Jack L. Arbiser

Curcumin is an in vivo inhibitor of angiogenesis.

BackgroundCurcumin is a small-molecular-weight compound that is isolated from the commonly used spice turmeric. In animal models, curcumin and its derivatives have been shown to inhibit the progression of chemically induced colon and skin cancers. The genetic changes in carcinogenesis in these organs involve different genes, but curcumin is effective in preventing carcinogenesis in both organs. A possible explanation for this finding is that curcumin may inhibit angiogenesis.Materials and MethodsCurcumin was tested for its ability to inhibit the proliferation of primary endothelial cells in the presence and absence of basic fibroblast growth factor (bFGF), as well as its ability to inhibit proliferation of an immortalized endothelial cell line. Curcumin and its derivatives were subsequently tested for their ability to inhibit bFGF-induced corneal neovascularization in the mouse cornea. Finally, curcumin was tested for its ability to inhibit phorbol ester-stimulated vascular endothelial growth factor (VEGF) mRNA production.ResultsCurcumin effectively inhibited endothelial cell proliferation in a dose-dependent manner. Curcumin and its derivatives demonstrated significant inhibition of bFGF-mediated corneal neovascularization in the mouse. Curcumin had no effect on phorbol ester-stimulated VEGF production.ConclusionsThese results indicate that curcumin has direct antiangiogenic activity in vitro and in vivo. The activity of curcumin in inhibiting carcinogenesis in diverse organs such as the skin and colon may be mediated in part through angiogenesis inhibition.

Clofazimine : a review of its medical uses and mechanisms of action

Clofazimine has been in clinical use for almost 40 years, but little is known of its mechanism of action. The primary indication for clofazimine is multibacillary leprosy, but it is useful in several infectious and noninfectious diseases, such as typical myocobacterial infections, rhinoscleroma, pyoderma gangrenosum, necrobiosis lipoidica, severe acne, pustular psoriasis, and discoid lupus erythematosus. Postulated mechanisms of action include intercalation of clofazimine with bacterial DNA and increasing levels of cellular phospholipase A2. Clinical experience, possible mechanisms of action, and side effects of clofazimine are summarized.

Immortalized human adult articular chondrocytes maintain cartilage-specific phenotype and responses to interleukin-1β

OBJECTIVEnTo develop a reproducible immortalized human chondrocyte culture model for studying the regulation of chondrocyte functions relevant to arthritic diseases in adult humans.nnnMETHODSnPrimary adult articular chondrocytes were immortalized with a retrovirus expressing a temperature-sensitive mutant of SV40-large T antigen (tsTAg). The established tsT/AC62 chondrocyte cell line was examined in monolayer and alginate culture systems. The levels of messenger RNA (mRNA) encoding cartilage matrix proteins and interleukin-1beta (IL-1beta)-inducible mRNA were analyzed by reverse transcriptase-polymerase chain reaction. Matrix protein synthesis was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of 35S-sulfate-labeled proteoglycans and Western blotting of type II collagen and aggrecan. Type II collagen (COL2A1)-luciferase reporter gene expression was analyzed by transient transfection. Phosphorylated stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), p38 mitogen-activated protein kinase (p38 MAPK), and activating transcription factor 2 (ATF-2) were detected by Western blotting.nnnRESULTSnThe tsT/AC62 cells expressed TAg at the permissive temperature (32degrees C), and the loss of TAg at 37 degrees C and 39 degrees C correlated with decreased cell proliferation. Cells in alginate culture deposited abundant alcian blue-stainable matrix and continued to proliferate at 32 degrees C. Preferential retention of aggrecan was observed in the cell-associated matrix, while biglycan and decorin were secreted into the medium of monolayer and alginate cultures. The levels of COL2A1 and aggrecan mRNA were increased after transfer from monolayer to alginate culture at 32 degrees C. Treatment with IL-1beta decreased COL2A1 and aggrecan mRNA levels and increased the levels of matrix metalloproteinases 1, 3, and 13 mRNA, as well as those of cyclooxygenase 2, type I collagen, and secretory phospholipase A2 type IIA mRNA, but not those of inducible nitric oxide synthase mRNA. IL-1beta also stimulated phosphorylation of p38 MAPK, SAPK/JNK, and ATF-2. The p38 MAPK-selective inhibitor, SB203580, partially reversed IL-1beta-induced inhibition of COL2A1 mRNA levels and COL2A1-luciferase reporter gene expression.nnnCONCLUSIONnThe tsT/AC62 cells provide a reproducible model that mimics the adult articular chondrocyte phenotype, particularly in alginate culture, and demonstrates characteristic responses to IL-1beta. These studies also show, for the first time, that p38 MAPK is one of the signals required for IL-1beta-induced inhibition of COL2A1 gene expression. Availability of this model will permit identification of signals that regulate cytokine responses, and will also provide rational strategies for targeting these pathways.

Angiogenesis and the skin: A primer

Angiogenesis is the development of a blood supply to a given area of tissue. This area of tissue may be part of normal embryonic development, revascularization of a wound bed, or the stimulation of vessel growth by inflammatory or malignant cells. Angiogenesis is of crucial importance to the dermatologist, as it is of key importance in pathologic processes such as psoriasis, warts, and cutaneous malignancy, and it is required for optimal wound healing. Other dermatologic processes wherein angiogenesis is defective or uncontrolled are decubitus ulcers, stasis ulcers, pyogenic granulomas, hemangiomas, Kaposis sarcoma, and possibly Spitz nevus, hypertrophic scars, and keloids. Recent advances in the understanding of growth factors will likely lead to advances in the treatment of skin cancer and psoriasis, and more rapid healing of wounds. In this review, I hope to summarize the most important growth factors, inhibitors of angiogenesis, and future directions in research and therapeutics involving angiogenesis.

Species-specific placental corticotropin releasing hormone messenger RNA and peptide expression

The human placenta is a major site of synthesis of the hypothalamic neuropeptide corticotropin releasing hormone (CRH). We have examined placentae of several other species for expression of the CRH gene in this tissue. CRH mRNA was detected in human, gorilla, and rhesus monkey placentae, but not in rat, guinea pig and lemur placentae. A nonhuman primate may therefore be a suitable experimental model for studying placental CRH gene expression in vivo.

Human corticotropin releasing hormone gene is located on the long arm of chromosome 8

The chromosomal locus of the human corticotropin releasing hormone (hCRH) gene was assigned to chromosome 8 using Southern blot analysis of human x rodent cell hybrids and was localized to band 8q13 using in situ hybridization to metaphase chromosomes. The absence of secondary hybridization strongly suggests that hypothalamic and placental CRH are transcribed from the same gene.

Genetic immunodeficiencies: cutaneous manifestations and recent progress.

In recent years, remarkable progress has been made in elucidating the pathophysiology of genetic immunodeficiency disorders. Dermatologic manifestations are prominent in these conditions; because of advances in diagnosis and therapy, patients are living longer, increasing the likelihood that dermatologists will encounter patients with these diseases. The genes of many of these disorders have been cloned, including chronic granulomatous disease, X-linked immunodeficiencies, and myeloperoxidase deficiency. Understanding the regulation and function of these genes will not only affect patients with these rare disorders, but may provide an insight into common dermatologic conditions, such as eczema and cutaneous infection. Diagnosis, dermatologic manifestations, and therapy are discussed.

Effects of hydroxyurea and cyclic adenosine monophosphate/protein kinase A inhibitors on the expression of the human chorionic gonadotropin alpha subunit and c-myc genes in choriocarcinoma

We have previously shown that treatment of choriocarcinoma cells with methotrexate or hydroxyurea leads to both cessation of cell growth, accompanied by repression of c-myc oncogene expression, and induction of genes associated with the placental phenotype, including both subunits of human chorionic gonadotropin (hCG) and placental alkaline phosphatase. Since the genes induced by these antimetabolites are also cyclic AMP inducible, we hypothesized that these antimetabolites may cause activation of the cyclic AMP/protein kinase A pathway, suppressing genes associated with cellular proliferation and inducing placental gene expression. Three inhibitors of the cyclic AMP/protein kinase A pathway were assayed for their ability to inhibit the induction of the human chorionic gonadotropin alpha gene by hydroxyurea, and none of these inhibitors eliminated this induction. In addition, blockade of the cyclic AMP/protein kinase A pathway did not reverse the suppression of c-myc by hydroxyurea. The results of the inhibitor studies suggest that hydroxyurea acts independently of the protein kinase A pathway to stimulate gene expression, and that suppression of c-myc is insufficient to cause the induction of the human chorionic gonadotropin alpha gene by hydroxyurea.

Effects of Thallium Ion on Cellular Components of the Skin

Thallium salts have been employed by dermatologists to cause depilation, and dermatologic features are prominent in thallium overdose. These features include alopecia and follicular hyperkeratosis. Administration of thallium to pregnant animals results in limb deformities, similar to those seen after thalidomide embryopathy. These findings suggest that thallium may act on keratinocytes, melanocytes, and endothelial cells. We show that thallium exerts pleiotropic effects on proliferation, cell shape and motility of multiple cell types. These findings may help explain the clinical findings of thallotoxicosis.