IL-6 in astrocytes and/or microglia in the spinal cord. In addition, the components of Atractylodis Lanceae Rhizoma, one of the constituent herbal medicines in yokukansan, may play an important role in the regulation of IL-6 expression and neuropathic pain control.

Effect of keishibukuryogan on genetic and dietary obesity models.

Obesity has been recognized as one of the most important risk factors for a variety of chronic diseases, such as diabetes, hypertension/cardiovascular diseases, steatosis/hepatitis, and cancer. Keishibukuryogan (KBG, Gui Zhi Fu Ling Wan in Chinese) is a traditional Chinese/Japanese (Kampo) medicine that has been known to improve blood circulation and is also known for its anti-inflammatory or scavenging effect. In this study, we evaluated the effect of KBG in two distinct rodent models of obesity driven by either a genetic (SHR/NDmcr-cp rat model) or dietary (high-fat diet-induced mouse obesity model) mechanism. Although there was no significant effect on the body composition in either the SHR rat or the DIO mouse models, KBG treatment significantly decreased the serum level of leptin and liver TG level in the DIO mouse, but not in the SHR rat model. Furthermore, a lower fat deposition in liver and a smaller size of adipocytes in white adipose tissue were observed in the DIO mice treated with KBG. Importantly, we further found downregulation of genes involved in lipid metabolism in the KBG-treated liver, along with decreased liver TG and cholesterol level. Our present data experimentally support in fact that KBG can be an attractive Kampo medicine to improve obese status through a regulation of systemic leptin level and/or lipid metabolism.

Comparing the effects of kamikihito in Japan and kami-guibi-tang in Korea on memory enhancement: working towards the development of a global study.

Traditional medicine is widely used in East Asia, and studies that demonstrate its usefulness have recently become more common. However, formulation-based studies are not globally understood because these studies are country-specific. There are many types of formulations that have been introduced to Japan and Korea from China. Establishing whether a same-origin formulation has equivalent effects in other countries is important for the development of studies that span multiple countries. The present study compared the effects of same-origin traditional medicine used in Japan and Korea in an in vivo experiment. We prepared drugs that had the same origin and the same components. The drugs are called kamikihito (KKT) in Japan and kami-guibi-tang (KGT) in Korea. KKT (500 mg extract/kg/day) and KGT (500 mg extract/kg/day) were administered to ddY mice, and object recognition and location memory tests were performed. KKT and KGT administration yielded equivalent normal memory enhancement effects. 3D-HPLC showed similar, but not identical, patterns of the detected compounds between KKT and KGT. This comparative research approach enables future global clinical studies of traditional medicine to be conducted through the use of the formulations prescribed in each country.

New Treatment for Alzheimer's Disease, Kamikihito, Reverses Amyloid-ß-Induced Progression of Tau Phosphorylation and Axonal Atrophy.

Aims. We previously reported that kamikihito (KKT), a traditional Japanese medicine, improved memory impairment and reversed the degeneration of axons in the 5XFAD mouse model of Alzheimer's disease (AD). However, the mechanism underlying the effects of KKT remained unknown. The aim of the present study was to investigate the mechanism by which KKT reverses the progression of axonal degeneration. Methods. Primary cultured cortical neurons were treated with amyloid beta (A ß ) fragment comprising amino acid residues (25-35) (10 µ M) in an in vitro AD model. KKT (10 µ g/mL) was administered to the cells before or after A ß treatment. The effects of KKT on A ß -induced tau phosphorylation, axonal atrophy, and protein phosphatase 2A (PP2A) activity were investigated. We also performed an in vivo assay in which KKT (500 mg/kg/day) was administered to 5XFAD mice once a day for 15 days. Cerebral cortex homogenates were used to measure PP2A activity. Results. KKT improved A ß -induced tau phosphorylation and axonal atrophy after they had already progressed. In addition, KKT increased PP2A activity in vitro and in vivo. Conclusions. KKT reversed the progression of A ß -induced axonal degeneration. KKT reversed axonal degeneration at least in part through its role as an exogenous PP2A stimulator.

A dietary restriction influences the progression but not the initiation of MSG-Induced nonalcoholic steatohepatitis.

The metabolic syndrome is a major worldwide health care issue and a dominant risk factor for cardiovascular disease. The liver manifestations of this syndrome include nonalcoholic fatty liver disease (NAFLD) and its progressive variant nonalcoholic steatohepatitis (NASH). Although significant research has been performed, the basic pathogenesis of NAFLD/NASH remains controversial and effective treatments are still unavailable. We have previously reported on a murine model of NASH induced by the neonatal injection of monosodium glutamate (MSG), which includes the clinical manifestations of central obesity, diabetes, hyperlipidemia, and ultimately liver inflammation, fibrosis, and cancer. Although MSG is considered a safe food additive, its administration to pregnant rats increases the voracity and growth hormone levels in the offspring. To further understand the biology of this model, we have investigated the influence of the calorie intake on these clinical manifestations by feeding animals a restrictive diet. MSG-treated animals fed a restrictive diet continue to manifest obesity and early stage NASH but have improvements in serum lipid profiles. At 12 months of age, mice had manifestations of obesity, whether animals were fed a restricted or control diet, but animals fed a restrictive diet had a reduction in the progression of NASH. In conclusion, MSG appears to be a critical factor in the initiation of obesity, whereas calorie intake may modulate the progression of disease.

The long-term effects of a kampo medicine, juzentaihoto, on maintenance of antibody titer in elderly people after influenza vaccination.

We have performed a broad-ranging analysis of the adjuvant effect of a Kampo medicine, juzentaihoto (JTT), on influenza vaccination in a multicenter randomized controlled trial. In this study, the enhancing effect of JTT on antibody titer after influenza vaccination was studied for 28 weeks in elderly people who were in the high-risk group for influenza infection. In total, 91 subjects over 65 years old were recruited from four long-term-care facilities located in Chiba, Gunma, and Toyama prefectures in Japan. Participants were randomly assigned to the JTT and the control groups. Blood samples were taken at 4 weeks before vaccination, at the time of vaccination, and then at 4, 8, 12, and 24 weeks after vaccination. The hemagglutination inhibition (HI) titers against A/California/7/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Brisbane/60/2008 were then manually measured. A significant increase in HI titer against H3N2 was observed at week 8 after vaccination in the JTT group compared with the control group (P = 0.0229), and the HI titer of the JTT group significantly increased from 4 to 24 weeks (P = 0.0468), compared with the control group. In conclusion, our results indicated that JTT increased and prolonged antibody production against A/Victoria/210/2009 (H3N2), in particular, after influenza vaccination.

Effectiveness of keishibukuryogan on chronic-stage lichenification associated with atopic dermatitis.

Atopic dermatitis (AD) is a common inflammatory skin disease with recurring episodes of itching and a chronic relapsing course. Keishibukuryogan (KBG) is a traditional herbal medicine, composed of five kinds of medical plants and has been administered to patients with blood stagnation in Japan. This study investigated the effect of KBG on the disease activity in AD (n = 45) patients. AD patients were administered KBG for 4 to 6 weeks in addition to their prescribed medications. The results showed that the SCORAD index and VAS score were significantly decreased after the administration of KBG (P < 0.01). KBG also decreased the serum LDH level significantly (P < 0.01). The global assessment of the clinical response in SCORAD index showed that 88.5% of the patients with moderate improvement to excellent response (n = 26) had a high lichenification score (lichenification score ≥2 in SCORAD). On the other hand, only 42.1% of the patients with no improvement to mild improvement (n = 19) had a high lichenification score. Furthermore, long-term administration of KBG for 9-67 weeks showed a marked improvement in patients with a high lichenification score. Therefore, KBG was found to be effective against AD, particularly in cases presenting with lichenified lesions.

Effect of keishibukuryogan on endothelial function in patients with at least one component of the diagnostic criteria for metabolic syndrome: a controlled clinical trial with crossover design.

We evaluated the effect of keishibukuryogan (KBG; Guizhi-Fuling-Wan), a traditional Japanese (Kampo) formula, on endothelial function assessed by reactive hyperemia peripheral arterial tonometry (Endo-PAT2000) in patients with metabolic syndrome-related factors by controlled clinical trial with crossover design. Ninety-two patients were assigned to group A (first KBG-treatment period, then control period; each lasting 4 weeks, with about one-year interval) or group B (first control, then KBG-treatment). In forty-nine (27, group A; 22, group B) patients completing all tests, the mean value of the natural logarithmic-scaled reactive hyperemia index (L_RHI) increased and those of serum nonesterified fatty acid (NEFA), malondialdehyde, and soluble vascular cell adhesion molecule 1 decreased significantly during the KBG-treatment period, but not during the control period, and 4-week changes of L_RHI, NEFA, and malondialdehyde between the 2 periods showed significance. These results suggest that KBG has beneficial effect on endothelial function in patients with metabolic syndrome-related factors.

Study of the effects of monacolin k and other constituents of red yeast rice on obesity, insulin-resistance, hyperlipidemia, and nonalcoholic steatohepatitis using a mouse model of metabolic syndrome.

Purpose. Nonalcoholic fatty liver disease (NAFLD) is a progressive and intractable disease associated with metabolic syndrome. Red yeast rice (RYR) contains monacolin K, a potent inhibitor of HMG-CoA reductase, and its consumption decreases cholesterol and triglyceride levels. We examined the efficacy of RYR constituents using a novel metabolic syndrome-NAFLD mouse model (MSG mice). Methods. Two types of RYR grown under different culture conditions were used. 1P-DU contained only 0.002 g/100 g of monacolin K, whereas 3P-D1 contained 0.131 g/100 g. MSG mice were divided into three groups: control (C) group fed standard food, RYR-C group fed standard food with 1% 1P-DU, and RYR-M group fed standard food with 1% 3P-D1. Mice were examined from 12 to 24 weeks of age. Results. Serum insulin, leptin, and liver damage as well as macrophage aggregation in visceral fat in RYR-C and RYR-M groups were lower than those in C group. The serum adiponectin levels in RYR-C group were significantly higher than those in RYR-M and C groups. Conclusions. RYR was effective against obesity-related inflammation, insulin resistance, and NAFLD in MSG mice irrespective of monacolin K levels. GABA and various peptides produced during fermentation were determined as the active constituents of RYR.

Traditional Japanese formula kigikenchuto accelerates healing of pressure-loading skin ulcer in rats.

We evaluated the effect of kigikenchuto (KKT), a traditional Japanese formula, in a modified rat pressure-loading skin ulcer model. Rats were divided into three groups, KKT extract orally administered (250 or 500 mg/kg/day for 35 days) and control. KKT shortened the duration until healing. Immunohistochemically, KKT increased CD-31-positive vessels in early phase and increased α-smooth muscle actin-(α-SMA-) positive fibroblastic cells in early phase and decreased them in late phase of wound healing. By Western blotting, KKT showed the potential to decrease inflammatory cytokines (MCP-1, IL-1ß, and TNF-α) in early phase, decrease vascular endothelial growth factor in early phase and increase it in late phase, and modulate the expression of extracellular protein matrix (α-SMA, TGF-ß1, bFGF, collagen III, and collagen I). These results suggested the possibility that KKT accelerates pressure ulcer healing through decreases of inflammatory cytokines, increase of angiogenesis, and induction of extracellular matrix remodeling.