Effect of Selected Pyrazine Derivatives on the Production of Phenolics and Rutin in Urtica dioica and Fagopyrum esculentum.

The effect of four pyrazine derivatives on the content of phenolic compounds in Urtica dioica L. and rutin in Fagopyrum esculentum Moench was studied. Pyrazine derivatives H1 and H2 were used on U. dioica, and derivatives S1 and S2 on F. esculentum, both separately and in combination with urea. The content of phenolic compounds in the stems of U. dioica after treatment with H2 at a concentration of 10(-3) M significantly increased compared with the control and to a lower concentration of the same pyrazine derivative. In the case of S1 and S2 for F. esculentum, rutin content also increased in stems, mainly after treatment together with urea. By contrast, rutin and phenolics contents in the leaves did not change in comparison with controls after application of H1, H2, S I and S2. Treatment with H1 and H2 in two chosen concentrations resulted in a significant increase in the net photosynthetic rate, transpiration rate and stomatal conductance. A slight increase in the rate of photosynthesis was observed also after application of variants of S1 and S1 with urea. Pyrazine derivatives did not show any effect on either the relative content of chlorophyll or chlorophyll fluorescence. A slight weight reduction of above ground biomass was shown only after application of Si and S2. Dark necrosis on the edges and center of the leaves was observed in all treated plants after pyrazine application. The results suggest that all the pyrazine derivatives possess herbicidal effects.

Use of core modification in the discovery of CC214-2, an orally available, selective inhibitor of mTOR kinase.

We report here the discovery of a novel series of selective mTOR kinase inhibitors and the identification of CC214-2, a compound with demonstrated anti-tumor activity upon oral dosing in a PC3 prostate cancer xenograft model. A series of 4,6-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-ones were discovered through a core modification of our original compound series. Analogs from this series have excellent mTOR potency and maintain selectivity over the related PI3Kα lipid kinase. Compounds such as CC214-2 were found to block both mTORC1(pS6) and mTORC2(pAktS473) signaling in PC3 cancer cells, in vitro and in vivo.

Coronary and systemic arterial physiology and immunohistochemical markers related to early coronary arterial lesions in beagle dogs given the potassium channel opener, ZD6169, or the endothelin receptor antagonist, ZD1611.

We evaluated immunohistochemistry (von Willebrand Factor [vWF] or fibrinogen) and systemic and coronary arterial physiological parameters in beagle dogs to investigate early arterial lesions induced by the potassium channel opener, ZD6169, or the endothelin receptor antagonist, ZD1611. Dogs given an oral dose of ZD6169 (experiment 1) were terminated 1 day later and showed arterial and myocardial lesions. Minimal arterial lesions exhibited few condensed medial smooth muscle cells only, with others showing segmental medial necrosis occasionally with medial/adventitial acute inflammation. Intercellular immunostaining was seen in ostensibly normal tissue, where no pathology was present in conventionally stained sections. vWF and fibrinogen are valuable tools for detecting disruption of arterial integrity. In experiment 2, 2 dogs were given a single high dose of ZD6169 or ZD1611 and BP/HR monitored by conventional measures or telemetry. Substantially reduced systolic/diastolic BP and increased HR occurred within 10 min of ZD6169 infusion: ZD1611 caused minor BP decrease and HR increase. In experiment 3, both drugs given to anaesthetized dogs induced markedly exaggerated systolic phasic forward and reverse flow in left descending and right coronary arteries. Diastolic coronary artery flows were unaffected with ZD1611 and increased slightly with ZD6169. In both coronary arteries, the ZD1611-induced increase in flows paralleled decreased resistance.

Anti-inflammatory and immunomodulatory effects of bortezomib in various in vivo models.

Bortezomib (Velcade®) is a proteasome inhibitor that has been approved for the treatment of multiple myeloma and mantle cell lymphoma. It has been shown to inhibit the expression of cell adhesion molecules, co-stimulatory molecules, and NFκB activation, to deplete alloreactive T lymphocytes, and to decrease Th1 cytokine production. The anti-inflammatory effects of bortezomib were further investigated in this current set of studies. Systemic treatment with bortezomib was efficacious in the thioglycolate-induced MCP-1 production model, and the dinitrofluorobenzene-induced delayed-type hypersensitivity model. Psoriasis is an autoimmune disease that affects about 2% of the world population. Many treatments have been reported with varying degrees of efficacy. A topical bortezomib formulation was developed to minimize systemic exposure. Its tolerability was investigated in a topical imiquimod (IMQ)-induced psoriasis model. Daily application of IMQ on mouse skin induced inflamed scaly skin lesions resembling plaque-type psoriasis. Fatality was observed in the 1-mg/ml dose group. At 0.1 and 0.01 mg/ml, bortezomib potentiated IMQ-induced erythema, scaling, skin thickening, and caused necrotic lesions. Lower doses had no effect on the clinical observations. Histologically, bortezomib dose-dependently increased parakeratosis, hyperkeratosis, acanthosis, and inflammatory cell infiltration. This study demonstrated that topical bortezomib is not suitable for the treatment of psoriasis.

Bortezomib attenuates murine collagen-induced arthritis.

OBJECTIVES: Nuclear factor kappa B (NF-kappaB) is a major regulator of pivotal proinflammatory cytokines in the pathogenesis of rheumatoid arthritis (RA). Bortezomib inhibits NF-kappaB activation by blocking the degradation of the NF-kappaB inhibitor, I-kappaB. In this study, the efficacy of bortezomib on murine collagen-induced arthritis (CIA) was investigated. METHODS: Thirty-five male DBA/1 mice were divided into five groups. All mice except controls were injected with type II collagen. Mice in the bortezomib-treated groups were injected intraperitoneally with 0.01, 0.1 and 1 mg/kg bortezomib twice a week for 2 weeks. Controls and mice in the untreated group were also injected intraperitoneally with phosphate-buffered saline in the same manner. Arthritis score and paw thickness were measured and histopathological assessment of joint sections was performed. The expression of proinflammatory cytokines and enzymes was evaluated by immunohistochemical staining. Joint destruction was confirmed using three-dimensional micro-computerised tomography (CT). Blood cells were counted and liver and kidney functions were monitored. RESULTS: Bortezomib significantly attenuated the severity of arthritis and histopathological findings in CIA mice. The expression of tumour necrosis factor alpha, IL-1beta, IL-6, matrix metalloproteinase 3, cyclooxygenase 2 and inducible nitric oxide synthase decreased in bortezomib-treated mice compared with untreated mice. In addition, micro-CT confirmed that bortezomib reduced joint destruction. No adverse effects in blood cells, liver or kidneys were observed with bortezomib treatment. CONCLUSIONS: These data suggest that bortezomib may play an anti-inflammatory role in the pathophysiology of RA and serve as a new therapeutic modality for RA.

[Effect of ligustrazine, synthetic borneol on lasting time of ciliary movement].

OBJECTIVE: To study the using of the method in vitro and in vivo of lasting time of ciliary movement in ligustrazine, synthetic borneol. METHODS: (1) Method in vitro-The lasting time of ciliary movement was observed with forty-fold optical microscope after dropping liquid medicine on exteacorporeal frog palate mucosa. Then mucosa was cleared. It was observed whether the ciliary movement was recovered and the lasting time was recorded from recovering to stopping once again. (2) Method in vivo-Liquid medicine or normal saline was dropped on frog palate mucosa by contacting thirty minutes. Then mucosa was cleared. The lasting time of ciliary movement was observed with forty-fold optical microscope by separating palate mucosa. RESULTS: Relatively percentage of lasting time of ciliary movement of ligustrazine in vitro and in vivo was 9.8%, 87.3%; The relatively percentage of synthetic borneol in vitro and in vivo was 9.3%, 89.5%. CONCLUSION: The method in vitro and in vivo of lasting time of ciliary movement can be the one of the selecting ways of Chinese drug's toxicity of nasal mucosa, and it have virtues and defects respectively. Ligustrazine, synthetic borneol have significantly toxical effect on exteacorporeal lasting time of ciliary movement.

The preclinical pharmacological profile of WAY-132983, a potent M1 preferring agonist.

Muscarinic M1 preferring agonists may improve cognitive deficits associated with Alzheimer's disease. Side effect assessment of the M1 preferring agonist WAY-132983 showed significant salivation (10 mg/kg i.p. or p.o.) and produced dose-dependent hypothermia after i. p. or p.o. administration. WAY-132983 significantly reduced scopolamine (0.3 mg/kg i.p.)-induced hyperswimming in mice. Cognitive assessment in rats used pretrained animals in a forced choice, 1-h delayed nonmatch-to-sample radial arm maze task. WAY-132983 (0.3 mg/kg i.p) significantly reduced scopolamine (0.3 mg/kg s.c.)-induced errors. Oral WAY-132983 attenuated scopolamine-induced errors; that is, errors produced after combining scopolamine and WAY-132983 (to 3 mg/kg p.o.) were not significantly increased compared with those of vehicle-treated control animals, whereas errors after scopolamine were significantly higher than those of control animals. With the use of miniosmotic pumps, 0.03 mg/kg/day (s.c.) WAY-132983 significantly reduced AF64A (3 nmol/3 microliter/lateral ventricle)-induced errors. Verification of AF64A cholinotoxicity showed significantly lower choline acetyltransferase activity in the hippocampi of AF64A-treated animals, with no significant changes in the striatal or frontal cortex. Cognitive assessment in primates involved the use of pretrained aged animals in a visual delayed match-to-sample procedure. Oral WAY-132983 significantly increased the number of correct responses during short and long delay interval testing. These effects were also apparent 24 h after administration. WAY-132983 exhibited cognitive benefit at doses lower than those producing undesirable effects; therefore, WAY-132983 is a potential candidate for improving the cognitive status of patients with Alzheimer's disease.

[Effects of tetramethylpyrazine and ferulic acid alone or combined on vascular smooth muscle, blood viscosity and toxicity].

The experiments showed that both tetramethylpyrazine and ferulic acid relaxed the norepinephrine-induced spasmodic contraction of rabbit and rat aorta strips, increased the coronary flow of isolated guinea pig hearts and reduced the whole blood viscosity in rats. Evaluated with Burgi's equation, the combined effect of these 2 drugs was obviously potentiated, but the combined acute toxicity in mice was greatly reduced.