Changes in the profiling of bioactive components with the roasting process in Lycium chinense leaves and the anti-obesity effect of its bioaccessible fractions.

BACKGROUND: This study aimed to investigate the profiles of bioactive components in roasted Lycium chinense leaves (LCLs) and its in vitro anti-obesity activity after digestion processes. RESULTS: Chlorogenic acid, kaempferol-3-sophoroside-7-glucoside, kaempferol-3-sophoroside, and kaempferol-3-glucoside were discovered as bioactive components in various ratios of ethanol (EtOH) extract in LCLs by using ultra-performance liquid chromatography-electrospray ionization-mass spectrophotometry (UPLC-ESI-MS). The roasting process followed by a 30% EtOH extraction tended to decrease the content of chlorogenic acid and kaempferol-3-glucoside, and enhanced the content of kaempferol-3-sophoroside-7-glucoside. It effectively inhibited pancreatic lipase activity by 62.50 ± 4.81%, which was approximately 1.71 percentage points higher than that of the dried-nonroasted LCL extract (60.79 ± 3.75%). Its bioaccessible fraction obtained from in vitro digestion significantly and dose dependently reduced intracellular lipid accumulation by adipocyte 3T3-L1 compared with a 30% EtOH extraction. At a concentration of 200 µg mL-1 , it inhibited lipid accumulation up to 29.55% in 3T3-L1 cells, which indicated that human digestive enzymes converted kaempferol-3-sophoroside-7-glucoside to kaempferol metabolites that have anti-obesity effects. CONCLUSION: This study suggests that the profiling of bioactive components by processing methods and a bioaccessible fraction could be crucial to improve the bioactivity of LCLs, and potentially be a natural anti-obesity ingredient after oral intake. © 2019 Society of Chemical Industry.

Deferasirox improves hematologic and hepatic function with effective reduction of serum ferritin and liver iron concentration in transfusional iron overload patients with myelodysplastic syndrome or aplastic anemia.

BACKGROUND: Transfusional iron overload and its consequences are challenges in chronically transfused patients with myelodysplastic syndromes (MDSs) or aplastic anemia (AA). STUDY DESIGN AND METHODS: This was a prospective, multicenter, open-label study to investigate the efficacy of deferasirox (DFX) by serial measurement of serum ferritin (S-ferritin) level, liver iron concentration (LIC) level using relaxation rates magnetic resonance imaging, and other laboratory variables in patients with MDS or AA. RESULTS: A total of 96 patients showing S-ferritin level of at least 1000 ng/mL received daily DFX for up to 1 year. At the end of the study, S-ferritin level was significantly decreased in MDS (p=0.02366) and AA (p=0.0009). LIC level was also significantly reduced by more than 6.7 mg Fe/g dry weight from baseline. Hemoglobin level and platelet counts were significantly increased from baseline (p=0.002 and p=0.025, respectively) for patients showing significant anemia or thrombocytopenia. Elevated alanine aminotransferase was also significantly decreased from baseline. CONCLUSIONS: This study shows that DFX is effective in reducing S-ferritin and LIC level in transfusional iron overload patients with MDS or AA and is well tolerated. In addition, positive effects in hematologic and hepatic function can be expected with DFX. Iron chelation treatment should be considered in transfused patients with MDS and AA when transfusion-related iron overload is documented.

Preventive effect of Ligularia fischerion inhibition of nitric oxide in lipopolysaccharide-stimulated RAW 264.7 macrophages depending on cooking method.

BACKGROUND: Ligularia fischeri (common name Gomchwi) is known for its pharmaceutical properties and used in the treatment of jaundice, scarlet-fever, rheumatoidal arthritis, and hepatic diseases; however, little is known about its anti-inflammatory effect. In this study the influence of blanching and pan-frying on the anti-inflammatory activity of Ligularia fischeri (LF) was evaluated. RESULTS: Fresh LF and cooked LF showed no significant effect on the viability of macrophages after 24 h incubation. Fresh LF was found to be the most potent inhibitor of nitric oxide (NO) production at 100 µg/ml, while pan-fried LF showed little inhibitory effect on lipoloysaccharide (LPS) stimulated murine machrophage RAW264.7 cells. In contrast with its effect on NO production, pan-fried LF showed significant attenuation of the expression of inducible nitiric oxide synthase (iNOS) compared with fresh LF. In the cooking method of LF, PGE2 production was not affected in the LPS-induced RAW 264.7 cells. In LPS-induced RAW 264.7 cells, pretreatment by fresh and cooked LF increased COX2 mRNA expression. The 3-O-caffeoylquinic acid content of blanching and pan-frying LF increased by 4.92 and 9.7 fold with blanching and pan-frying respectively in comparison with uncooked LF. CONCLUSIONS: Regardless of the cooking method, Ligularia fischeri exhibited potent inhibition of NO production through expression of iNOS in LPS-induced RAW264.7 cells.

Anticancer, antiobesity, and anti-inflammatory activity of Artemisia species in vitro.

OBJECTIVE: To investigate the anticancer, anti-inflammatory, and antiobesity activity of methanol extracts of eight distinct species: Artemisia Stolonifera (AST), Artemisia Selengensis (ASE), Artemisia Japonica, Artemisia Montana, Artemisia Capillaris (ACA), Artemisia Sylvatica (ASY), Artemisia Keiskeana (AKE), and Artemisia Scoparia (ASC) in vitro. METHODS: Antiproliferative activity was investigated in human breast cancer estrogen receptor-a positive T47D and negative HS578T cell lines exposed to the extracts at various concentrations (5-200 mg/ mL) for 24, 48, and 72 h. For evaluating the anti-inflammatory activity of the extracts, inhibition of nitrite synthesis was investigated in lipopolysaccharide (LPS)-stimulated cultures of macrophages cells exposed to 10, 50, 100, and 200 mg/mL for 24 h. The antiobesity activity of the extracts was determined as triglyceride content and by a lipolysis assay in differentiated 3T3-L1 cells exposed to the extracts for 72 h at the same concentrations described above. RESULTS: All extracts showed similar antiproliferative activity in a dose- and time-dependent manner in HS578T cells. Although extracts at lower concentrations and shorter times stimulated growth of T47D cells, the antiproliferative effects of the extracts on T47D cells at higher concentrations (> 100 mg/ mL) for 72 h were significantly greater than those of HS578T cells. In case of anti-inflammatory activity, some extracts (AST, ASE, ACA, and AKE) significantly reduced nitric oxide production at higher concentrations in the presence of LPS compared with that in control cells. Antiobesity activity was showed with reducing lipid accumulation significantly (> 50%) at concentrations above 100 mg/mL in most extracts (except AST and ACA). Additionally, AKE and ASC increased lipolysis by 11%-24% compared with that in the control. CONCLUSION: Artemisia spp. demonstrates potential as bioactive food supplements.

A high-fat diet increases angiogenesis, solid tumor growth, and lung metastasis of CT26 colon cancer cells in obesity-resistant BALB/c mice.

We evaluated whether high-fat diet (HFD), in the absence of increased calorie intake, increases colon cancer growth and metastasis. Four-week-old male BALB/c mice were fed on an HFD (60 kcal% fat) or control diet (10 kcal% fat) for 16 wk, after which CT26 colon cancer cells were subcutaneously injected into the right flank. Solid tumor growth and the number and volume of tumor nodules in the lung were increased markedly in the HFD group with only a slight increase in body weight (5.9%). HFD feeding increased tumor tissue levels of Ki67, cyclin A, cyclin D1, CDK2, Bcl-xL, and Bcl-2; reduced p53 levels and TUNEL-positive apoptotic cells; increased the levels of CD45, CD68, CD31, VEGF, P-VEGF receptor-2, iNOS, and COX-2 as well as hemoglobin content; and increased the levels of HIF-1α, P-STAT3-Y705, P-STAT3-S727, P-IκB-α, P-p65, p65, P-c-Jun, P-Akt, P-ERK1/2, P-p38, and P-SAPK/JNK. HFD feeding increased the serum levels of EGF, insulin, IGF-I, IFN-γ, leptin, RANTES, MCP-1, IL-1ra, and SDF-1α and media conditioned by epididymal fat tissue explants from HFD-fed mice caused an increase in microvessel outgrowth from the mouse aorta and tube formation of human umbilical vein endothelial cells. These results indicate that the chronic consumption of an HFD increases colon cancer cell proliferation, tumor angiogenesis, and lung metastasis in mice in the absence of discernible weight gain. HFD feeding increases the levels of growth factors which activate transcription factors, thereby inducing the expression of many genes involved in the stimulation of inflammation, angiogenesis, and cellular proliferation.

Dietary fat increases solid tumor growth and metastasis of 4T1 murine mammary carcinoma cells and mortality in obesity-resistant BALB/c mice.

INTRODUCTION: High-fat diets (HFDs) are known to cause obesity and are associated with breast cancer progression and metastasis. Because obesity is associated with breast cancer progression, it is important to determine whether dietary fat per se stimulates breast cancer progression in the absence of obesity. This study investigated whether an HFD increases breast cancer growth and metastasis, as well as mortality, in obesity-resistant BALB/c mice. METHODS: The 4-week-old, female BALB/c mice were fed HFD (60% kcal fat) or control diet (CD, 10% kcal fat) for 16 weeks. Subsequently, 4T1 mammary carcinoma cells were injected into the inguinal mammary fat pads of mice fed continuously on their respective diets. Cell-cycle progression, angiogenesis, and immune cells in tumor tissues, proteases and adhesion molecules in the lungs, and serum cytokine levels were analyzed with immunohistochemistry, Western blotting, and enzyme-linked immunosorbent assay (ELISA). In vitro studies were also conducted to evaluate the effects of cytokines on 4T1 cell viability, migration, and adhesion. RESULTS: Spleen and gonadal fat-pad weights, tumor weight, the number and volume of tumor nodules in the lung and liver, and tumor-associated mortality were increased in the HFD group, with only slight increases in energy intake and body weight. HF feeding increased macrophage infiltration into adipose tissues, the number of lipid vacuoles and the expression of cyclin-dependent kinase (CDK)2, cyclin D1, cyclin A, Ki67, CD31, CD45, and CD68 in the tumor tissues, and elevated serum levels of complement fragment 5a (C5a), interleukin (IL)-16, macrophage colony-stimulating factor (M-CSF), soluble intercellular adhesion molecule (sICAM)-1, tissue inhibitors of metalloproteinase (TIMP)-1, leptin, and triggering receptor expressed on myeloid cells (TREM)-1. Protein levels of the urokinase-type plasminogen activator, ICAM-1, and vascular cell adhesion molecule-1 were increased, but plasminogen activator inhibitor-1 levels were decreased in the lungs of the HFD group. In vitro assays using 4T1 cells showed that sICAM-1 increased viability; TREM-1, TIMP-1, M-CSF, and sICAM-1 increased migration; and C5a, sICAM-1, IL-16, M-CSF, TIMP-1, and TREM-1 increased adhesion. CONCLUSIONS: Dietary fat increases mammary tumor growth and metastasis, thereby increasing mortality in obesity-resistant mice.

3,3'-diindolylmethane suppresses 12-O-tetradecanoylphorbol-13-acetate-induced inflammation and tumor promotion in mouse skin via the downregulation of inflammatory mediators.

3,3'-Diindolylmethane (DIM) is a major acid-condensation product of indole-3-carbinol and is present in cruciferous vegetables. In this study, we evaluated the effects of DIM on antiinflammatory and antitumor promotion activity in mouse skin and explored the relevant mechanisms. When 12-O-tetradecanoylphorbol-13-acetate (TPA) was applied topically to the mouse ear to induce inflammation, DIM pretreatment effectively inhibited TPA-induced ear edema formation. To evaluate the mechanisms underlying DIM's antiinflammatory effects, DIM was topically treated to the shaved backs of mice 30 min before TPA treatment. DIM inhibited the TPA-induced increases in the expression of cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS), chemokine (C-X-C motif) ligand (CXCL) 5, and interleukin (IL)-6 in mouse skin. DIM also inhibited nuclear factor-kappa B (NF-kappaB)'s DNA binding activity, the nuclear translocation of p65, and the degradation of inhibitor of kappaB (IkappaB) alpha in TPA-stimulated mouse skin. Furthermore, DIM reduced TPA-induced increases in the activity of extracellular signal regulated protein kinase (ERK)-1/2 and IkappaB kinase (IKK). When mouse skin papillomas were initiated via the topical application of 7,12-dimethylbenz[alpha]anthracene (DMBA) and promoted with repeated topical applications of TPA, repeated topical applications of DIM prior to each TPA treatment significantly suppressed the incidence and multiplicity of the papillomas. DIM also reduced the expression of COX-2 and iNOS, ERK phosphorylation, and the nuclear translocation of p65 in papillomas. Collectively, these results show that DIM exerts antiinflammatory and chemopreventive effects in mouse skin via the downregulation of COX-2, iNOS, CXCL5, and IL-6 expression, which may be mediated by reductions in NF-kappaB activation.

Weekly rituximab followed by monthly rituximab treatment for steroid-refractory chronic graft-versus-host disease: results from a prospective, multicenter, phase II study.

BACKGROUND: Since it was suggested that B cells play a role in the pathogenesis of chronic graft-versus-host disease, rituximab, an anti-CD20 monoclonal antibody targeting B cells, has been shown to be effective in steroid-refractory, chronic graft-versus-host disease. However, most of the data were from small numbers of patients or retrospective analyses. We, therefore, conducted a multicenter phase II study to confirm the efficacy of this treatment strategy that targets B cells. DESIGN AND METHODS: We diagnosed and evaluated chronic graft-versus-host disease according to the National Institute of Health criteria for clinical trials on this condition. The treatment consisted of weekly intravenous infusions of rituximab for 4 weeks followed by monthly rituximab for 4 months. We evaluated the patients' responses and monitored their disease activity until their final visit, which was on day 365. We also assessed the patients' subsequent quality of life and serum levels of B-cell-activating factor of the tumor necrosis factor family. RESULTS: Among 37 patients enrolled (median age, 29 years; range 8-57 years), 32 patients responded to rituximab with 8 complete and 24 partial responses. Twenty-one patients maintained their response for 1 year, so their steroid treatment was discontinued or its dose reduced (21/37, or 56.8%), and their scores representing quality of life were improved although these changes were not statistically significant. The responses were better for clinical manifestations of the skin, oral cavity and musculoskeletal system (response rate, 71.4-100%) than for other organs. However, infectious complications and primary disease relapse accounted for the majority of treatment failure. The pre-treatment serum level of B cell-activating factor of the tumor necrosis factor family was not associated with better treatment outcome (P=0.147). CONCLUSIONS: Rituximab could improve clinical responses and quality of life of patients with steroid-refractory chronic graft-versus-host disease, although such patients may need active prophylaxis against infection.

Luteolin improves hypercholesterolemia and glucose intolerance through LXRα-dependent pathway in diet-induced obese mice.

Luteolin, a naturally derived flavonoid, exerts beneficial effects such as antitumor, antioxidant, and anti-inflammatory effects. However, the molecular mechanism underlying the effect of luteolin in hypercholesterolemia remains unclear. In this study, we demonstrated that luteolin upregulated the expression of liver X receptor (LXR) α, ATP-binding cassette transporter G1 (ABCG1), and scavenger receptor class B member 1 (SRB1), which play a major role in cholesterol efflux, in HepG2 hepatocytes. Luteolin-stimulated expression of ABCG1 and SRB1 was reversed by inhibitory compound of LXRα. Luteolin administration also upregulated the expression of ABCG1, and SRB1 as well as cholesterol 7 α-hydroxylase (Cyp7α1) in the liver of diet-induced obese mice. Luteolin decreased the level of blood cholesterol and non-high-density lipoprotein cholesterol in obese mice. In addition, luteolin ameliorated glucose intolerance and reduced expression of gluconeogenesis-associated enzymes in an LXRα-dependent manner. PRACTICAL APPLICATIONS: Luteolin is known to possess various pharmacological activities. This research revealed that luteolin ameliorates hypercholesterolemia and glucose intolerance in diet-induced obesity. The results indicate that the potential properties of luteolin in cholesterol metabolism could be explained, at least in part, as being due to upregulated expression of ABCG1, and SRB1 through activation of liver X receptor, LXRα signaling pathway in HepG2 cells.

Oral administration of 3,3'-diindolylmethane inhibits lung metastasis of 4T1 murine mammary carcinoma cells in BALB/c mice.

3,3'-diindolylmethane (DIM) is the major in vivo product of the acid-catalyzed oligomerization of indole-3-carbinol present in cruciferous vegetables, and it has been shown to exhibit anticancer properties. In this study, we assessed the effects of DIM on the metastasis of 4T1 mouse mammary carcinoma cells. In vitro culture studies showed that DIM dose-dependently inhibited the migration, invasion, and adhesion of 4T1 cells at concentrations of 0-10 micromol/L without attendant changes in cell viability. In an in vivo lung metastasis model, 4T1 cells (2 x 10(5) cells/mouse) were injected into the tail veins of syngeneic female BALB/c mice. Beginning on the second day, the mice were subjected to gavage with 0-10 mg DIM/(kg body weight x d) for 13 d. Oral DIM administration resulted in a marked reduction in the number of pulmonary tumor nodules. DIM treatment significantly reduced the levels of matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1, and vascular cell adhesion molecule (VCAM)-1 and increased TIMP-2 levels in the sera and lungs of mice injected with 4T1 cells. Additionally, DIM treatment reduced the serum concentrations of interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)alpha. We have demonstrated that DIM profoundly inhibits the lung metastasis of 4T1 cells, which was accompanied by reduced levels of MMP, adhesion molecules, and proinflammatory cytokines. These results indicate that DIM has potential as an antimetastatic agent for the treatment of breast cancer.

Vitisin A inhibits adipocyte differentiation through cell cycle arrest in 3T3-L1 cells.

Inhibition of adipocyte differentiation is one approach among the anti-obesity strategies. This study demonstrates that vitisin A, a resveratrol tetramer, inhibits adipocyte differentiation most effectively of 18 stilbenes tested. Fat accumulation and PPARgamma expression were decreased by vitisin A in a dose-dependent manner. Vitisin A significantly inhibited preadipocyte proliferation and consequent differentiation within the first 2 days of treatment, indicating that the anti-adipogenic effect of vitisin A was derived from anti-proliferation. Based on cell cycle analysis, vitisin A blocked the cell cycle at the G1-S phase transition, causing cells to remain in the preadipocyte state. Vitisin A increased p21 expression, while the Rb phosphorylation level was reduced. Therefore, vitisin A seems to induce G1 arrest through p21- and consequent Rb-dependent suppression of transcription. On the other hand, ERK and Akt signaling pathways were not involved in the anti-mitotic regulation by vitisin A. Taken together, these results suggest that vitisin A inhibits adipocyte differentiation through preadipocyte cell cycle arrest.

Sulindac enhances arsenic trioxide-mediated apoptosis by inhibition of NF-kappaB in HCT116 colon cancer cells.

To study whether the apoptotic effect of arsenic trioxide (As2O3) on colon cancer cells could be enhanced by the addition of sulindac, HCT116 cells were treated with As2O3 (1, 5, 10 microM) and sulindac (0.5 mM), either alone or in combination. As2O3 alone slightly inhibited the growth of HCT116 cells, whereas the combination of As2O3 and sulindac reduced cell growth by 30-40%. Annexin V staining indicated that the synergistic effect of the combination was mediated through increased apoptosis. We examined whether the combination of As2O3 and sulindac on apoptosis is mediated by inhibition of the NF-kappaB pathway in HCT116 colon cancer cells. Western blot analysis showed that the level of nuclear NF-kappaB (p65) was not changed significantly by As2O3 or sulindac treatment alone, while the level of nuclear NF-kappaB (p65) was drastically decreased in the combination treatment by inhibiting the phosphorylation and the degradation of IkappaB-alpha. These results suggest that sulindac enhances apoptosis when combined with As2O3 by inhibiting NF-kappaB activation mediated through the blocking of phosphorylation and degradation of IkappaB-alpha.

Caffeic Acid Phenethyl Ester Improves Metabolic Syndrome by Activating PPAR-γ and Inducing Adipose Tissue Remodeling in Diet-Induced Obese Mice.

SCOPE: This study investigated the effects of caffeic acid phenethyl ester (CAPE), a bioactive component of honeybee hives, on the prevention and treatment of metabolic syndrome (MetS) by comparing the efficacy of CAPE intake at the beginning of obesity and after obesity. The functional mechanism of CAPE was also investigated. METHODS AND RESULTS: C57BL/6 mice were fed a high-fat diet (HFD) containing 0.05% CAPE (HFD+C) for 12 weeks (HFD+C(Pre) group) or received HFD+C for 6 weeks after consuming the HFD for 6 weeks (HFD+C(Post) group). Both CAPE-fed groups showed significant improvements in body weight, fatty liver, inflammation, and insulin resistance, but not serum lipid levels. Hyperlipidemia was only ameliorated in the HFD+C(Pre). Adipose tissue (AT) remodeling occurred in the CAPE-fed groups. Specifically, CAPE induced PPAR-γ activation, resulting in adipogenesis, a smaller and more uniform distribution of adipocytes, and decreased immune cell penetration and inflammation; CAPE also improved the disturbed pattern of adipokine secretion. Hypoxia was improved by promoting angiogenesis in AT. CONCLUSION: CAPE ameliorates metabolic disease by inducing PPAR-γ activation and AT remodeling. Additionally, this study reveals that the intake of CAPE after obesity, as well as in the early stage of obesity, helps in the prevention and treatment of MetS.

Shaofu Zhuyu decoction ameliorates obesity-mediated hepatic steatosis and systemic inflammation by regulating metabolic pathways.

Shaofu Zhuyu decoction (SFZYD, also known as Sobokchugeo-tang), a classical prescription drug in traditional East Asian medicine, has been used to treat blood stasis syndrome (BSS). Hepatic steatosis is the result of excess caloric intake, and its pathogenesis involves internal retention of phlegm and dampness, blood stasis, and liver Qi stagnation. To evaluate the effects of treatment with SFZYD on obesity-induced inflammation and hepatic steatosis, we fed male C57BL/6N mice a high fat diet (HFD) for 8 weeks and then treated them with SFZYD by oral gavage for an additional 4 weeks. The results of histological and biochemical examinations indicated that SFZYD treatment ameliorates systemic inflammation and hepatic steatosis. A partial least squares-discriminant analysis (PLS-DA) scores plot of serum metabolites showed that HFD mice began to produce metabolites similar to those of normal chow (NC) mice after SFZYD administration. We noted significant alterations in the levels of twenty-seven metabolites, alterations indicating that SFZYD regulates the TCA cycle, the pentose phosphate pathway and aromatic amino acid metabolism. Increases in the levels of TCA cycle intermediate metabolites, such as 2-oxoglutaric acid, isocitric acid, and malic acid, in the serum of obese mice were significantly reversed after SFZYD treatment. In addition to inducing changes in the above metabolites, treatment with SFZYD also recovered the expression of genes related to hepatic mitochondrial dysfunction, including Ucp2, Cpt1α, and Ppargc1α, as well as the expression of genes involved in lipid metabolism and inflammation, without affecting glucose uptake or insulin signaling. Taken together, these findings suggest that treatment with SFZYD ameliorated obesity-induced systemic inflammation and hepatic steatosis by regulating inflammatory cytokine and adipokine levels in the circulation and various tissues. Moreover, treatment with SFZYD also reversed alterations in the levels of metabolites of the TCA cycle, the pentose phosphate pathway and aromatic amino acid metabolism.

Successful eradication of relapsed primary effusion lymphoma with high-dose chemotherapy and autologous stem cell transplantation in a patient seronegative for human immunodeficiency virus.

Primary effusion lymphoma (PEL) is a recently recognized disease that occurs most often in immunosuppressed patients, either with human immunodeficiency virus (HIV) or in the posttransplantation setting, and it occasionally occurs in nonimmunosuppressed patients. Patients present with lymphomatous effusions in serous cavities--pleura, pericardium, or peritoneum--without any identifiable tumor mass. PEL rarely responds to systemic chemotherapy, and the prognosis is poor, with a median survival time of less than 6 months for most cohorts. A standard treatment for PEL has not yet been identified. We describe a patient with HIV-seronegative PEL who relapsed after combination chemotherapy and then underwent successful treatment with high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT). The treatment was well tolerated, and the patient has been in remission for 12 months after HDC and ASCT.

Tongqiaohuoxue decoction ameliorates obesity-induced inflammation and the prothrombotic state by regulating adiponectin and plasminogen activator inhibitor-1.

ETHNOPHARMACOLOGICAL RELEVANCE: Tongqiaohuoxue decoction (THD), a water extract of a mixture of eight species of medicinal herbs, has been used for the treatment of blood stasis and hypercoagulation in traditional East Asian medicine since 18th century. AIM OF THE STUDY: To investigate the in vivo efficacy of THD using high-fat diet (HFD)-induced obese mice with chronic inflammation and a prothrombotic state as an early vascular model. MATERIALS AND METHODS: THD was prepared by hot water extraction and freeze-drying. Male C57BL/6 mice were divided into three groups. Group 1 (NC) mice were fed normal chow. Mice in group 2 (HFD) and 3 (HFD+THD) were fed with HFD for 12 weeks. In addition, Group 3 mice were administered with 100mg/kg body weight THD for 4 weeks after onset of obesity by HFD for 8 weeks. Glucose tolerance tests and histological tissue examinations were performed. The levels of adipokines, inflammatory markers, and prothrombotic markers were assessed. RESULTS: The oral administration of THD for 4 weeks had no effect on the liver, adipose tissue, or total body weight when the HFD and HFD+THD groups were compared. Nevertheless, mice treated in THD interestingly showed a significant increase in adiponectin in blood and adipose tissue. To verify the effect of THD on adiponectin, 3T3-L1 adipocytes were treated with THD; it stimulated adiponectin production in a dose-dependent manner. In the HFD+THD group, pro-inflammatory cytokines were significantly down-regulated in the blood, adipose tissue, and liver. Insulin resistance was also notably improved by THD. Simultaneously, THD significantly reduced plasminogen activator inhibitor-1 (PAI-1) levels in serum, adipose tissue, and liver. Fibrin deposition and tPA activity, downstream targets of PAI-1, were also notably reduced in the HFD+THD group compared to the HFD group. CONCLUSIONS: THD improved obesity-induced inflammation and insulin resistance by increasing adiponectin production. Additionally, THD administration exerted an anti-thrombotic effect through the regulation of PAI-1 and fibrinolysis. This study demonstrates the efficacy of a traditional East Asian medicine by providing scientific evidence and suggesting a possible mechanism of action.

Biochanin A improves hepatic steatosis and insulin resistance by regulating the hepatic lipid and glucose metabolic pathways in diet-induced obese mice.

SCOPE: Natural compounds that regulate peroxisome proliferator-activated receptor alpha (PPARα) have been reported to have beneficial effects in obesity-mediated metabolic disorders. In this study, we demonstrated that biochanin A (BA), an agonist of PPAR-α, improved hepatic steatosis and insulin resistance by regulating hepatic lipid and glucose metabolism. METHODS AND RESULTS: C57BL/6 mice were fed a normal chow diet, a high-fat diet (HFD), and an HFD supplemented with 0.05% BA for 12 weeks. Histological and biochemical examinations indicated that BA prevented obesity-induced hepatic steatosis and insulin resistance in HFD-fed mice. BA stimulated the transcriptional activation of PPAR-α in vitro and increased the expression of PPAR-α and its regulatory proteins in the liver. CE-TOF/MS analyses indicated that BA administration promoted the recovery of metabolites involved in phosphatidylcholine synthesis, lipogenesis, and beta-oxidation in the livers of obese mice. BA also suppressed the levels of gluconeogenesis-related metabolites and the expression of the associated enzymes, glucose 6-phosphatase and pyruvate kinase. CONCLUSION: Taken together, these results showed that BA ameliorated metabolic disorders such as hepatic steatosis and insulin resistance by modulating lipid and glucose metabolism in diet-induced obesity. Thus, BA may be a potential therapeutic agent for the prevention of obesity-mediated hepatic steatosis and insulin resistance.

Intrathecal Trastuzumab Treatment in Patients with Breast Cancer and Leptomeningeal Carcinomatosis.

Leptomeningeal carcinomatosis is a fatal manifestation of metastatic breast cancer. Investigation of intrathecal (IT) trastuzumab for leptomeningeal carcinomatosis is currently underway; however, there has been no consensus. We report on two cases of human epidermal growth factor receptor 2 positive (HER2+) breast cancer following IT trastuzumab for leptomeningeal carcinomatosis. The first patient was treated with weekly IT 15 mg methotrexate plus IT 50 mg trastuzumab for 7 months, followed by IT trastuzumab (50 mg > 25 mg) for 18 months. The other patient received IT trastuzumab with systemic chemotherapy (trastuzumab and/or paclitaxel) for 13 months. Good control of leptomeningeal disease was achieved with IT trastuzumab in both patients, with survival durations of 20 and 29 months, respectively. We suggest that IT trastuzumab is a promising treatment for patients with HER2+ breast cancer and leptomeningeal carcinomatosis.

Adipose Natural Killer Cells Regulate Adipose Tissue Macrophages to Promote Insulin Resistance in Obesity.

Obesity-induced inflammation mediated by immune cells in adipose tissue appears to participate in the pathogenesis of insulin resistance. We show that natural killer (NK) cells in adipose tissue play an important role. High-fat diet (HFD) increases NK cell numbers and the production of proinflammatory cytokines, notably TNFα, in epididymal, but not subcutaneous, fat depots. When NK cells were depleted either with neutralizing antibodies or genetic ablation in E4bp4(+/-) mice, obesity-induced insulin resistance improved in parallel with decreases in both adipose tissue macrophage (ATM) numbers, and ATM and adipose tissue inflammation. Conversely, expansion of NK cells following IL-15 administration or reconstitution of NK cells into E4bp4(-/-) mice increased both ATM numbers and adipose tissue inflammation and exacerbated HFD-induced insulin resistance. These results indicate that adipose NK cells control ATMs as an upstream regulator potentially by producing proinflammatory mediators, including TNFα, and thereby contribute to the development of obesity-induced insulin resistance.

Docetaxel plus epirubicin as first-line chemotherapy in MBC (KCSG 01-10-05): phase II trial and the predictive values of circulating HER2 extracellular domain and vascular endothelial growth factor.

The anthracyclines and taxanes are considered to be the most active drugs in metastatic breast cancer (MBC). We conducted a multicenter phase II study to evaluate the efficacy and tolerability of the docetaxel plus epirubicin combination chemotherapy as first-line treatment in MBC and performed a prospective assessment of the predictive values of circulating HER2 extracellular domain (ECD) and vascular endothelial growth factor (VEGF). Docetaxel 75 mg/m(2) and epirubicin 75 mg/m(2) were given intravenously every 3 weeks. Prophylactic G-CSF was not used. Pretreatment serum HER2 ECD and VEGF levels were measured by enzyme immunoassay. Forty MBC patients were enrolled, and 39 patients were evaluable for toxicities and 38 for response. Complete response was observed in 3 (7.9%) patients, partial response in 20 (52.6%) (overall response rate 60.5%), stable disease in 11 (28.9%) and disease progression in 4 (10.5%). After a median follow-up of 22.5 months, the median duration of response was 28 weeks, median time to disease progression was 32 weeks, and median survival was 15.8 months. Two-hundred and fifteen cycles of treatment were administered (median, 6 cycles per patient). Grade 3 and 4 neutropenia were observed during 24 (11.2%) and 74 (35%) cycles respectively, and grade 3 or 4 febrile neutropenia in 24 (11.2%) cycles. Elevated circulating HER2 ECD levels were found to be associated with a shorter response duration (p<0.005) and shorter time to progression (p<0.005). However, elevated VEGF levels were not found to be correlated with response rate or survival. We concluded that the docetaxel and epirubicin combination is an effective first-line treatment in MBC patients and that elevated serum HER2 ECD levels, but not circulating VEGF levels, predict a poor outcome.