Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UMLS:C0011570 (depression)
172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Our laboratory has synthesized and evaluated the anticancer activity of a number of sulfonylhydrazine DNA modifying agents. As a class, these compounds possess broad spectrum antitumor activity, demonstrating significant activity against a variety of experimental murine tumors, including the P388 and L1210 leukemias, B16 melanoma, M109 lung carcinoma, and M5076 reticulum cell sarcoma, as well as against the human LX-1 lung carcinoma xenograft. The current report describes the activity of a more recently synthesized member of this class, 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-(methylamino)carbonylhydrazine (101M). 101M was active in mice against the i.p. implanted L1210 leukemia over a wide range of doses and produced long-term survivors when administered as a single i.p. bolus of 10, 20, 40, 60, or 80 mg/kg, demonstrating a wider margin of safety than the nitrosourea, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). Curative therapy was achieved with doses of 101M that did not produce depression of the bone marrow. 101M was also highly effective against the L1210 leukemia when administered by the oral route. The ability of 101M to penetrate the blood-brain barrier and eradicate leukemia cells in the brain was remarkable (>6 log kill). This agent was also curative against L1210 variants resistant to cyclophosphamide, BCNU, or melphalan. Mice implanted with the murine C26 colon carcinoma were also cured by two injections of 10 or 20 mg/kg of 101M. Administration of 101M by two different well-tolerated regimens caused complete regression of established human glioblastoma U251 xenografts in 100% of treated mice, and significant responses were also obtained with 101M against advanced murine M109 lung carcinomas in mice. The broad spectrum of anticancer activity of the sulfonylhydrazine prodrug 101M coupled with the wide range of therapeutic safety exhibited by this agent, makes 101M particularly attractive for further development and clinical evaluation.
...
PMID:1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-(methylamino)carbonylhydrazine (101M): a novel sulfonylhydrazine prodrug with broad-spectrum antineoplastic activity. 1130 84

Extracts of Hypericum perforatum (St. John's wort) are widely and effectively used in the treatment of mild to moderate depression. In addition, hypericin, a component of Hypericum p. extracts, exhibits light-dependent phototoxic properties and can be used in phototherapy. We therefore investigated the cytotoxic activity of two total Hypericum p. extracts, namely from fresh and dried plants in the dark and after exposure to 7.5 J/cm2 white light illumination and compared it with the effect of hypericin on K562, U937, LN229 glioblastoma cell lines and normal human astrocytes. The chemical toxicity of non-illuminated Hypericum p. extracts in the cells tested is low as expressed by a LC50 between 1.9-4.1 mg/ml, which corresponds to 10.3-17.3 microM hypericin and 114.4-190.7 microM hyperforin after 48 h treatment. Hypericum p. extracts induced dose-dependent growth arrest of human malignant cells in the absence of illumination with GI50 values between 0.43-1.77 mg/ml (2.3-9.7 microM hypericin, 26.1-106.7 microM hyperforin) for the fresh plant extract and 0.59-3.03 mg/ml (2.5-12.8 microM hypericin, 24.2-124.7 microM hyperforin) for the dried extract. The growth inhibitory effect of fresh Hypericum p. extract was more pronounced in leukemia cell lines K562 and U937, the GI50 concentrations being about 7-fold lower than the corresponding LC50 for the cell lines K562 and U937, but almost the same as the LC50 for LN229 and NHA cells. GI50 (microgram/ml) for tumor cell lines K562 and U937 (432 and 799) established after 48 h differed significantly (p < 0.05) from those of LN229 and normal human astrocytes (1767 and 2900). The light-exposed extracts were more toxic, their LC50 and GI50 values were reduced to values corresponding to LC50 concentration of 3.7-7.4 microM and a GI50 of 1.3-3.5 microM for phototoxic hypericin. After exposure to light, there was a significant difference (p = 0.006) between the GI50 of glioblastoma LN229 cells (582 micrograms/ml) and normal human astrocytes (1050 micrograms/ml). Morphological examination by light microscopy and phosphaditylserine exposure on the outer plasma membrane investigated by Annexin V-binding with flow cytometry after 24 h confirmed that Hypericum p. extracts caused apoptosis of treated cells without exposure to light. Hypericum p. extracts derived from fresh herbs and from dried herbs which differ in their levels of phloroglucinols (hyperforin and adhyperforin) were compared. The hyperforin content of fresh St. John's wort extract exceeded that of dried plant extract by 47% and the GI50 values of fresh plant extract were 73%, 77% and 58% of those established for dried extract in the three malignant cell lines K562, U937 and LN229 in the dark (p < 0.05). Under white light (7.5 J/cm2), both extracts exerted comparable growth inhibitory and apoptosis inducing effects due to the phototoxicity of hypericin, the corresponding concentrations of which were in the range of 1.3-3.5 microM. The data reported in this study suggest that illumination is not essential for the growth inhibitory and apoptotic effects of Hypericum p. extracts, but light activation potentiates them. Furthermore, the constituent hyperforin is at least partly responsible for these effects in the dark.
...
PMID:Aqueous ethanolic extract of St. John's wort (Hypericum perforatum L.) induces growth inhibition and apoptosis in human malignant cells in vitro. 1206 Dec 57

Soluble form of intercellular adhesion molecules (sICAM) are increased in serum of many inflammatory diseases and tumours: the expression of such molecules is regulated by cytokines. In the present paper serum levels of interleukin-2 (IL-2), soluble interleukin-2 receptor (sIL-2R) and sICAM-1 were evaluated in patients with glioma compared with different tumours (lung and kidney carcinoma) in order to investigate the compromise of the immune system in these malignancies and to understand the host defence mechanisms. 14 cases of astrocytomas (WHO grade II, III), 20 cases of glioblastomas (GBL, WHO grade IV), 5 cases of lung carcinoma and 6 cases of kidney carcinoma were studied; the results were compared with 15 healthy controls. IL-2, sIL-2R, sICAM-1 concentrations were assessed by an enzyme-linked immunosorbent assay (ELISA) technique. The results were analyzed by Student's t test. Our findings showed that serum levels of IL-2 and sIL-2R were increased in all cancer patients; on the contrary, sICAM-1 serum levels were not significantly increased in GBL and astrocytoma patients. The increased values of IL-2 and sIL-2R are in agreement with a depression of the immune reactivity in patients with glioblastoma and astrocytoma, as reported in literature. On the contrary the levels of sICAM-1 are unchanged in astrocytic tumours while patients with kidney carcinoma presented the higher levels and an unfavourable prognosis.
...
PMID:Evaluation of serum levels of cytokines and intercellular adhesion molecule-1 (ICAM-1) in astrocytic tumours. 1289 44

There has been a recent upsurge of interest in radiation-induced bystander effects. Previously we reported that the accumulation of inducible nitric oxide (NO) synthase (iNOS) was induced only in human glioblastoma mutant (m) p53 cells by acute irradiation with X-rays, suggesting a suppression of iNOS induction after acute irradiation with X-rays in wtp53 cells. NO secreted from the irradiated mp53 cells induced the accumulation of p53 in unirradiated wtp53 cells. The radiosensitivity of wtp53 cells was reduced by exposure to the conditioned medium from irradiated mp53 cells, suggesting that NO is an initiator of radiation-induced bystander effects. In the present study, we found that the accumulation of iNOS in wtp53 cells was induced by chronic irradiation with gamma-rays followed by acute irradiation with X-rays, but not by each one. It is suggested that the accumulation of iNOS may be due to the depression of acute irradiation-induced p53 functions by pre-chronic irradiation. We found that chronic irradiation with gamma-rays did not inhibit the accumulation of p53 after exposure to the conditioned medium from the irradiated mp53 cells. However, the decay of accumulated p53 was stimulated by chronic irradiation with gamma-rays. At the same time, the accumulation of Hdm2 was observed; suggesting that chronic irradiation with gamma-rays may stimulate the degradation of p53 accumulated by NO-mediated bystander effects.
...
PMID:Indirect influences of radiation on unirradiated cells through irradiated cells. 1467 5

Members of the ADAR (adenosine deaminases acting on RNA) gene family are involved in one type of RNA editing that converts adenosine residues to inosine. The A-to-I editing of serotonin receptor subtype 2C (5-HT(2C)R) mRNA leads to replacement of three amino acid residues located within the intracellular loop II domain, resulting in dramatic alterations in G-protein coupling functions of the receptor. It has been speculated that RNA editing may play a role in several pharmacological and behavioral processes where the serotonergic plasticity is mediated through 5-HT(2C)R. Interferon-alpha (IFN-alpha) often causes severe depression in patients treated for chronic viral hepatitis and certain malignancies. In this study, we examined the effects of IFN-alpha on RNA editing in human glioblastoma cell lines, which express 5-HT(2C)R mRNAs. ADAR1 expression and the pattern of the 5-HT(2C)R mRNA editing rapidly changed in response to IFN-alpha, leading to the dominant expression of the 5-HT(2C)R-VSI isoform predicted to have reduced G-protein coupling functions. Our results support the hypothesis that 5-HT(2C)R mRNA editing has causative relevance in the pathophysiology of depression associated with cytokine therapy.
...
PMID:Altered RNA editing of serotonin 5-HT2C receptor induced by interferon: implications for depression associated with cytokine therapy. 1509 87

The authors performed a comprehensive analysis of the functional outcome of 10 patients who had survived 5 years from a diagnosis of glioblastoma. Neurologic deficits were mild in most patients, but neuropsychological testing demonstrated cognitive deficits in all patients. Depression and anxiety were common. Although most patients thought that their social functioning and work ability were impaired, little reduction in overall quality of life was perceived.
...
PMID:Surviving glioblastoma for more than 5 years: the patient's perspective. 1643 62

During the past decade, numerous molecular mediators of neurodegenerative diseases and neurological disorders have been identified and validated, yet few novel therapies have emerged and the unmet medical needs remain high. These molecular mediators belong to target classes such as ion channels, neurotransmitters and neurotransmitter receptors, cytokines, growth factors, enzymes and other proteins. In some cases, substantial pre-clinical validation exists, but the molecular target has not been readily druggable with small molecules, proteins or antibodies. RNA interference represents a therapeutic approach applicable to such non-druggable targets. Both non-viral and viral delivery strategies are being undertaken for in vivo silencing of molecular targets by RNA interference, which has resulted in robust efficacy in animal models of Alzheimer's disease, ALS, Huntington's disease, spinocerebellar ataxia, anxiety, depression, neuropathic pain, encephalitis and glioblastoma. These proof-of-concept data in animal models, together with the commencement of clinical trials using RNA interference for macular degeneration and respiratory syncytial virus infection, point to the potential of direct RNA interference for neurological disorders and neurodegenerative diseases.
...
PMID:Therapeutic potential of RNA interference for neurological disorders. 1681 77

S100A16 protein is a new and unique member of the EF-hand Ca(2+)-binding proteins. S100 proteins are cell- and tissue-specific and are involved in many intra- and extracellular processes through interacting with specific target proteins. In the central nervous system S100 proteins are implicated in cell proliferation, differentiation, migration, and apoptosis as well as in cognition. S100 proteins became of major interest because of their close association with brain pathologies, for example depression or Alzheimer's disease. Here we report for the first time the purification and biochemical characterization of human and mouse recombinant S100A16 proteins. Flow dialysis revealed that both homodimeric S100A16 proteins bind two Ca(2+) ions with the C-terminal EF-hand of each subunit, the human protein exhibiting a 2-fold higher affinity. Trp fluorescence variations indicate conformational changes in the orthologous proteins upon Ca(2+) binding, whereas formation of a hydrophobic patch, implicated in target protein recognition, only occurs in the human S100A16 protein. In situ hybridization analysis and immunohistochemistry revealed a widespread distribution in the mouse brain. Furthermore, S100A16 expression was found to be astrocyte-specific. Finally, we investigated S100A16 intracellular localization in human glioblastoma cells. The protein was found to accumulate within nucleoli and to translocate to the cytoplasm in response to Ca(2+) stimulation.
...
PMID:S100A16, a novel calcium-binding protein of the EF-hand superfamily. 1703 May 13

Sometimes patients with organic brain lesions in neurologically silent brain areas might present only with psychiatric symptoms, such as depression, anxiety disorders, schizophrenia, anorexia nervosa, or cognitive dysfunction. This study presents eight cases of patients with brain lesions (four cases of meningiomas, one case of intracerebral cysts, one case of anaplastic oligodendroglioma, one case of multiform glioblastoma, and one case of occlusive hydrocephalus) who, for a significant period of time, were diagnosed and treated for psychiatric disorders (three cases of Alzheimer's disease, two cases of schizoaffective disorder, one case of schizophrenia, one case of depression, and one case of organic emotional lability disorder). When neurologic symptoms developed, they underwent neuroimaging studies and organic brain lesions were diagnosed. Further treatment required neurosurgical interventions. These cases show that brain tumors can be neurologically silent for a sufficient period of time and manifest as psychiatric disorders. Therefore, neuroimaging studies are needed when atypical changes in mental status or neurologic symptoms and signs develop.
...
PMID:Brain lesions manifesting as psychiatric disorders: eight cases. 1903 81

Stress can affect the brain and lead to depression; however, the molecular pathogenesis is unclear. An association between stress and stress-induced hypersecretion of glucocorticoids occurs during stress. Dexamethasone (a synthetic glucocorticoid steroid) has been reported to induce apoptosis and increase the activity of monoamine oxidase (MAO) (Youdim et al. 1989). MAO is an enzyme for the degradation of aminergic neurotransmitters; dopamine, noradrenaline and serotonin and dietary amines and MAO inhibitors are classical antidepressant drugs. In this study, we have compared the ability of rasagiline (Azilect) and its main metabolite, R-aminoindan with selegiline (Deprenyl) in prevention of dexamethasone-induced brain cell death employing human neuroblastoma SH-SY5Y cells and glioblastoma 1242-MG cells. Dexamethasone reduced cell viability as measured by MTT test, but rasagiline, selegiline, and 1-R-aminoindan could significantly prevent dexamethasone-induced brain cell death. Among three drugs, rasagiline had the highest neuroprotective effect. Furthermore, the inhibitory effects of these drugs on MAO B catalytic activity and on apoptotic DNA damage (TUNEL staining) were examined. Rasagiline exhibited highest inhibition on MAO B enzymatic activity and prevention on DNA damage as compared to selegiline and 1-R-aminoindan. In summary, the greater neuroprotective effect of rasagiline may be associated with the combination of the parent drug and its metabolite 1-R-aminoindan.
...
PMID:Comparative neuroprotective effects of rasagiline and aminoindan with selegiline on dexamethasone-induced brain cell apoptosis. 1938 1


1 2 3 4 Next >>

---