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tions of extreme stress. Rapid turnover of HA in the normal state indicates constant synthesis and degradation. Inhibition of degradation would provide a far swifter response to the sudden demand for increased HA levels, than increasing the rate of HA synthesis. The ability to provide quickly high HA levels is a survival mechanism for the organism. This might explain the apparent inefficiency for the rapid rates of HA turnover that occur in the vertebrate animal under basal conditions. It can be compared to the need to suddenly drive an automobile much faster in the case of an emergency, not by stepping on the accelerator, but by taking a foot off the break.

If inhibition of HA degradation by hyaluronidase occurs, then a class of molecules that have not been explored, the hyaluronidase inhibitors, are very important. It can be postulated that with extreme stress, hyaluronidase inhibitors would be found in the circulation as acute phase proteins, the stress response products synthesized by the liver. These would prevent the ever present rapid destruction and allow levels of HA to quickly increase.

Circulating hyaluronidase inhibitor activity has been identified in human serum over half a century ago (144,145). Modifications in levels of inhibitor activity have been observed in the serum of patients with cancer (146,147), liver disease (148), and with certain dermatological disorders (149). This area of biology is unexplored, and though some early attempts were made (150-152), and even though a review appeared (153), these hyaluronidase inhibitors have never been isolated nor characterized at the molecular level.

Inhibitors of mammalian origin, such as the serum inhibitor or heparin, are far more potent than the rather mild inhibitors of plant origin. Hyaluronidase inhibitors of animal origin would provide a means for enhancing levels of HA in skin, and represent an important research area in attempting to enhance skin moisture.

Low Molecular Weight Inhibitors

Classes of lower molecular weight inhibitors of hyaluronidase have been identified, some of which come from folk medicines, from the growing field of ethno-pharmacology. Some anti-inflammatories as well as some of the ancient beauty aids and practices for freshening of the skin may have as the basis of their mechanism of action, some of these compounds.

Those that have been identified in recent times include flavonoids (154- -g

156), aurothiomalate (157), hydrangenol (158), occurring in the leaves of Hydran- |

gea, tannins (159), derivatives of tranilast (160), curcumin (161), an extract of |

the spice turmeric, glycyrrhizin (162), found in the roots and rhizomes of licorice -c

(Glycyrrhiza glabra L.), used as an effective anti-inflammatory agent used in <

Chinese medicine.

Clinically, heparin used as an anticoagulant, has potent antihyaluronidase

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