A novel chemically modified curcumin reduces inflammation-mediated connective tissue breakdown in a rat model of diabetes: periodontal and systemic effects.

BACKGROUND AND OBJECTIVE: Periodontal disease is the most common chronic inflammatory disease known to mankind (and the major cause of tooth loss in the adult population) and has also been linked to various systemic diseases, particularly diabetes mellitus. Based on the literature linking periodontal disease with diabetes in a "bidirectional manner", the objectives of the current study were to determine: (i) the effect of a model of periodontitis, complicated by diabetes, on mechanisms of tissue breakdown including bone loss; and (ii) the response of the combination of this local and systemic phenotype to a novel pleiotropic matrix metalloproteinase inhibitor, chemically modified curcumin (CMC) 2.24. MATERIAL AND METHODS: Diabetes was induced in adult male rats by intravenous injection of streptozotocin (nondiabetic rats served as controls), and Escherichia coli endotoxin (lipopolysaccharide) was repeatedly injected into the gingiva to induce periodontitis. CMC 2.24 was administered by oral gavage (30 mg/kg) daily; untreated diabetic rats received vehicle alone. After 3 wk of treatment, the rats were killed, and gingiva, jaws, tibia and skin were collected. The maxillary jaws and tibia were dissected and radiographed. The gingival tissues of each experimental group (n = 6 rats/group) were pooled, extracted, partially purified and, together with individual skin samples, analyzed for matrix metalloproteinase (MMP)-2 and MMP-9 by gelatin zymography; MMP-8 was analyzed in gingival and skin tissue extracts, and in serum, by western blotting. The levels of three bone-resorptive cytokines [interleukin (IL)-1ß, IL-6 and tumor necrosis factor-α], were measured in gingival tissue extracts and serum by ELISA. RESULTS: Systemic administration of CMC 2.24 to diabetic rats with endotoxin-induced periodontitis significantly inhibited alveolar bone loss and attenuated the severity of local and systemic inflammation. Moreover, this novel tri-ketonic phenylaminocarbonyl curcumin (CMC 2.24) appeared to reduce the pathologically excessive levels of inducible MMPs to near-normal levels, but appeared to have no significant effect on the constitutive MMPs required for physiologic connective tissue turnover. In addition to the beneficial effects on periodontal disease, induced both locally and systemically, CMC 2.24 also favorably affected extra-oral connective tissues, skin and skeletal bone. CONCLUSION: This study supports our hypothesis that CMC 2.24 is a potential therapeutic pleiotropic MMP inhibitor, with both intracellular and extracellular effects, which reduces local and systemic inflammation and prevents hyperglycemia- and bacteria-induced connective tissue destruction.

Effect of retinoids on follicular cells.

It has been demonstrated that topical application of all-trans retinoic acid and other retinoids can alter the hair-growth cycle in the C3H mouse model. The anagen phase is prolonged and the telogen phase is shortened. This effect is similar to the effect of minoxidil on the hair-cycle dynamics in this animal model. The levels of cellular retinoic acid binding protein measured by radioreceptor assay in whole skin of C3H mice were higher during anagen and lower during telogen. Topical application of certain retinoids caused elevated levels of cellular retinoic acid-binding protein (cRABP) in the whole skin homogenates during both phases of the cycle. Of the retinoids tested, those most effective in altering the levels of cRABP in the skin of the mice were also capable of significantly altering the hair-cycle dynamics. There appeared to be a relationship between the ability of retinoid to increase cRABP, increase 3H-thymidine incorporation, and alter the dynamics of the hair cycle. Only cRABP-II is detectable in human cultured dermal fibroblasts and dermal papilla cells. Dermal fibroblasts showed higher amounts of cRABP-II as compared to dermal papilla cells. The difference in cRABP-II expression might explain a distinct response to RA by these two cell populations. Whether the difference in expression of cRABP-II might be of physiologic importance remains to be determined. Treatment of human dermal papilla cells in culture with retinoic acid does not appear to affect proliferation, at least at the doses tested.

Embolic and metastatic cardiac myxoma.

This paper presents a case of a cardiac myxoma with cutaneous emboli. The diagnosis of a cardiac lesion was anticipated after the histologic examination of a skin lesion. The first clue to the existence of a cardiac myxoma was a distinctive intravascular lesion of a dermal vessel. The clinical and pathologic features of cardiac myxoma are discussed. In addition, new evidence regarding the nature of a previously reported case of metastasizing cardiac myxoma is also presented.

Retinoids: compounds important to hair growth.

Although the mechanisms of follicular regression in androgenetic alopecia are not fully understood, retinoids may be important in changing the status of regressing follicles. There are many reports documenting reversal of epithelial dysplastic changes with retinoids. Although none of the studies with retinoids have concentrated on the precise mechanisms of follicular growth (regression or regeneration), these limited observations, and our early studies suggest that further work should be done on the effect retinoids have on the hair follicle during the various growth and regression phases of the follicular life cycle in humans. We propose that certain retinoids increase the rate of hair growth, prolong the anagen phase of the hair cycle, play a role in converting vellus to terminal hairs, and act synergistically with minoxidil to produce more dense hair regrowth from regressing follicles than either compound alone. Larger controlled studies and better methods for assessing hair growth are necessary to support these early results. Other retinoids as well as certain minoxidil analogs should also be studied.

Topical tretinoin for hair growth promotion.

Topical all-trans-retinoic acid (tretinoin) alone and in combination with 0.5% minoxidil has been tested for the promotion of hair growth in 56 subjects with androgenetic alopecia. After 1 year, the combination of topical tretinoin with 0.5% minoxidil resulted in terminal hair regrowth in 66% of the subjects studied. Tretinoin was shown to stimulate some hair regrowth in approximately 58% of the subjects studied. One female subject with pronounced alopecia for more than 20 years had regrowth of hair using only tretinoin for a period of 18 months. Tretinoin has been shown to promote and regulate cell proliferation and differentiation in the epithelium and may promote vascular proliferation. These factors are important for hair growth promotion. These preliminary results indicate that more work should be done on the role of retinoids in hair growth. The synergistic effect of retinoids in combination with a low concentration of minoxidil should also be further investigated.