Clinical effects of slim-diet, with lifestyle modification for childhood obesity in community-based healthcare program: A case series.

RATIONALE: Although there are several reports on the effect of herbal medicine on weight loss in adults, evidence supporting its efficacy and safety in obese pediatrics is insufficient. Herein, we clinically investigated the preliminary experience of community-based healthcare program in cases of childhood obesity treated with an herbal complex, Slim-diet (SD), along with lifestyle modification. PATIENT CONCERNS: Seventeen subjects with childhood obesity participated in a community-based healthcare program, which consisted of twice-a-week play type physical activity and dietary counseling program with simultaneous twice-a-day administration of SD for 4 weeks. DIAGNOSES: The data of 13 obese pediatrics (body mass index [BMI] ≥ the 95th percentile for children of the same age and sex) in their 3rd to 6th grade who finally completed at least 6 visits out of a total of 8 visits of the program including baseline and endpoint assessments were analyzed. INTERVENTIONS: Participants received 20 g of SD daily. Simultaneously, play-type physical activity program with an exercise therapist and dietary counseling with a dietitian for lifestyle modification were conducted at every visit. Body composition, blood chemistry, the Korean Youth Physical Activity Questionnaire (KYPAQ) score, and the preference for salt density and sugar content were assessed at baseline and endpoint. OUTCOMES: After SD administration, body mass index decreased from 26.74 ±â€Š2.11 kg/m to 26.50 ±â€Š2.20 kg/m (P < .05) with statistically significant increases in height, weight, and skeletal muscle mass. The results of blood chemistry and the KYPAQ score showed no significant change. The preferences for salt density were improved in 8, maintained in 2, and worsened in 3 participants and those for sugar content were improved in 6 and maintained in 7 participants with no worsening. LESSONS: In the present study, we showed the clinical effects of SD with lifestyle modification in patients with childhood obesity who participated in community-based healthcare program. Further clinical studies investigating the effects of SD are required.

Dietary schizophyllan reduces mitochondrial damage by activating SIRT3 in mice.

Schizophyllan (SPG), produced by Schizophyllum commune, is an exopolysaccharide with multiple academic and commercial uses, including in the food industry and for various medical functions. We previously demonstrated that SPG conjugated with c-Src peptide exerted a significant therapeutic effect on mouse models of the acute inflammatory diseases polymicrobial sepsis and ulcerative colitis. Here we extended these results by investigating whether SPG exerted a protective effect against mitochondrial damage in the liver via sirtuin 3 (SIRT3) induction, focusing on the deacetylation of succinate dehydrogenase A (SDHA) and superoxide dismutase 2 (SOD2). Liver damage models induced by alcohol or conjugated linoleic acid (CLA, which simulates lipodystrophy) in SIRT3-/-, SOD2-/-, and SDHA-/- mice were used. Results showed that dietary supplementation with SPG induced SIRT3 activation; this was involved in mitochondrial metabolic resuscitation that countered the adverse effects of alcoholic liver disease and CLA-induced damage. The mitochondrial SIRT3 mediated the deacetylation and activation of SOD2 in the liver and SDHA in adipose tissues, suggesting that SPG supplementation reduced ethanol-induced liver damage and CLA-induced adverse dietary effects via SIRT3-SOD2 and SIRT3-SDHA signaling, respectively. Together, these results suggest that dietary SPG has a previously unrecognized role in SIRT3-mediated mitochondrial metabolic resuscitation during mitochondria-related diseases.

Parapheromones Suppress Chemotherapy Side Effects.

The cytotoxic drugs used in chemotherapy are often accompanied by nausea and vomiting. Despite the use of antiemetic drugs, chemotherapy-induced nausea and vomiting (CINV) remain significant side effects for cancer patients and are associated with serotonin type 3 receptor (5-HT3R) activation in the brainstem. Farnesol and nerolidol are sesquiterpene alcohols found in essential oils of plants such as roses, citronella, and lemon grass and are used as antiemetic parapheromones. Medicinal plants often are effective in treating gastrointestinal disorders, including CINV, although the mechanism of action remains unclear. In the current work, the antiemetic efficacy of the naturally occurring racemic mixture of farnesol (m-farnesol) and nerolidol (m-nerolidol) against cisplatin CINV was tested using the pica behavior (consumption of nonnutritive substances) of rats. Animals treated with m-farnesol or m-nerolidol consumed a smaller amount of kaolin than of saline-treated control animals. This result is consistent with the antiemetic efficacy of farnesol and nerolidol. Compared with controls, m-farnesol- but not m-nerolidol-treated animals consumed more food and lost less body weight. Thus, farnesol effectively reduced appetite suppression and weight loss induced by cisplatin. In separate experiments, isomers of farnesol and nerolidol were tested on 5-HT-induced responses of acutely isolated nodose neurons using patch-clamp methods. All the tested constituents inhibited 5-HT3R-mediated current in a noncompetitive manner. Thus, both farnesol and nerolidol may exert antiemetic efficacy by inhibiting 5-HT signaling in cranial visceral afferents, resulting in interruption of emetogenic signaling; however, nerolidol failed to suppress cisplatin-induced anorexia and weight loss, suggesting that additional mechanisms may contribute.

A novel neurological function of rice bran: a standardized rice bran supplement promotes non-rapid eye movement sleep in mice through histamine H1 receptors.

SCOPE: Although rice bran has been shown to be associated with a wide spectrum of health benefits, to date, there are no reports on its effects on sleep. We investigated the effect of rice bran on sleep and the mechanism underlying this effect. METHODS AND RESULTS: Electroencephalography was used to evaluate the effects of standardized rice bran supplement (RBS) and doxepin hydrochloride (DH), a histamine H1 receptor (H1 R) antagonist used as a positive control, on sleep in mice. The mechanism of RBS action was investigated using knockout (KO) mice and ex vivo electrophysiological recordings. Oral administration of RBS and DH significantly decreased sleep latency and increased the amount of non-rapid eye movement sleep (NREMS) in mice. Similar to DH, RBS fully inhibited H1 R agonist-induced increase in action potential frequency in tuberomammillary nucleus neurons. In H1 R KO mice, neither RBS nor DH administration led to the increase in NREMS and decrease in sleep latency observed in WT mice. These results indicate that the sleep-promoting effect of RBS is completely dependent on H1 R antagonism. CONCLUSIONS: RBS decreases sleep latency and promotes NREMS through the inhibition of H1 R, suggesting that it could be a promising therapeutic agent for insomnia.

HS-23, a Lonicera japonica extract, reverses sepsis-induced immunosuppression by inhibiting lymphocyte apoptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Lonicera japonica Thunberg, a widely used traditional Chinese medicine, possesses antibacterial, antiviral, and antiendotoxin activities. This study investigated the molecular mechanisms of HS-23, the ethanol extract of the dried flower buds of L. japonica, on sepsis-induced immunosuppression. MATERIALS AND METHODS: Male ICR mice were intravenously administered HS-23 (10, 20, and 40mg/kg) immediately (0h) and 22h after cecal ligation and puncture (CLP). The spleen was isolated for biochemical assays 24h after CLP. RESULTS: HS-23 improved sepsis-induced mortality. CLP induced a marked decrease in the number of splenocytes, B cells, and natural killer cells, which was attenuated by HS-23. HS-23 also attenuated CLP-induced apoptosis in CD4(+) and CD8(+) T cells and inhibited both the intrinsic and extrinsic apoptotic pathway in the spleen. HS-23 attenuated the CLP-induced decrease in interleukin (IL)-17 production. CLP significantly decreased splenic production of tumor necrosis factor-α and IL-2, and these effects were attenuated by HS-23. CONCLUSION: Our findings suggest that HS-23 reverses immunosuppression during the late phase of sepsis by inhibiting lymphocyte apoptosis and enhancing Th1 cytokine production. HS-23 warrants further evaluation as a potential therapeutic agent for the treatment of sepsis.

HS-23, Lonicera japonica extract, attenuates septic injury by suppressing toll-like receptor 4 signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Lonicera japonica Thunberg is a traditional herbal medicine widely used in East Asia as an anti-bacterial, anti-inflammatory, and antiviral agent. This study was designed to investigate the effects of HS-23, ethanol extract of the dried flower buds of Lonicera japonica, in experimental models of sepsis and elucidate the mechanisms of action of HS-23. MATERIALS AND METHODS: Male ICR mice were intravenously administered HS-23 (20 and 40 mg/kg) for 0 (immediately) and 24 h after cecal ligation and puncture (CLP) for survival tests, and HS-23 (40 mg/kg) immediately after CLP for biochemical assays. RESULTS: HS-23 improved sepsis-induced mortality, enhanced bacterial clearance, and attenuated multiple organ failure. The mechanisms of action of HS-23 included attenuation of increased toll-like receptor (TLR)4 protein and mRNA expression. HS-23 suppressed sepsis-induced increases in protein expression of myeloid differentiation primary response protein 88, p38 and c-Jun N-terminal kinase in both liver and lung, as well as TIR-domain-containing adapter-inducing interferon-ß and interferon regulatory transcription factor 3 protein expression in liver. CONCLUSION: The results of this study revealed that HS-23 attenuated sepsis through suppression of TLR signaling pathways. Therefore, our findings suggest that HS-23 might be useful as a potential therapeutic agent for treatment of sepsis.

Ginger and its pungent constituents non-competitively inhibit serotonin currents on visceral afferent neurons.

Nausea and emesis are a major side effect and obstacle for chemotherapy in cancer patients. Employ of antiemetic drugs help to suppress chemotherapy-induced emesis in some patients but not all patients. Ginger, an herbal medicine, has been traditionally used to treat various kinds of diseases including gastrointestinal symptoms. Ginger is effective in alleviating nausea and emesis, particularly, for cytotoxic chemotherapy drug-induced emesis. Ginger-mediated antiemetic effect has been attributed to its pungent constituents-mediated inhibition of serotonin (5-HT) receptor activity but its cellular mechanism of action is still unclear. Emetogenic chemotherapy drugs increase 5-HT concentration and activate visceral vagal afferent nerve activity. Thus, 5-HT mediated vagal afferent activation is essential to provoke emesis during chemotherapy. In this experiment, water extract of ginger and its three major pungent constituent's effect on 5-HT-evoked responses were tested on acutely dispersed visceral afferent neurons with patch-clamp methods. The ginger extract has similar effects to antiemetic drug ondansetron by blocking 5-HT-evoked responses. Pungent constituents of the ginger, [6]-shogaol, [6]-gingerol, and zingerone inhibited 5-HT responses in a dose dependent manner. The order of inhibitory potency for these compounds were [6]-shogaol>[6]-gingerol>zingerone. Unlike well-known competitive 5-HT3 receptor antagonist ondansetron, all tested ginger constituents acted as non-competitive antagonist. Our results imply that ginger and its pungent constituents exert antiemetic effects by blocking 5-HT-induced emetic signal transmission in vagal afferent neurons.

Marine polyphenol phlorotannins promote non-rapid eye movement sleep in mice via the benzodiazepine site of the GABAA receptor.

RATIONALE: In psychopharmacology, researchers have been interested in the hypnotic effects of terrestrial plant polyphenols and their synthetic derivatives. Phlorotannins, a marine plant polyphenol, could have potential as a source of novel hypnotic drugs. OBJECTIVES: The effects of phlorotannins and major phlorotannin constituent eckstolonol on sleep-wake profiles in mice were evaluated in comparison with diazepam, and their hypnotic mechanism was also investigated. METHODS: The effects of phlorotannin preparation (PRT) and eckstolonol orally given on sleep-wake profiles were measured by recording electroencephalograms (EEG) and electromyograms in C57BL/6N mice. Flumazenil, a GABAA-benzodiazepine (BZD) receptor antagonist, was injected 15 min before PRT and eckstolonol to reveal its hypnotic mechanism. RESULTS: PRT administration (>250 mg/kg) produced a significant decrease in sleep latency and an increase in the amount of non-rapid eye movement sleep (NREMS). Eckstolonol significantly decreased sleep latency (>12.5 mg/kg) and increased the amount of NREMS (50 mg/kg). PRT and eckstolonol had no effect on EEG power density of NREMS. The hypnotic effects of PRT or eckstolonol were completely abolished by pretreatment with flumazenil. CONCLUSIONS: We demonstrated that phlorotannins promote NREMS by modulating the BZD site of the GABAA receptor. These results suggest that phlorotannins can be potentially used as an herbal medicine for insomnia and as a promising structure for developing novel sedative-hypnotics.

Korean red ginseng extract induces proliferation to differentiation transition of human acute promyelocytic leukemia cells via MYC-SKP2-CDKN1B axis.

ETHNOPHARMACOLOGICAL RELEVANCE: Korean red ginseng has been used as traditional medicine in East Asia. Recent scientific research revealed multiple effects of Korean red ginseng, including anticancer activity. To evaluate the effect of Korean red ginseng extract (KRGE) in acute promyelocytic leukemia (APL) and elucidate its molecular mechanism. MATERIALS AND METHODS: NB4 cells were treated with 1mg/ml KRGE for 48 h and examined for cell proliferation and differentiation. Cell cycle distribution of KRGE-treated cells was analyzed and the expression level of G1 phase regulators was determined. MYC was overexpressed by retroviral transduction and its effect on SKP2 and CDKN1B gene expression, cell proliferation, cell cycle and differentiation was evaluated in KRGE-treated cells. RESULTS: KRGE alone was sufficient to induce granulocytic differentiation accompanied with growth inhibition. KRGE treatment resulted in cell cycle arrest at the G1 phase with augmented Cdkn1b proteins without changes in transcript levels. Cycloheximide treatment revealed reduced degradation of Cdkn1b protein by KRGE. In addition, KRGE treatment reduced expression of MYC and SKP2 genes, both at mRNA and protein levels. Upon ectopic expression of MYC, the effect of KRGE was reversed with lesser reduction and induction of SKP2 gene and Cdkn1b protein, respectively. Taken together, these results suggest a sequential molecular mechanism from MYC reduction, SKP2 reduction, Cdkn1b protein stabilization, G1 phase arrest to granulocytic differentiation by KRGE in human APL. CONCLUSIONS: KRGE induces leukemic proliferation to differentiation transition in APL through modulation of the MYC-SKP2-CDKN1B axis.

Potentiating effect of glabridin on GABAA receptor-mediated responses in dorsal raphe neurons.

Flavonoid-rich ethanol extracts of licorice root have sedative and anxiolytic effects. Glabridin is a major flavonoid component from licorice which we evaluated by examining GABA responses in acutely isolated dorsal raphe neurons of the rat. Neurons were recorded with patch-clamp methods at a holding potential of - 50 mV. Glabridin potentiated GABA-induced responses by positively modulating GABAA receptor responses with different concentration range. GABA (2 × 10(-6) M)-evoked currents were potentiated in a stepwise pattern increasing glabridin concentration. Between 10(-12) and 10(-8) M glabridin increased GABA responses by about 140 % of the control. At concentrations above 10(-7) M, a much larger, dose-dependent potentiation occurred before reaching a plateau at 3 × 10-6 M glabridin. A hypnotic drug, zolpidem, also induced biphasic concentration-potentiation relationship. The glabridin potentiation ratio was 2.2 times larger than the maximum potentiation to the benzodiazepine receptor full agonist diazepam. Benzodiazepine receptor antagonist, flumazenil (3 × 10(-7) M), failed to inhibit glabridin (3 × 10(-7) M)-induced potentiation. This result implies that glabridin may exhibit sedative and hypnotic effects by potentiating GABAergic inhibition in dorsal raphe neurons by GABAA receptor actions.

Geniposidic acid protects against D-galactosamine and lipopolysaccharide-induced hepatic failure in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Geniposidic acid (GA) is an iridoid glucoside isolated from Gardeniae jasminoides Ellis (Rubiaceae) that has long been used to treat inflammation, jaundice and hepatic disorders. AIMS OF THE STUDY: This study examined the cytoprotective properties of GA against D-galactosamine (GalN)/lipopolysaccharide (LPS)-induced fulminant hepatic failure. MATERIALS AND METHODS: Mice were given an intraperitoneal injection of GA (12.5, 25, 50 mg/kg) 1h before receiving GalN (800 mg/kg)/LPS (40 µg/kg). Liver and blood samples were collected 1 and 8 h after GalN/LPS injection. RESULTS: The survival rate of the GA group was significantly higher than the control. GalN/LPS increased serum aminotransferase activity, serum tumor necrosis factor-α level and hepatic lipid peroxidation and decreased hepatic glutathione content. These changes were attenuated by GA. GA augmented increases in serum interleukin-6 level, heme oxygenase-1 and NF-E2-related factor 2 protein expression. Mice treated with GA decreased cleaved caspase-8 and caspase-3 protein expression and showed significantly fewer apoptotic cells. GA increased Bcl-xL protein expression and decreased Bax protein expression. Moreover, GA treatment enhanced phosphorylation of signal transducer and activator of transcription 3. CONCLUSION: Our findings suggest that geniposidic acid alleviates GalN/LPS-induced liver injury by enhancing antioxidative defense system and reducing apoptotic signaling pathways.

Protective effect of Codonopsis lanceolata root extract against alcoholic fatty liver in the rat.

Alcohol intake remains the most important cause of fatty liver throughout the world. The current study was undertaken to determine whether dietary supplementation with Codonopsis lanceolata root water extract attenuates the development of alcoholic fatty liver in rats and to elucidate the molecular mechanism for such an effect. Male Sprague-Dawley rats were fed normal diet (ND), ethanol diet (ED) (36% of total energy from ethanol), or 0.5% C. lanceolata root extract-supplemented ethanol diet (ED+C) for 8 weeks. C. lanceolata root water extract supplemented to rats with chronic alcohol consumption ameliorated the ethanol-induced accumulations of hepatic cholesterol and triglyceride. Chronic alcohol consumption up-regulated the hepatic expression of genes involved in inflammation, fatty acid synthesis, and cholesterol metabolism, including tumor necrosis factor alpha (TNFalpha), liver X receptor alpha (LXRalpha), sterol regulatory element-binding protein (SREBP)-1c, fatty acid synthase, acetyl-coenzyme A carboxylase alpha (ACC), stearoyl-coenzyme A desaturase 1, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR), and low-density lipoprotein receptor (LDLR). The ethanol-induced up-regulations of TNFalpha, LXRalpha, SREBP-1c, HMGR, and LDLR genes in the liver were reversed by feeding C. lanceolata root water extract for 8 weeks. Moreover, ethanol-induced decreases in the ratio of phospho-5'-AMP-activated protein kinase (AMPK) alpha/AMPKalpha and phospho-ACC/ACC protein levels in the liver were significantly restored (135% and 35% increases, respectively, P < .05) by supplementing them with C. lanceolata root water extract. In conclusion, C. lanceolata root water extract appears to be protective against alcoholic fatty liver through the regulation of SREBP-1c, LXRalpha, HMGR, and LDLR genes and by the phosphorylation of AMPKalpha and ACC, which are implicated in lipid metabolism.

Induction of nitric oxide synthase by Oldenlandia diffusa in mouse peritoneal macrophages.

Oldenlandia diffusa (OD) has been used to treat malignant tumors. In this study using mouse peritoneal macrophages, we have examined the mechanism by which OD regulates nitric oxide (NO) production. When OD (1 mg/ml) was used in combination with 10 U/ml of recombinant interferon-gamma (rIFN-gamma), there was a marked cooperative induction of NO production (36.13+/-7.12 microM) by the Griess method (nitrite). Treatment of macrophages with rIFN-gamma plus OD (1 mg/ml) caused a significant increase in tumor necrosis factor-alpha (TNF-alpha) production (4.49+/-1.43 ng/ml) by enzyme-linked immunosorbent assay. The increased production of NO and TNF-alpha from rIFN-gamma-plus OD-stimulated cells was almost completely inhibited by pretreatment with 100 microM of pyrrolidine dithiocarbamate (PDTC), an inhibitor of nuclear factor kappa B (NF-kappaB). PDTC also inhibited phosphorylation of IkappaB in rIFN-gamma-plus OD-stimulated cells. These findings demonstrate that OD increases the production of NO and TNF-alpha by rIFN-gamma-primed macrophages and suggest that NF-kappaB plays a critical role in mediating these effects of OD.