Steroid protein conjugates

Sex hormone-binding globulin (SHBG) is thought to mainly function as a transporter and reservoir for the estradiol and testosterone sex hormones. However it has also been demonstrated that SHBG can bind to a cell surface receptor (SHBG-R). The SHBG-R has not been completely characterized. A subset of steroids are able to bind to the SHBG/SHBG-R complex resulting in an activation of adenylyl cyclase and synthesis of the cAMP second messenger. [19] Hence the SHBG/SHBG-R complex appears to act as a transmembrane steroid receptor that is capable of transmitting signals to the interior of cells.

Glucocorticoid resistance is a serious clinical problem in chronic inflammatory diseases, because many patients with rheumatoid arthritis, asthma, or Crohn's disease fail to respond to steroid treatment. The molecular mechanisms underlying this unresponsiveness, however, are completely unknown. The effects of steroids are largely mediated by the interference of the glucocorticoid receptor (GR) with proinflammatory transcription factors. In the present study, we therefore investigated the activation of the transcription factors nuclear factor-kappaB (NF-kappaB), activator protein-1 (AP-1), and the upstream kinases p38 and c-Jun N-terminal kinase (JNK) in steroid-sensitive and steroid-resistant patients with Crohn's disease. We demonstrated that steroid-sensitive and steroid-resistant patients reveal a remarkably different cellular activation pattern of these proinflammatory mediators. In steroid-sensitive patients, activation of NF-kappaB, AP-1, p38, and JNK was mainly found in lamina propria macrophages. In contrast, steroid-resistant patients revealed activation of all these mediators mostly in epithelial cells. The functional interference of the proinflammatory mediators with the glucocorticoid response was supported by reporter gene assays. Expression of NF-kappaB and, interestingly, also JNK1 and p38 inhibited the activity of the GR. Thus, our results suggest that steroid resistance is associated with increased epithelial activation of stress-activated protein kinases and NF-kappaB, which might inhibit the anti-inflammatory action of a limited number of GRs.

Laws and Penalties:  Concerns over growing illegal AAS abuse by teenagers, and many of the just discussed long-term effects, led Congress in 1991 to place the whole AAS class of drugs into Schedule III of the Controlled Substances Act (CSA).  Under this legislation, AAS are defined as any drug or hormonal substance, chemically and pharmacologically related to T (other than estrogens, progestins, and corticosteroids) that promotes muscle growth.  The possession or sale of AAS without a valid prescription is illegal.  Since 1991, simple possession of illegally obtained AAS carry a maximum penalty of one year in prison and a minimum $1,000 fine if this is an individual’s first drug offense.  The maximum penalty for trafficking (selling or possessing enough to be suspected of selling) is five years in prison and a fine of $250,000 if this is the individual’s first felony drug offense.  If this is the second felony drug offense, the maximum period of imprisonment and the maximum fine both double.  While the above listed penalties are for federal offenses, individual states have also implemented fines and penalties for illegal use of AAS.  State executive offices have also recognized the seriousness of AAS abuse and other drugs of abuse in schools. For example, the State of Virginia enacted a law that will allow student drug testing as a legitimate school drug prevention program (48, 49).

Steroid protein conjugates

steroid protein conjugates


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