We previously screened neurite outgrowth activities of several Ginseng drugs in human neuroblastoma, and demonstrated that protopanaxadiol (ppd)-type saponins were active constituents. Since ppd-type saponins are known to be completely metabolized to 20-O-b-D-glucopyranosyl-20(S)-protopanaxadiol (M1) by intestinal bacteria when taken orally, M1 and ginsenoside Rb 1 , as a representative of ppd-type saponins, were examined for cognitive disorder. In a mouse model of Alzheimer's disease (AD) by Ab(25-35) i.c.v. injection, impaired spatial memory was recovered by p.o. administration of ginsenoside Rb 1 or M1. Although the expression levels of phosphorylated NF-H and synaptophysin were reduced in the cerebral cortex and the hippocampus of Ab(25-35)-injected mice, their levels in ginsenoside Rb 1 -and M1-treated mice were almost completely recovered up to control levels. Potencies of the effects were not different between ginsenoside Rb 1 and M1 when given orally, suggesting that most of the ginsenoside Rb 1 may be metabolized to M1, and M1 is an active principal of ppd-type saponins for the memory improvement. In cultured rat cortical neurons, M1 showed extension activity of axons, but not dendrites. The axon-specific outgrowth was seen even when neuritic atrophy had already progressed in response to administration of Ab(25-35) as well as in the normal condition. These results suggest that M1 has axonal extension activity in degenerated neurons, and improve memory disorder and synaptic loss induced by . M1 was shown to be effective in vitro and in vivo, indicating that Ginseng drugs containing ppd-type saponins may reactivate neuronal function in AD by p.o. administration.

Inhibition of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) represents a promising strategy for the discovery of a new generation of anticancer chemotherapeutics. Our synthetic efforts, beginning from the lead compound 2, were directed at improving antiproliferative activity against cancer cells as well as various drug properties. These efforts led to the discovery of N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide dimethylsulfoxide solvate (GSK1120212, JTP-74057 DMSO solvate; 1), a selective and highly potent MEK inhibitor with improved drug properties. We further confirmed that the antiproliferative activity correlates with cellular MEK inhibition and observed significant antitumor activity with daily oral dosing of 1 in a tumor xenograft model. These qualities led to the selection of 1 for clinical development.

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ABSTRACT-Extension of axons and dendrites in neurons may compensate for and repair damaged neuronal networks in the dementia brain. To find out drugs capable of regenerating the neuronal network, we focused on several herbal drugs belonging to the genus Panax, kinds of Ginseng, and investigated neurite outgrowth activity of their extracts and compounds. We found that the methanol extracts of Ginseng (root of P. ginseng), Notoginseng (root of P. notoginseng) and Ye-Sanchi in Chinese (rhizome of a relative to P. vietnamensis) increased neurite outgrowth in SK-N-SH cells. The protopanaxadiol-type saponins, ginsenosides Rb 1 and Rb 3 , and notoginsenosides R 4 and Fa isolated from Ye-Sanchi extract extended neurites, while protopanaxatriol-, ocotillol-and oleanane-type saponins had no effect on the neurite outgrowth. The percentage of cells with multipolar neurites and number of varicosities were intensely high in cells treated with the methanol extract of Ye-Sanchi as well as ginsenosides Rb 1 and Rb 3 , and notoginsenosides R 4 and Fa. Both phosphorylated NF-H-expressing neurites and MAP2-expressing ones were extended by treatment with those saponins and the extract. Especially, longer neurites were mainly positive for phosphorylated NF-H. These results suggest that protopanaxadiol-type saponins enhance axonal and dendritic formation activity.Keywords: Ginseng, Protopanaxadiol saponin, Axon, Dendrite, SK-N-SH cell Despite the growing social problem of dementia, there is not yet any drug available for reliable treatment against dementia. Cholinomimetic agents in the form of acetylcholine esterase inhibitors are primarily used in the treatment of dementia patients. These drugs, however, just slow down the progression of dementia rather than actually restoring brain function. Regardless of the type (Alzheimer's or cerebrovascular), dementia is induced by neuronal degeneration and atrophy. Inhibiting the cause of the disease, an accumulation of amyloid b in Alzheimer's brain (1 -3), and attempts for neuroprotection have lately been considered attractive. Such protective measures may reduce progression of dementia, but can not recover severe disfunction of the brain. Therefore, one strategy for achieving an irreversible amelioration of dementia may be reconstruction of synaptic formation in the brain. Although it is difficult to repair neurons or to increase cell number after neurodegeneration in the central nervous system, new synapses could possibly be formed through the activation of remaining immature and mature neurons. Since synaptic formation is based on neurite outgrowth and dendrite and axon maturation, drugs activating these steps could possibly initiate a recovery of brain function.Ginseng, root of Panax ginseng, is the most famous drug in traditional medicine as a tonic and an anti-amnesic agent. It has been reported that significant improvement in learning and memory was observed in brain-damaged rats (4, 5) and aged rats (5) after oral administration of ginseng powder. Furthermore, neurites of rat culture...

Summary:Case reportA 40-year-old man was diagnosed with AML in January We report an unusual case of a patient who was cured of one autoimmune disease (palmoplantar pustular pso-1992. Bone marrow cytology revealed M6 by the FAB classification with trilineage myelodysplasia. The patient riasis (PPP)) but developed another autoimmune disease (autoimmune thyroiditis) after allogeneic BMT. A 40-went into complete remission following induction chemotherapy with daunorubicin, 6-mercaptopurine, and behenoyl year-old man suffering from AML with PPP underwent allogeneic BMT from his HLA-identical sister for the cytosine arabinoside. After receiving three courses of consolidation chemotherapy, he developed skin lesions on the treatment of AML. The patient experienced complete clearance of the cutaneous PPP despite the cessation of palms and soles ( Figure 1). The skin lesions were diagnosed as PPP by histological examination in February 1993. immunosuppressive therapy for over 2 years. However, he developed hyperthyroidism with anti-thyroglobulin They were treated with combinations of topical corticosteroids and etretinate, but showed only partial response. antibodies 5 months after BMT, although he had showed normal thyroid functions without anti-thyrogloIn November 1993, after myeloablation with BU (16 mg/kg) and CY (120 mg/kg), the patient received an bulin antibodies before BMT. The donor had no history of thyroid diseases and showed normal thyroid funcallogeneic BMT from his HLA-identical younger sister, who did not suffer from PPP. The mixed lymphocyte reactions but was positive for anti-thyroglobulin antibodies. Thus, even when the donor is in a subclinical state, autotion was negative. Although the patient's elder sister had died of hyperthyroidism, his younger sister had no history immune thyroiditis may be transferred from donors to recipients by BMT.of thyroid diseases and showed normal thyroid functions, but was positive for anti-thyroglobulin antibodies. Keywords: autoimmune thyroiditis; palmoplantar pustular psoriasis; bone marrow transplantation; autoimmunity CYA and MTX were used for GVHD prophylaxis. The hematological follow-up showed stable engraftment with complete hematopoietic recovery and sustained complete chimerism. There were no signs of acute GVHD. After his It is well known that the hematopoietic and immune system of recipients is eventually replaced by donor-derived cells after allogeneic BMT. Experimental work in animal models has demonstrated that BMT can be used to treat systemic and organ-specific autoimmune diseases. 1 In humans, the resolution of immune-mediated diseases after BMT has recently been reported. [2][3][4] On the other hand, autoimmune diseases have also been transferred from donors to recipients in both mice 5 and humans 6-8 by BMT. We report the unusual case of a patient who was cured of palmoplantar pustular psoriasis (PPP) but developed autoimmune thyroiditis after allogeneic BMT. This is the first case report in which a pre-existing immune-mediated disease was cured while ...