Extract of Cordyceps militaris inhibits angiogenesis and suppresses tumor growth of human malignant melanoma cells.

Angiogenesis is essential for tumor development and metastasis. Among several angiogenic factors, vascular endothelial growth factor receptor (VEGF) is important for tumor-derived angiogenesis and commonly overexpressed in solid tumors. Thus, many antitumor strategies targeting VEGF have been developed to inhibit cancer angiogenesis, offering insights into the successful treatment of solid cancers. However, there are a number of issues such as harmful effects on normal vascularity in clinical trials. Taking this into consideration, we employed Cordyceps militaris as an antitumor approach due to its biological safety in vivo. The herbal medicinal mushroom Cordyceps militaris has been reported to show potential anticancer properties including anti-angiogenic capacity; however, its concrete properties have yet to be fully demonstrated. In this study, we aimed to elucidate the biological role of Cordyceps militaris extract in tumor cells, especially in regulating angiogenesis and tumor growth of a human malignant melanoma cell line. We demonstrated that Cordyceps militaris extract remarkably suppressed tumor growth via induction of apoptotic cell death in culture that links to the abrogation of VEGF production in melanoma cells. This was followed by mitigation of Akt1 and GSK-3ß activation, while p38α phosphorylation levels were increased. Extract treatment in mouse model xenografted with human melanoma cells resulted in a dramatic antitumor effect with down-regulation of VEGF expression. The results suggest that suppression of tumor growth by Cordyceps militaris extract is, at least, mediated by its anti-angiogenicity and apoptosis induction capacities. Cordyceps militaris extract may be a potent antitumor herbal drug for solid tumors.

Hypercobalaminemia induced by an energy drink after total gastrectomy: a case report.

We encountered a case of hypercobalaminemia induced by oral intake of an energy drink after total gastrectomy. The patient was referred to our hospital due to findings suspicious for gastric cancer on screening. A 20 mm type 0-IIc lesion was detected in the gastric subcardia on esophagogastroduodenoscopy. Total gastrectomy followed by Roux-en-Y reconstruction was performed. He was discharged without complications. His basal serum vitamin B12 level was initially maintained with monthly intramuscular injections of vitamin B12. After 9 months, his serum vitamin B12 level suddenly increased up to 36-fold higher than the normal range and persisted there for one year without vitamin B12 injections. The patient ultimately reported consuming half a bottle of an energy drink each day during this time period. This case demonstrates the risk of unexpected hypervitaminemia resulting from self-administration of nutritional supplements.

Efficacy and safety of additional 200-mg dose of celecoxib in adult patients with postoperative pain following extraction of impacted third mandibular molar: a multicenter, randomized, double-blind, placebo-controlled, phase II study in Japan.

BACKGROUND: Although third mandibular molar extraction is a widely used and validated model of acute pain for evaluating analgesic efficacy, a large proportion of patients experience moderate or severe pain following this procedure and require analgesia. Current treatment options have been associated with safety concerns and alternative therapies are sought. OBJECTIVE: Our aim was to assess the efficacy and safety of an additional 200-mg dose of celecoxib, administered 5 to 12 hours after an initial 400-mg dose of the drug for the treatment of moderate or severe acute pain following extraction of an impacted third mandibular molar. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, Phase II study. Patients experiencing moderate or severe pain within 1 to 2 hours following extraction of an impacted third mandibular molar received an initial 400-mg dose of celecoxib. Patients requiring additional analgesia were subsequently randomized to receive either an additional 200-mg dose of celecoxib or placebo 5 to 12 hours after the initial dose. The study was designed and conducted by Pfizer Inc. for approval of celecoxib in Japan for the indication of acute pain. The primary end point was the patient's impression of efficacy (4-category global evaluation scale). Secondary efficacy end points included pain intensity on a 4-category pain intensity scale, pain intensity on a 100-mm visual analog scale (VAS), and the pain intensity difference (100-mm VAS). In an exploratory analysis, use of rescue medication was evaluated. Primary and secondary end points were analyzed using the full analysis set. Assessment of the safety profile included a physical examination, measurement of pulse rate and blood pressure, standard 12-lead ECG, and laboratory tests. RESULTS: A total of 69 patients (celecoxib, 42/64 [65.6%]; placebo, 27/58 [46.6%]) received the additional dose of study medication; all completed the study without the need for rescue medication. A significantly higher proportion of patients in the celecoxib 200 mg group (41/64 [64.1%]) compared with the placebo group (15/58 [25.9%]) rated the study medication as "good" or "excellent" ≥ 2 hours after the additional dose (P < 0.0001). Pain intensity (VAS) 2 hours after the additional dose was significantly higher in the placebo group than in the celecoxib 200 mg group (P = 0.0003). The reduction in pain intensity from baseline to 2 hours after the additional dose of study medication was also significantly greater in the celecoxib 200 mg group than in the placebo group (P < 0.0001). The incidence of treatment-related, all-cause adverse events was slightly lower in patients receiving celecoxib 200 mg (20.3%) compared with placebo (31.0%). CONCLUSIONS: Overall, an additional 200-mg dose of celecoxib was well tolerated and efficacious in reducing the pain associated with extraction of an impacted third mandibular molar in the study population. ClinicalTrials.gov identifier: NCT01062113.

Theoretical study of pyrazolate-bridged dinuclear platinum(II) complexes: interesting potential energy curve of the lowest energy triplet excited state and phosphorescence spectra.

Four kinds of 3,5-dialkylpyrazolate(R2pz)-bridged dinuclear platinum(II) complexes [Pt2(mu-R2pz)2(dfppy)2] (dfppy=2-(2,4-difluorophenyl)pyridine; R2pz=pyrazolate in 1, 3,5-dimethylpyrazolate in 2, 3-methyl-5- tert-butylpyrazolate in 3, and 3,5-bis(tert-butyl)pyrazolate in 4) were theoretically investigated by the DFT(B3PW91) method. The Stokes shift of their phosphorescence spectra was discussed on the basis of the potential energy curve (PEC) of the lowest energy triplet excited state (T1). This PEC significantly depends on the bulkiness of substituents on pz. In 1 and 2, bearing small substituents on pz, one local minimum is present in the T1 state besides a global minimum. The local minimum geometry is similar to the S0-equilibrium one. The T1 state at this local minimum is characterized as the pi-pi* excited state in dfppy, where the dpi orbital of Pt participates in this excited state through an antibonding interaction with the pi orbital of dfppy; in other words, this triplet excited state is assigned as the mixture of the ligand-centered pi-pi* excited and metal-to-ligand charge transfer excited state ((3)LC/MLCT). The geometry of the T1-global minimum is considerably different from the S0-equilibrium one. The T1 state at the global minimum is characterized as the triplet metal-metal-to-ligand charge transfer ((3)MMLCT) excited state, which is formed by the one-electron excitation from the dsigma-dsigma antibonding orbital to the pi* orbital of dfppy. Because of the presence of the local minimum, the geometry change in the T1 state is suppressed in polystyrene at room temperature (RT) and frozen 2-methyltetrahydrofuran (2-MeTHF) at 77 K. As a result, the energy of phosphorescence is almost the same in these solvents. In fluid 2-MeTHF at RT, on the other hand, the geometry of the T1 state easily reaches the T1-global minimum. Because the T1-global minimum geometry is considerably different from the S0-equilibrium one, the phosphorescence occurs at considerably low energy. These are the reasons why the Stokes shift is very large in fluid 2-MeTHF but small in polystyrene and frozen 2-MeTHF. In 3 and 4, bearing bulky tert-butyl substituents on pz, only the T1-global minimum is present but the local minimum is not. The electronic structure of this T1-global minimum is assigned as the (3)MMLCT excited state like 1 and 2. Though frozen 2-MeTHF suppresses the geometry change of 3 and 4 in the T1 state, their geometries moderately change in polystyrene because of the absence of the T1-local minimum. As a result, the energy of phosphorescence is moderately lower in polystyrene than in frozen 2-MeTHF. The T1-global minimum geometry is much different from the S0-equilibrium one in 3 but moderately different in 4, which is interpreted in terms of the symmetries of these complexes and the steric repulsion between the tert-butyl group on pz and dfppy. Thus, the energy of phosphorescence of 3 is much lower in fluid 2-MeTHF than in frozen 2-MeTHF like 1 and 2 but that of 4 is moderately lower; in other words, the Stokes shift in fluid 2-MeTHF is small only in 4.

Pharmacological properties of traditional medicine (XXIX): effect of Hange-shashin-to and the combinations of its herbal constituents on rat experimental colitis.

Hange-shashin-to (HST) has been used as an herbal formula to treat inflammatory ulcerative gut diseases complicated with psychoneurosis in Japanese traditional Kampo medicine. The aim of the present study is to clarify anti-colitic effect of HST using a model of colitis induced by intracolonic instillation of 2,4,6-trinitrobenzene sulfonic acid (TNBS) in rats, and to evaluate the pharmaceutical properties of its herbal components. The colonic damage was elucidated by macroscopic damage scores, colon wet weight and area of mucosal necrosis. Orally administered HST significantly reduced the colonic damage. Other rats were orally treated with single-component berberine (BE), baicalin (BA), glycyrrhizin (GL) or saponin fraction of ginsenosides (GS), or with the mixture (TL) of BA, BE, GL and GS, or with the combinations of BA plus BE (BA-BE), or that of GL plus GS (GL-GS). Oral treatment of TL ameliorated colitis observations. However, no effects were found in the treatment of single-component BA, BE, GL or GS, whereas the GL-GS combination ameliorated the colitis. These results suggest that HST might suppress inflammatory bowel disease (IBD) and imply that there will be a potential benefit in the traditionally derived herbal combination.

Anti-stress effects of 3,4,5-trimethoxycinnamic acid, an active constituent of roots of Polygala tenuifolia (Onji).

3,4,5-trimethoxycinnamic acid (TMCA) is one of the constituents in Onji (roots of Polygala tenuifolia WILLD), an herbal medicine used for sedative in Japanese traditional Kampo medicine. Our previous study revealed that oral administration of this compound prolongs sleeping time induced by hexobarbital in mice to exhibit sedative action. In the present study, we investigate the effects of TMCA on the stress induced with repeated cold exposure or intracerebroventricular injection of corticotrophin-releasing hormone (CRH). Both types of stress significantly reduced the sleeping time induced with pentobarbital in rat, which was significantly prolonged by intraperitoneal injection of TMCA. The intracerebroventricular injection of CRH significantly augmented the content of norepinephrine (NE) in locus coeruleus (LC) of rats, which was significantly suppressed by the intracerebroventricular injection of TMCA. These findings suggest that TMCA would exhibit sedative effects by suppressing NE content in LC.

Anti-allergic effect of Perilla frutescens and its active constituents.

The leaves of Perilla frutescens Britton (Labiatae) are one of the most popular garnishes in Japan, used as an antidote for fi sh and crab meat allergy or as a food colorant. The present study was conducted to evaluate its anti-allergic effect and to identify its active constituents using mice ear-passive cutaneous anaphylaxis (PCA)-reaction. 48 h after the cutaneous injection of anti-ovalbumin serum into the ears of mice, ovalbumin and evansblue dye were intravenously injected. Perilla was extracted with boiling water, and intraperitoneally injected 15 min before ovalbumin-treatment. Thirty min after ovalbumin-treatment, the ears were removed and the colorant in the ear was colorimetrically quantitated. Perilla extract significantly suppressed the PCA-reaction, which was brought about by rosmarinic acid with a partial contribution from some macromolecular compounds. The anti-allergic titer of rosmarinic acid was more effective than tranilast, which is a modern anti-allergic drug. Perilla and rosmarinic acid are potentially promising agents for the treatment of allergic diseases.

Pharmacological properties of traditional medicines (XXVII). Interaction between Ephedra Herb and Gypsum under hyperthermal conditions in rats.

There are many important considerations in the interactions among the herbal constituents in a prescription of traditional Chinese medicine (TCM). Ephedra Herb [Chinese characters: see text] (Eph) is described a warm and acrid agent in TCM. The combination of Eph and Gypsum [Chinese characters: see text] (Eph-Gyp) shows specific actions in patients with different body temperatures. Previous reports suggested that Gypsum prevents the thermogenesis effect induced by ephedrine at an ambient temperature of 22 degrees C. In this investigation, the properties of Eph-Gyp in hyperthermal rats were studied in detail. It was shown that Gypsum Extract (GyE) enhanced the thermogenesis of Eph in hyperthermal rats, although not in normal rats. The results support not only the opposite actions of Eph-GyE but also the clinical differences in the symptomatic patterns of body temperature for Makyo-Kanseki-To [Chinese characters: see text] and Dai-Seiryu-To [Chinese characters: see text].

Effects of Kangen-karyu on coagulation system and platelet aggregation in mice.

Kangen-karyu (KGK) is a herbal formula created under the theory of traditional Chinese herbal medicine to invigorate the blood and dispel blood stasis. It contains 6 herbs: peony root, cnidium rhizome, safflower, cyperus rhizome, saussurea root (JP XIV), and Salvia miltiorrhiza root. The present study has been conducted to evaluate the in vivo anti-thrombotic activity of KGK using normal mice. Three consecutive days of oral administration of KGK to mice significantly extended tail-bleeding time and suppressed ex vivo platelet aggregation, while it did not extend the prothrombin time of plasma. It was revealed that the anti-thrombotic effects of KGK did not depend on the downregulation of the coagulation system, but depended in part on the inhibition of platelet aggregation. These results explain one of the pharmacological activities of KGK to invigorate the blood and dispel blood stasis.