Ameliorative effect of bofutsushosan (Fangfengtongshengsan) extract on the progression of aging-induced obesity.

This study aimed to compare fat accumulation in young and aged mice raised on a high-fat diet and to characterize the obesity-reducing effects of a Kampo medicine, bofutsushosan (BTS; fangfengtongshengsan in Chinese). Aged mice fed a high-fat diet containing 2% BTS extract for 28 days exhibited a significant reduction in weight gain and accumulation of visceral and subcutaneous fat, which were greater degree of reduction than those of the young mice. When the treatment period was extended to two months, the serum aspartate aminotransferase and alanine aminotransferase levels and the accumulation of fat droplets in the hepatocytes decreased. The mRNA expression of mitochondrial uncoupling protein 1 (UCP1) in the brown adipose tissue was significantly reduced in the aged mice compared to the young mice but increased by 2% in the BTS-treated aged mice. Additionally, the effect of BTS extract on oleic acid-albumin-induced triglyceride accumulation in hepatoblastoma-derived HepG2 cells was significantly inhibited in a concentration-dependent manner. Evaluation of the single crude drug extracts revealed that Forsythia Fruit, Schizonepeta Spike, and Rhubarb were the active components in BTS extract. These results suggest that BTS extract is effective against visceral, subcutaneous, and ectopic fats in the liver, which tend to accumulate with aging. Thus, BTS extract is useful in preventing and ameliorating the development of obesity and metabolic syndrome.

Bangpungtongsung-san for patients with major depressive disorder: study protocol for a randomized controlled phase II clinical trial.

BACKGROUND: Bangpungtongsung-san (BTS) is a representative herbal medicine that has been widely used for patients with obesity in east Asian countries. Various preclinical studies have demonstrated the anti-depressive effect of BTS granules in various animal models of depression. This phase II trial aimed to explore the efficacy and safety of BTS in human patients with depression. METHODS: A total of 126 patients diagnosed with major depressive disorder and who are not underweight (body mass index ≥ 18.5 kg/m2) will be enrolled in this study. Eligible participants will be randomly allocated into three groups: the high-dose BTS, low-dose BTS, and placebo groups in a 1:1:1 ratio. BTS or placebo granules will be orally administered twice a day for 8 weeks. The BTS and placebo granules will be made to have identical color, scent, and shape, and participants and investigators will be blinded to the allocation. The primary efficacy endpoint is the change from baseline of the 17-item Hamilton Depression Rating Scale total score at 8 weeks. The superiority of the high- and low-dose BTS granules to the placebo granules will be tested. DISCUSSION: The results of this clinical trial will provide evidence on the efficacy and safety of BTS for patients with major depressive disorder. This study will be conducted in accordance with ethical and regulatory guidelines, and the results will be submitted and published in international peer-reviewed journals. TRIAL REGISTRATION: CRIS registration Number: KCT0007571; registered on 2022/07/26 ( https://cris.nih.go.kr/cris/search/detailSearch.do/23192 ).

Inhibitory effect of Bofutsushosan (Fangfengtongshengsan) extract on the absorption of fructose in rats and mice.

Bofutsushosan (BTS; fangfengtongshengsan in Chinese) is a formula in traditional Japanese Kampo and Chinese medicine comprising 18 crude drugs and used to treat obesity and metabolic syndrome. In our previous study, BTS boiling water extract inhibited the uptake of fructose absorbed via glucose transporter 5 into cultured cells. In this study, the inhibitory effect of BTS extract on the absorption of fructose from the intestine was investigated in vivo. The extract of BTS was orally administered to rats at doses equivalent to 25-fold of the daily dose for humans. One minute after sample administration, fructose was orally administered and blood samples were collected from the jugular vein 0.5, 1, 1.5, 2, and 4 h after the administration of fructose. The absorption of fructose from the intestine was significantly reduced by treatment with BTS extract, and this in vivo study reproduced previous in vitro results. Subsequently, the blood samples were collected from the portal vein 30 min after the oral administration of fructose in mice. BTS extract significantly reduced fructose absorption in mice, and compared the effect of modified BTS samples by removing one to several crude drugs from BTS. We found that the dried rhizome of Rheum palmatum (RR) significantly contributed to the inhibitory effect of BTS on fructose absorption. We found sennoside A to be the active ingredient of RR for the inhibition of fructose absorption, and that its effect almost saturated at a dose of 3 mg/kg. These results support the action mechanisms of BTS when used for the treatment of obesity in clinics and drug stores.

Drug-induced Cystitis Following Administration of Two Kampo Medicines Containing Scutellariae Radix : A Case Report / 日本東洋医学雑誌

We report a case of drug-induced cystitis caused by the administration of two different Kampo medicines containing Scutellariae radix. The patient was prescribed bofutsushosan for weight gain at the age of 55. She visited her primary care physician approximately one month later for micturition pain and other symptoms, and was prescribed antibacterial agents based on a diagnosis of bacterial cystitis. The patient’s symptoms persisted even after she was treated for one month ; therefore, she was referred to the urology department of a general hospital. All medicines including Kampo medicines were discontinued ; her subjective symptoms and urinary findings improved within 2 weeks. Her symptoms of cystitis flared up after a few days of re-administration of bofutsushosan. Four months later, she developed cystitis-like symptoms again after using nyoshinsan for menopausal symptoms. Based on the aforementioned clinical observations, she was diagnosed with drug-induced cystitis due to bofutsushosan and nyoshinsan administration. The components of these two Kampo medicines and past history of Kampo medicine use were reviewed and Scutellariae radix was considered to be the causative agent. Drug-induced cystitis caused by herbal medicines generally takes a long time to develop, and symptoms resolve within a relatively short period following discontinuation of the causative agent. Several reports in the literature implicate Scutellariae radix as the etiological agent in such cases. We believe that it is necessary to pay close attention to the risk of cystitis in patients receiving long-term Kampo therapy.

Analysis of Drug-Induced Liver Injury from Bofutsushosan Administration Using Japanese Adverse Drug Event Report (JADER) Database.

Bofutsushosan is a traditional Japanese Kampo medicine. In recent years, it has been reported to be effective in the treatment of lifestyle-related diseases, and its use is increasing. However, side effects from bofutsushosan administration are common, with drug-induced liver injury being the most frequently reported complication. In this study, we analyzed the Japanese Adverse Drug Event Report (JADER) database regarding the occurrence of liver injury after bofutsushosan administration. The results showed that bofutsushosan presented a significant reporting odds ratio (ROR) signal [crude ROR 14, 95% confidence interval (CI) 12-17; p < 0.001], indicating liver injury. Furthermore, the incidents of adverse events following bofutsushosan administration, as recorded in the JADER database, were higher in women aged between 30 and 59 years. The results of logistic regression analysis in patients taking this agent showed that females in the aforementioned age range had higher odds of developing drug-induced liver injury (adjusted ROR 5.5, 95% CI 2.8-11; p < 0.001). Therefore, although bofutsushosan is a useful drug for lifestyle-related diseases, it may be necessary to refrain from its overuse, and caution should be taken during its occasional use to avoid severe adverse events.

Drug-induced cystitis caused by herbal medicine (Bofutsushosan).

Bofutsushosan (BTS), one of many traditional Japanese medicines (Kampo medicines) is attracting attention for obesity and metabolic syndrome. We report allergic cystitis caused by 8-year BTS usage in a 70-year-old female. The patient presented with micturition pain with sterile pyuria over a 3-month period. Cystoscopy showed diffuse urothelial erythema and edema. Urine cytology specimens showed increased eosinophilic cells. By discontinuing BTS, the cystitis symptoms disappeared after 4 days, and urinalysis normalized. Resuming BTS without physician approval resulted in cystitis symptoms and after cessation the symptoms rapidly subsided. This is the first English case report linking allergic cystitis to herbal medicine.

A Case of Palmoplantar Pustulosis Successfully Treated with Kampo Medicine Switched Between Fundamental Treatment and Local and Symptomatic Treatment / 日本東洋医学雑誌

We experienced a case of palmoplantar pustulosis in which the patient's dermatological symptoms im­proved after treatment with a combination of bofutsushosan and keishibukuryogan. The patient was a 42-year-old woman. She had been prescribed biotin and a steroid ointment, but her condition did not improve. At her first visit to our Kampo clinic, we observed impetigo, cracks, and scaling on both palms and plantar surfaces. We determined that the patient was of the poisoned organ (zodoku) and stagnant blood (oketsu) constitutions,as outlined in the Ikkando school of medical thought. We prescribed bofutsushosan and keishibukuryogan as fundamental treatment and then in a few days, the patient's dermatological symptoms resolved. The patient later developed hyperthyroidism, which caused her symptoms to worsen again, we therefore switched to shofusan and eppikajutsuto as local and symptomatic treatment, and then she once again improved. Soon after, we returned to keishibukuryogan and bofutsusho for her to maintain remission. Since poisoned organ and stagnant blood constitutions contribute greatly to the Kampo pathology of palmoplantar pustulosis, we believe bofutsushosan and keishibukuryogan are effective formulations for the treatment of this condition. As far as we searched, there were no papers that selected bofutsushosan or blood stasis agents as the main cure from the viewpoint of the poisoned organ constitution and the stagnant blood constitution. Therefore, this case was considered to be a valuable case.

Increase of Akkermansia muciniphila by a Diet Containing Japanese Traditional Medicine Bofutsushosan in a Mouse Model of Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is considered a worldwide healthcare problem that mirrors the increased prevalence of obesity. Gut microbiota plays a crucial role in the progression and treatment of NAFLD. Bofutsushosan (BTS), a pharmaceutical-grade Japanese traditional medicine, has long been prescribed in Japan for obesity and obesity-related syndrome. Although BTS has been reported to exert an anti-obesity effect in obese patients as well as various obesity-model animals, its effect on gut microbiota is unknown. Here, the effects of BTS on obesity, liver damage, and the gut microbiome in genetically obese mice, ob/ob, were studied. Seven-week-old ob/ob mice were fed a standard diet with (BTS group) or without (CONT group) 5% BTS for 4 weeks. By comparison to the CONT group, the BTS group showed reduced body weight gain and hyperlipidemia as well as improved liver function. Moreover, gut microbiota in the CONT and BTS group formed a significantly different cluster. Specifically, the genera Akkermansia, Bacteroides and an unknown genus of the family Enterobacteriaceae expanded dramatically in the BTS group. Noteworthy, the population of Akkermansia muciniphila, which is reported to elicit an anti-obesity effect and improve various metabolic abnormalities, was markedly increased (93-fold) compared with the CONT group. These results imply that BTS may be a promising agent for treating NAFLD.

Identification of baicalin from Bofutsushosan and Daisaikoto as a potent inducer of glucose uptake and modulator of insulin signaling-associated pathways.

Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by hyperglycemia that can lead to long-term complications including heart diseases, stroke, retinopathy, and renal failure. Treatment strategies include stimulating glucose uptake and controlling blood glucose level. Bofutsushosan (BOF) and Daisaikoto (DAI) are two herb-based kampo medicines that have been demonstrated to improve metabolism-associated disorders including obesity, hyperlipidemia, and nonalcoholic fatty liver. Given their bioactivities against metabolic syndromes, we explored in this study the effect of BOF and DAI extracts on glucose absorption and used them as source to identify phytochemical stimulator of glucose absorption. Glucose uptake and mechanistic studies were evaluated in differentiated C2C12 skeletal muscle cells, and HPLC analysis was used to determine the molecular bioactive constituents. Our results indicated that the ethanolic extracts of BOF and DAI (BOFEE and DAIEE, respectively) enhanced the glucose uptake ratio in the differentiated C2C12 cells, and further analysis identified the flavone baicalin as a major constituent capable of efficiently stimulating glucose absorption. Mechanistic studies revealed that the effect from baicalin involved the activation of IRS-1 and GLUT-4, and implicated the AMPK, PI3K/Akt, and MAPK/ERK signaling cascades. Due to its potency, we suggest that baicalin merit further evaluation as a potential candidate anti-hyperglycemic agent for the treatment and management of T2DM.

[Pharmacological Mechanisms of Boiogito and Bofutsushosan in Diabetes and Obesity Models].

　The antihyperglycemic activities of extracts of boiogito (BOT) and bofutsushosan (BTS) were investigated in streptozotocin-induced (STZ)-diabetic mice. BOT extract containing Stephania tetrandra S. MOORE root (stephania), has more potent antihyperglycemic activity than BOT extract containing sinomenium stem (sinomenium). Extracts of stephania and astragalus root (astragalus) exert combined effects in the antihyperglycemic and insulinotropic activities of BOT extract. Fangchinoline, but not tetrandrine, in stephania plays a role in its activity. Formononetin in astragalus potentiates the actions of fangchinoline. Tetrandrine has antiangiogenic effects on choroidal vessels in STZ-diabetic rats, which are associated with the inhibition of tumor necrosis factor (TNF)-α-induced nuclear factor (NF)-κB activation. BTS extract has shown antihyperglycemic and insulinotropic activities whereas gardenia fruit (gardenia) extract in BTS has antihyperglycemic, but not insulinotropic, activity in the diabetic mice. Gardenia extract decreased the HOMA-IR level and increased insulin-stimulated 2-deoxyglucose (2-DG) uptake to skeletal muscle. The effects of gardenia extract on 2-DG uptake were associated with the upregulation of glucose transporter type 4 and Akt phosphorylation. Gardenia extract was also shown to have antihyperglycemic and insulinotropic actions in high-fat diet (HFD)-fed and STZ-diabetic mice. In addition, gardenia extract decreased the production of TNF-α and leptin, and increased the production of adiponectin in the visceral adipose tissues. In the early administration period, BTS extract increased mRNA expression levels of leptin, adiponectin, and UCP1 in brown adipose tissues in HFD-fed obese mice. With a longer duration of administration, BTS extract improved insulin resistance and subsequently reduced serum leptin and triglyceride levels in parallel with visceral adipose tissue volume and size.

Promotive effect of Bofutsushosan (Fangfengtongshengsan) on lipid and cholesterol excretion in feces in mice treated with a high-fat diet.

ETHNOPHARMACOLOGICAL RELEVANCE: Bofutsushosan (fangfengtongshengsan in Chinese, BTS) is a formula in traditional Japanese Kampo medicine and Chinese medicine comprising 18 crude drugs that is used for treating obesity and metabolic syndrome. AIM OF THE STUDY: We evaluated the promotive effects of BTS on lipid and cholesterol elimination in mice. MATERIALS AND METHODS: Mice were reared with a high-fat diet containing boiled water extract of BTS for 30 days, and their biochemical parameters as well as the weight and lipid content of feces were measured. We also measured cholesterol uptake into Caco-2 cells cultured with or without BTS extract. RESULTS: The body weight and amounts of visceral fat and subcutaneous fat on day 28; the weights of epididymal, perirenal, and mesenteric fat; and the serum concentrations of triglyceride, glucose, and hemoglobin A1c on day 30 were significantly lower in the BTS extract-treated groups than in the control in a dose-dependent manner. The amounts of lipid and cholesterol in the feces collected from day 6-23 were significantly greater than in the control. When Caco-2 cells were incubated with BTS extract, the uptake of cholesterol into cells was significantly reduced in a concentration-dependent manner. Among the components of BTS, the methanol extracts of Platycodi Radix and Zingiberis Rhizoma contribute but the extracts of Ephedrae Herba and Rhei Rhizoma counteract the suppressive effect of BTS on cholesterol uptake into Caco-2 cells. CONCLUSIONS: BTS has beneficial effects on obesity and metabolic syndrome, and its mechanisms of action include the promotion of lipid elimination and the inhibition of cholesterol absorption in the intestine.

Inhibitory effect of bofutsushosan (fang feng tong sheng san) on glucose transporter 5 function in vitro.

Bofutsushosan (BTS; fang feng tong sheng san in Chinese) is a formula in traditional Japanese Kampo medicine and Chinese medicine comprising eighteen crude drugs, and is used to treat obesity and metabolic syndrome. Fructose is contained in refreshing beverages as high-fructose corn syrup, and is associated with obesity. Fructose is absorbed via glucose transporter 5 (GLUT5) in the intestine. Therefore, the inhibition of GLUT5 is considered to be a target of obesity drugs. We evaluated the inhibitory effects of BTS extract and its constituents on fructose uptake using Chinese hamster ovary K1 cells, i.e., cells stably expressing GLUT5. Boiled water extract of BTS significantly suppressed GLUT5 function in a concentration-dependent manner without cytotoxicities. Among 18 components of BTS, the boiled water extracts of the rhizome of Zingiber officinale, the root and rhizome of Saposhnikovia divaricata, and the root of Platycodon grandiflorum exhibited significant inhibitory effects on fructose uptake with IC50 values of 314, 119 and 475 µg/ml, respectively. Among the constituents of the rhizome of Z. officinale extract, 6-gingerol significantly inhibited GLUT5 with an IC50 value of 39 µM, while 6-shogaol exhibited a significant but weak inhibition on GLUT5 at 100 µM. One of the mechanisms of action of BTS may be the inhibition of fructose absorption in the intestine, and one of the active components of BTS is the rhizome of Z. officinale and 6-gingerol.

Mechanisms for the anti-obesity actions of bofutsushosan in high-fat diet-fed obese mice.

BACKGROUND: The Kampo medicine bofutsushosan (BTS; Pulvis ledebouriellae compositae; Fang Feng Tong Sheng San) has been used as an anti-obesity treatment in overweight patients. In this study, we assessed the underlying physiological changes induced by BTS in obese mice maintained on a high-fat diet. METHODS: Male ICR mice were fed a 60% kcal fat diet for 5 weeks starting at 4 weeks of age and then fed the same diet with administration of water (control) or aqueous BTS extract (1.0-2.0 g/kg) for 25 days. Body weight, wet weight of isolated white adipose tissue, and obesity-related serum parameters (glucose, lipids, leptin, adiponectin) were measured after treatment. The mRNA expression levels of leptin, adiponectin, and UCP1 in the adipose tissues were determined by quantitative real-time polymerase chain reaction after the first 5 days of treatment. RESULTS: Bofutsushosan (1.5-2.0 g/kg) significantly decreased total body weight and total wet weight of white adipose tissue isolated from subcutaneous (retroperitoneal) and visceral regions (epididymal, mesenteric, and perirenal). At 2.0 g/kg, BTS also decreased total fat mass, visceral fat mass, and ratio of fat mass to body weight as measured by computed tomography, and significantly decreased epididymal adipocyte size after 14 and 25 days' treatment. Twenty-five days' treatment lowered serum glucose, insulin, leptin, and triglycerides, and reduced homeostasis model assessment-insulin resistance. Alternatively, 2.0 g/kg BTS significantly increased mRNA levels of adiponectin, leptin, and UCP1 in interscapular brown adipose tissue but not epididymal white adipose tissue after 5 days' administration. CONCLUSION: In the early administration period, BTS increased mRNA expression levels of leptin, adiponectin, and UCP1 in brown adipose tissues. With longer administration, BTS improved insulin resistance, and subsequently reduced serum levels of leptin and triglyceride in parallel with decreased visceral white adipose tissue volume and adipocyte size.

Bofutsushosan ameliorates obesity in mice through modulating PGC-1α expression in brown adipose tissues and inhibiting inflammation in white adipose tissues.

The inducible co-activator PGC-1α plays a crucial role in adaptive thermogenesis and increases energy expenditure in brown adipose tissue (BAT). Meanwhile, chronic inflammation caused by infiltrated-macrophage in the white adipose tissue (WAT) is a target for the treatment of obesity. Bofutsushosan (BF), a traditional Chinese medicine composed of 17 crude drugs, has been widely used to treat obesity in China, Japan, and other Asia countries. However, the mechanism underlying anti-obesity remains to be elucidated. In the present study, we demonstrated that BF oral administration reduced the body weight of obese mice induced by high-fat diet (HFD) and alleviated the level of biochemical markers (P < 0.05), including blood glucose (Glu), total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL-C) and insulin. Our further results also indicated that oral BF administration increased the expression of PGC-1α and UCP1 in BAT. Moreover, BF also reduced the expression of inflammatory cytokines in WAT, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). These findings suggested that the mechanism of BF against obesity was at least partially through increasing gene expression of PGC-1α and UCP1 for energy consumption in BAT and inhibiting inflammation in WAT.

A case study of bofutsushosan-induced pulmonary injury in a patient: Case report.

Bofutsushosan, a herbal (traditional Kampo) medicine, is administered to obese patients in North-East Asia. Bofutsushosan has been reported to exert various anti-obesity effects by stimulating the adipose tissue. The present study describes the case of a patient who developed a severe pulmonary injury that was potentially associated with bofutsushosan therapy. A 52-year-old woman was admitted to Mito Medical Center, University of Tsukuba, Mito Kyodo General Hospital (Mito, Japan) due to progressive dyspnea. Two months previously, bofutsushosan had been newly prescribed for her obesity. Bilateral ground-glass opacities and progressive respiratory deterioration suggested respiratory failure due to a therapeutic agent-induced lung injury. With discontinuation of bofutsushosan and the administration of a corticosteroid, an improvement in her respiratory condition was achieved, although sequelae remained in certain areas of the lungs. Resumption of other therapeutic agents did not reinduce the lung injury. Therefore, a diagnosis of bofutsushosan-induced lung injury was made. Although bofutsushosan-induced lung injury is particularly rare, clinicians should consider it when bofutsushosan is used.

Bofutsushosan ameliorates obesity in mice through modulating PGC-1α expression in brown adipose tissues and inhibiting inflammation in white adipose tissues / 中国天然药物

The inducible co-activator PGC-1α plays a crucial role in adaptive thermogenesis and increases energy expenditure in brown adipose tissue (BAT). Meanwhile, chronic inflammation caused by infiltrated-macrophage in the white adipose tissue (WAT) is a target for the treatment of obesity. Bofutsushosan (BF), a traditional Chinese medicine composed of 17 crude drugs, has been widely used to treat obesity in China, Japan, and other Asia countries. However, the mechanism underlying anti-obesity remains to be elucidated. In the present study, we demonstrated that BF oral administration reduced the body weight of obese mice induced by high-fat diet (HFD) and alleviated the level of biochemical markers (P < 0.05), including blood glucose (Glu), total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL-C) and insulin. Our further results also indicated that oral BF administration increased the expression of PGC-1α and UCP1 in BAT. Moreover, BF also reduced the expression of inflammatory cytokines in WAT, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). These findings suggested that the mechanism of BF against obesity was at least partially through increasing gene expression of PGC-1α and UCP1 for energy consumption in BAT and inhibiting inflammation in WAT.

<b>Examination of Frequency and Nature of Side Effects Caused by Over-The-Counter Kampo Formulations Based on the Data Published by the Japanese Ministry of Health, Labour and Welfare</b> / 日本東洋医学雑誌

The number and the nature of reported side effects caused by over-the-counter Kampo formulations (OKF), as well as their changes over 10 years (fiscal years 2005 through 2014), were investigated using the data published on the website of the Japanese Ministry of Health, Labour and Welfare. The total number of side effects reports regarding OKF was 367 during the period, including 151 reports of liver dysfunction, 54 reports of drug eruption/hypersensitivity, and 51 reports of lung injury. Annual incidence of reported side effects increased nearly threefold over the period, from 16 in 2005 to 43 in 2014. Bofutsushosan was involved in 110 cases, kakkonto in 45 cases, hachimijiogan in 15 cases, and daisaikoto in 14 cases. The number of side effects due to bofutsushosan and kakkonto showed an increasing trend during the period from 2005 to 2014. Bofutsushosan was associated with 65 cases of liver dysfunction and 23 cases of lung injury. Kakkonto was associated with 21 cases of drug eruption/hypersensitivity. Under the current circumstances, severe side effects requiring medical treatments such as liver dysfunction and lung injury are showing a tendency to increase. To improve safety, we recommend tighter control over the sale of OKF, especially bofutsushosan and kakkonto,which accounted for nearly half of all reported side effects.

Impact of GNB3-C825T, ADRB3-Trp64Arg, UCP2-3'UTR 45 bp del/ins, and PPARγ-Pro12Ala polymorphisms on Bofutsushosan response in obese subjects: a randomized, double-blind, placebo-controlled trial.

Obesity is known to be influenced by a number of genes, including the ß3 subunit of G protein (GNB3), ß3-adrenergic receptor (ADRB3), uncoupling protein 2 (UCP2), and peroxisome proliferator activated receptor gamma (PPARγ). The single nucleotide polymorphisms (SNPs) of the above genes, such as GNB3-C825T, ADRB3-Trp64Arg, UCP2-3'UTR 45 bp del/ins, and PPARγ-Pro12Ala, are associated with obesity and body mass index. The present study evaluates the impact of Bofutsushosan, a traditional Eastern Asian herbal medicine with known anti-obesity properties, on obese subjects according to the presence of the above-mentioned SNPs. Upon randomization, the volunteers were allocated to receive Bofutsushosan (n=55) or placebo (n=56) treatments for 8 weeks. Following the treatment schedule, significant reductions in total cholesterol and significant improvement in the Korean version of obesity-related quality of life scale were seen in the Bofutsushosan-treated group, but not in placebo. Bofutsushosan exerted significant anti-obesity effects on a number of parameters in the carriers of the GNB3-825T allele, but only on waist circumference in the GNB3-C/C homozygote. Significant anti-obesity impact of Bofutsushosan was also seen on a number of obesity-indices in both ADRB3-Arg64 carriers and ADRB3-Trp64 homozygotes, as well as in UCP2-D/D carriers, but not in UCP2-D/I+I/I variants. The effect of Bofutsushosan was more pronounced in PPARγ-Pro/Pro genotype compared to PPARγ-Pro/Ala variants. Thus, the results revealed differential responses of the subjects to the anti-obesity effects of Bofutsushosan treatment according to the polymorphism of the vital obesity-related genes. Our study provides new insight into individualized clinical applications of Bofutsushosan for obesity.

Effects of kampo formulas on the progression of hypercholesterolemia and Fatty liver induced by high-cholesterol diet in rats.

BACKGROUND: Bofutsushosan is a well known Kampo, traditional Japanese medicine, based on ancient Chinese medicine mainly used in the treatment of hypercholesterolemia in Japan. We selected two Kampo formulas, Boiogito and Keishibukuryogan mainly used in the treatment of hypercholesterolemia in China to compare with Bofutsushosan and cholesterol absorption inhibitor ezetimibe. METHODS: Hypercholesterolemia and fatty liver were induced by high cholesterol (containing 2% cholesterol and 0.5% cholic acid) diet in male Wistar rats for 6 and 12 weeks. Kampo formulas Boiogito, Bofutsushosan, Keishibukuryogan and ezetimibe were added to the high-cholesterol diet, respectively. After 6 and 12 weeks, body and liver weights, blood chemistry, cholesterol concentrations, fat-related and inflammatory-related factors were examined. RESULTS: High-cholesterol diet increased body and liver weights, and serum cholesterol concentrations. Boiogito and ezetimibe improved them. Serum ICAM-1 and RBP4 were increased in the high cholesterol diet group. Boiogito and ezetimibe improved them too. In the histological examinations of liver and adipose tissues, we observed a significant improvement after treatment. Immunostaining expression of ICAM-1 in aorta was improved by Boiogito, Bofutsushosan, Keishibukuryogan and ezetimibe. The mRNA expression of RBP4, HFABP, CFABP, MCP1 and CCR2 in liver and adipose tissue were decreased by Boiogito and ezetimibe. CONCLUSION: Boiogito has a protective effect on the progression of hypercholesterolemia and fatty liver induced by high-cholesterol diet in rats and more effective than Bofutsushosan and Keishibukuryogan. The lipid-lowering effect of Boiogito is not stronger than ezetimibe. But the anti-inflammatory (MCP1, CCR2) and anti-arteriosclerotic (ICAM-1) effects of Boiogito are more potent than ezetimibe.

Bofutsushosan, an Oriental Herbal Medicine, Attenuates the Weight Gain of White Adipose Tissue and the Increased Size of Adipocytes Associated with the Increase in Their Expression of Uncoupling Protein 1 in High-Fat Diet-Fed Male KK/Ta mice.

Bofutsushosan (BOF), an oriental herbal medicine, has been used as an anti-obesity drug in overweight patients. In the present study, to evaluate the anti-obesity and anti-diabetic effects of BOF, we investigated the effects of BOF on the white adipose tissue (WAT) weight, the size of adipocytes, adiponectin expression, and oral glucose tolerance test results in high-fat diet-fed male KK/Ta mice. In addition, the mRNA expression levels of uncoupling protein 1 (UCP1) and UCP2 mRNA in WAT and brown adipose tissue (BAT) were measured. 6-week-old KK/Ta mice were divided into four groups and fed a purified powdered basal diet (the BD group), a purified high-fat (HF) powdered diet containing suet powder at 37.5 g/100 g diet (the HF group), a high-fat diet plus 1.0% bofutsushosan (BOF) treatment (the HF + BOF group), or a high-fat diet plus 1.0% daisaikoto (DAI) treatment (the HF + DAI group) for 4 weeks. The weight of WAT and the size of adipocytes were increased in the HF group compared with those in the BD group, and these increases in the HF group were significantly inhibited in the HF + BOF group, but not affected in the HF + DAI group. There were no statistically significant differences in plasma levels and tissue mRNA levels of adiponectin among the four groups. There were no significant differences in UCP1 mRNA expression of BAT among the four groups. The expression of UCP1 mRNA in WAT was found in the HF + BOF group, but little expression was seen in the WAT of the BD, HF, or HF + DAI groups. The elevated plasma glucose levels and responses after the glucose loading in the HF group tended to decrease in the HF + BOF group. These results suggest that BOF decreases the weight and size gains of WAT along with up-regulating UCP1 mRNA in WAT in high-fat diet-fed mice.