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Sacramento, CA, United States

Silverberg J.I.,St Lukes Roosevelt Hospital Center | Patel M.,New York University | Brody N.,New York University | Jagdeo J.,New York University | And 2 more authors.
Journal of Drugs in Dermatology | Year: 2012

Oxidative damage by reactive oxygen species (ROS) plays a major role in aging and carcinogenesis. Little is known about either the effects of acute ROS in necrosis and inflammation of skin or the therapeutic agents for prevention and treatment. Previously, our laboratory identified caffeine as an inhibitor of hydrogen peroxide (H 2O2)-generated lipid peroxidation products in human skin fibroblasts. Here, we study effects of caffeine on acute ROS-mediated necrosis. Human skin fibroblasts were incubated with caffeine, followed by H2O2 challenge. Flow cytometry was used to analyze cell morphology, counts, apoptosis and necrosis, and ROS. We found that caffeine protects from H2O2 cell damage at lower (0.01 mM) and intermediate (0.1 mM) doses. The beneficial effects of caffeine appear to be mediated by a mechanism other than antioxidant function. Copyright © 2012 Journal of Drugs in Dermatology.

Wang A.S.,University of California at Davis | Barr K.L.,University of California at Davis | Jagdeo J.,University of California at Davis | Jagdeo J.,Sacramento Veterans Affairs Medical Center | Jagdeo J.,SUNY Downstate Medical Center
Dermatology Online Journal | Year: 2013

Ingestion of raw or undercooked shiitake mushrooms is associated with a distinctive flagellate erythema. We describe a 61-year-old Caucasian man who presented with a pruritic, erythematous eruption of multiple linear streaks on the trunk and extremities starting 1 day after eating raw shiitake mushrooms. His symptoms and skin lesions resolved with minimal hyperpigmentation within approximately 1 week after treating with topical steroids and oral antihistamines. Skin biopsy showed non-specific findings, including a sparse perivascular and interstitial dermatitis as well as focal vacuolar interface changes. Our case illustrates that this condition is a visibly striking dermatitis with a self-limited course. The pathomechanism of the skin eruption remains unclear. © 2013 Dermatology Online Journal.

Ishimaru T.,University of California at Davis | Lau J.,University of California at Davis | Jackson A.L.,University of Minnesota | Modiano J.F.,University of Minnesota | Weiss R.H.,Sacramento Veterans Affairs Medical Center
Journal of Urology | Year: 2010

Purpose We evaluated the effect of roscovitine (Sigma-Aldrich®), a pharmacological inhibitor of cyclin dependent kinase, on renal cell carcinoma cell lines in vitro. Materials and Methods We exposed several renal cell carcinoma cell lines to roscovitine and examined apoptotic signaling pathways using immunoblotting and immunohistochemistry. Results As expected, roscovitine caused dose and time dependent inhibition of cyclin dependent kinase 2 autophosphorylation, and of cyclin dependent kinase mediated Pol II phosphorylation in the ACHN (p53-wt) and 786-O (p53 inactive) renal cell carcinoma cell lines (ATCC®). Roscovitine also induced apoptosis in each cell line within a narrow concentration range (about 10 μg/ml). Apoptosis induction was more efficient in ACHN than in 786-O cells and at least partly due to p53 activity. In ACHN cells roscovitine induced apoptosis was associated with p21 induction, and decreased Akt1, XIAP and phospho-Rb expression. These changes also depended on p53 and were not present (p21) or showed a different dose pattern (Akt1, XIAP and phospho-Rb) in 786-O cells. Partial restoration of roscovitine induced apoptosis in 786-O cells by the Mdm-2 inhibitor nutlin-3 (Sigma-Aldrich) suggests that the inactivating mutation of VHL in these cells and its destabilizing effect on p53 are responsible for the decreased sensitivity to apoptosis. Conclusions Our data extend previous studies documenting the pro-apoptotic effect of roscovitine and to our knowledge show for the first time that this activity is restricted to a narrow dose range in renal cell carcinoma cells and partly depends on p53. Thus, roscovitine is a novel potential chemotherapy in a subset of patients with renal cell carcinoma if a narrow therapeutic window is used. These data also provide insight into the role of VHL mutation and p53 in the renal cell carcinoma response to therapeutic cyclin dependent kinase manipulation. © 2010 American Urological Association Education and Research, Inc.

Taylor S.L.,University of California at Davis | Ganti S.,University of California at Davis | Bukanov N.O.,Genzyme | Chapman A.,Emory University | And 5 more authors.
American Journal of Physiology - Renal Physiology | Year: 2010

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease and affects 1 in 1,000 individuals. Ultrasound is most often used to diagnose ADPKD; such a modality is only useful late in the disease after macroscopic cysts are present. There is accumulating evidence suggesting that there are common cellular and molecular mechanisms responsible for cystogenesis in human and murine PKD regardless of the genes mutated, and, in the case of complex metabolomic analysis, the use of a mouse model has distinct advantages for proof of principle over a human study. Therefore, in this study we utilized a urinary metabolomics-based investigation using gas chromatography-time of flight mass spectrometry to demonstrate that the cystic mouse can be discriminated from its wild-type counterpart by urine analysis alone. At day 26 of life, before there is serological evidence of kidney dysfunction, affected mice are distinguishable by urine metabolomic analysis; this finding persists through 45 days until 64 days, at which time body weight differences confound the results. Using functional score analysis and the KEGG pathway database, we identify several biologically relevant metabolic pathways which are altered very early in this disease, the most highly represented being the purine and galactose metabolism pathways. In addition, we identify several specific candidate biomarkers, including allantoic acid and adenosine, which are augmented in the urine of young cystic mice. These markers and pathway components, once extended to human disease, may prove useful as a noninvasive means of diagnosing cystic kidney diseases and to suggest novel therapeutic approaches. Thus, urine metabolomics has great diagnostic potential for cystic renal disorders and deserves further study. Copyright © 2005 by the American Physiological Society.

Inoue H.,University of California at Davis | Kauffman M.,Karyopharm Therapeutics | Shacham S.,Karyopharm Therapeutics | Landesman Y.,Karyopharm Therapeutics | And 4 more authors.
Journal of Urology | Year: 2013

Purpose: Renal cell carcinoma often presents asymptomatically and patients are commonly diagnosed at the metastatic stage, when treatment options are limited and survival is poor. Since progression-free survival using current therapy for metastatic renal cell carcinoma is only 1 to 2 years and existing drugs are associated with a high resistance rate, new pharmacological targets are needed. We identified and evaluated the nuclear exporter protein CRM1 as a novel potential therapy for renal cell carcinoma. Materials and Methods: We tested the efficacy of the CRM1 inhibitors KPT-185 and 251 in several renal cell carcinoma cell lines and in a renal cell carcinoma xenograft model. Apoptosis and cell cycle arrest were quantified and localization of p53 family proteins was assessed using standard techniques. Results: KPT-185 attenuated CRM1 and showed increased cytotoxicity in renal cell carcinoma cells in vitro with evidence of increased apoptosis as well as cell cycle arrest. KPT-185 caused p53 and p21 to remain primarily in the nucleus in all renal cell carcinoma cell lines, suggesting that the mechanism of action of these compounds depends on tumor suppressor protein localization. Furthermore, when administered orally in a high grade renal cell carcinoma xenograft model, the bioavailable CRM1 inhibitor KPT-251 significantly inhibited tumor growth in vivo with the expected on target effects and no obvious toxicity. Conclusions: The CRM1 inhibitor protein family is a novel therapeutic target for renal cell carcinoma that deserves further intensive investigation for this and other urological malignancies. © 2013 American Urological Association Education and Research, Inc.

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