High doses of testosterone increases the number of androgen receptors in muscle fibers

   What is a molecule of testosterone, you know, once again we are on the characteristics of its structure will not stop. Just recall that by virtue of these features easily aromatize testosterone, that is, converted to estradiol. Besides estrogen testosterone by the enzyme.  Reductase is easily converted to dihydrotestosterone (DHT), which means the strengthening of its androgenic properties (action on the prostate body hair and scalp, sebaceous glands, as well as increased libido), but the erosion of the cells of skeletal muscles.

   According to studies, the use of high doses of testosterone increases the number (upregulation) of androgen receptors in muscle fibers. Results from another study also deserve to play them here in full. Here they are: "anabolic steroids in combination with strength training provokes an increase in muscle size as a result of their hypertrophy, and due to the formation of new muscle fibers. The key to this, obviously, must be regarded as the activation of satellite cells, which significantly increases with high doses of steroids. " Furthermore, it was also established experimentally that the use of testosterone enanthate at a dose of only 3 mg per kg of body weight per week raises the level of growth hormone in the blood by 22% and insulin-like growth factor by 21%.

Testosterone Enanthate

       "We were the first and still the best" - this motto is the best suited drugs such as Testosterone Enanthate that are effective in the matter are different esters of testosterone. It is unlikely that today there is at least one bodybuilder, based pre-season which is not testosterone.  

     On the impact of testosterone is one of the best preparations for a set of mass, and the ratio of price / quality, and it does not equal.  

   What can I say: the king - even in Africa the king!

RNA Targets Therapeutic for the Alzheimer's Disease Amyloid Precursor Protein

 Our goal to suppress Alzheimer's APP gene expression at the translational level has the advantage that the APP 5'UTR RNA target is unique, thus affording a higher degree of selectivity.

    There are regulatory sites in the 3'UTR of APP mRNA that can be utilized as targets to suppress APP gene expression. However, our finding that the 5'UTR of APP mRNA is a powerful, translational enhancer element makes this RNA structure a very attractive target for regulating APP gene expression as a therapeutic strategy to slow AD progression.

      The vaccination strategy to target and suppress steady-state levels of A(3 peptide has been successfully developed by Elan Pharmaceuticals, who reduced later stage formation of (3-amyloid plaques, neuritic dystrophy, and astrogliosis, and other "Alzheimer's disease-like pathology" in the PDAPP transgenic mouse. RNA targeting and vaccination approaches may ultimately be complementary approaches as therapeutic strategies to help AD patients.

   Werstuck and Green  demonstrated a model system for the selection of RNA-binding compounds to inhibit translation of reporter proteins under the control of specific upstream RNA stemloops.

DNA TARGETING

       Like the use of protease inhibitors to limit APP cleavage, drug-induced down-regulation of APP-gene transcriptional control has the intrinsic problem that DNA motifs are shared with several other genes. Certainly targeting the DNA promoter sites in front of the APP gene as a therapeutic strategy for AD has the disadvantage that several genes share the common enhancer sequences that control APP gene expression. As an example, NFkB is a well-characterized transcription enhancer that controls immunoglobulin gene expression, in addition to APP gene expression, in response to inflammatory signals.

    AP-1 sites are palindromes in front of the APP gene, which bind the cJun/cFos proto-oncogenes during stress, but the presence of this site in the enhancers of several other stress-responsive genes precludes the use of this site as a therapeutic target for AD. These considerations imply that new DNA-targeting drugs will not only suppress the gene of interest (e.g., APP for AD), but will also interfere with the expression of related and essential housekeeping genes, resulting in unwanted metabolic side effects. Despite these difficulties, companies such as Abbott Laboratories  and Hoechst Marion Roussel (Ringheim et al., 1998) have explored the potential
to modulate APP gene transcription.

RNA TARGETING

       RNA Targets in HIV, Infectious Disease, and Cytokines RNA structure has become the focus for developing therapeutic strategies to regulate the expression of many disease-associated genes because any given RNA structure is unique to the gene from which it is expressed. However, the concept that RNA-directed compounds can confer a therapeutic impact is not new. For decades, antibiotics, like erythromycin, have been characterized to be bactericidal based on their capacity to bind to unique ribosomal RNA sequences in the bacterial 23S ribosome subunit. The B component of streptogramins inhibits peptide elongation in vivo during the early rounds of protein synthesis in a manner similar to that of the smaller microlides, including erythromycin. Ribotargets (Cambridge, UK) is a company that seeks to inhibit the essential TAT-Tar interaction to prevent HIV infection and AIDS.

     In this case, the TAT transactivating protein binds to the TAR stemloop at the viral LTR to promote viral growth. Blocking this interaction with selected compounds will interfere with the viral life cycle and be of therapeutic benefit. Scriptgen Inc. has a drug-discovery program directed to a single RNA target, the replication origin of hepatitis C virus. Message Pharmaceuticals (Malvern, PA), is the only company interested in diseaseassociated RNA targets of endogenously expressed genes . A major project in their program is to modulate cytokine expression as a therapeutic strategy for arthritis and cancer. Tumor necrosis factor (TNF) and interleukin-1 (IL-1) gene expression is up-regulated in the joints aof arthritis patients. Low molecular weight RNA-binding compounds can be screened for their capacity to inhibit binding of the AUF-1 to the AU-rich sequences in the 3'UTR of these cytokine mRNAs.

    Another class of drugs (CSAIDS) were previously shown to interfere with a kinase that phosphorylates the 3'UTR AUF-1, which controls cytokine mRNA stability in response to cellular signaling.

PROTEIN TARGETING

      Many existing drugs are designed to bind to the active sites and then suppress protein activities that promote the development of disease progress. For example, cocktails of protease inhibitors are used to therapeutically block hepatitis C virus infections (Fattori et al., 2000) by inactivating the viral NS3 protease (Barbato et al., 2000). Statins are low molecular-weight compounds that suppress HMG-CoA reductase activity and, thus, cholesterol synthesis, to therapeutically assist patients at risk for coronary heart disease (Penzak, Chuck, & Stajich, 2000). RNA aptmers are also used as protease inhibitors .

     There are some drawbacks to the use of viral-associated protein targets for drug selection. In the case of HIV-associated diseases, rapid genetic drift in protein sequences makes viral targets immunoevasive. Therefore, these protein sequences are less attractive targets for long-term therapeutic strategies.

 Most AD patients are currently treated with acetylcholinesterase inhibitors, which act as cognitive enhancers. Acetylcholinesterase inhibitors (e.g., Aricept, Eisai Co Ltd, Tokyo, Japan; Pfizer Inc., New York, NY) are proteintargeted inhibitors of the esterase that cleaves acetylcholine, the cholinergic neurotransmitter. These drugs slow down the rate of cognitive decline by increasing acetylcholine neurotransmitter levels in the brain (al-Jafari, Kamal, Greig, Alhomida, & Perry, 1998). The anticholinesterases provide limited improvement of cognitive performance in AD patients, and thus are of only partial benefit to AD patients early in disease progression. One problem associated with the use of anticholinesterases is that they have not been shown to confer any therapeutic action on the neuropathological events that might cause AD (i.e., amyloid, apolipoprotein E, alpha-1 antichymotrypsin, heparan sulfate proteoglycans, and the microtubule-associated protein, tau). We will discuss our discovery that a new anticholinesterase, phenserine, directly suppresses APP mRNA translation through the 5'UTR, thus imparting a therapeutic impact on A(3-peptide buildup, in addition to being an anticholinesterase (Shaw, Utsuki, Rogers, Yu, Lahiri, & Grieg, 2001). Current protein-based therapeutic approaches for AD aim to arrest the accumulation of the major amyloid plaque-associated protein, the A(3 peptide. The exact mechanism by which amyloid becomes toxic is unknown, but the presence of copper and iron and oxidative stress is a critical event (Huang et al., 1999; Bush et al., 2000). At the same time, neurotoxic protofibrils deposit in the neuritic amyloid plaques as Ap peptide is converted from an open-coil structure into a beta-sheet conformation (Kimberly, Xia, Rahmati, Wolfe, & Selkoe, 2000; Teplow, 1998; Walsh et al., 1999). Haass et al. (1992) first showed that Ap peptide is secreted from all cells in the body after being cleaved from the transmembrane APP. The elegant work of Wolfe et al. (1999) demonstrated that two transmembrane aspartates in presenilin-1 constitute the endoproteolytic peptidase conferring y-secretase activity. Thus, PS-1 mutations cause familial AD (Levy- Lahad, 1995; Scheuner et al., 1996), and PS-1 appears to function as the y-secretase that catalyzes the final cleavage of APP to Ap (Wolfe et al., 1999).

    Companies, including Bristol-Myers Squibb, have programs to screen, from large combinatorial libraries, for small molecules that can suppress the secretases (PS-1 and PS-2) that cleave APP to the 40-42 amino acid Ap peptide. One drawback of developing drugs that inhibit both (3 and y-secretase activity (and hence the generation of A(3 peptide) is that these secretases have other cellular targets. For example, the transcription factor notch is cleaved by PS-1, and it remains to be seen whether drug-induced inhibition of y-secretase will generate cytotoxic side effects associated with the disappearance of an essential downstream transcriptionally activated protein (Song et al., 1999). This concern was addressed by recent work showing that transfectants bearing PS-1 and PS-2 mutations maintain nuclear translocation of notch to the nucleus with relative preservation of notch-1 signaling (Berezovska et al., 2000). However, new protease inhibitors directed toward (3- and y-secretases may also affect other unrelated cellular targets, although this subject remains open to the development of a drug that proves the concept

Targeting an RNA Structure in the Amyloid Precursor Protein Gene as a New Therapeutic Strategy for Alzheimer's Disease

     Recently, the possibility of developing drugs that knock out the unwanted genetic function associated with unique RNA structures has led laboratories in industry and academia to screen for medicinal compounds directed to disease-associated RNA targets.

    Small molecules that influence RNA  directed activity are to be screened from large combinatorial libraries of compounds. To date, most accumulated knowledge in this field centers around the development of drugs that offer therapies against infectious diseases. For example, drug discovery related to hepatitis C virus infection targets a unique translation control signal, the internal ribosome initiation site (IRES), which is essential for the viral life cycle (Anwar, Ali, Tanveer, & Siddiqui, 2000).

   We will discuss the RNA structure formed by the 5' untranslated region (5'UTR) of the endogenous amyloid precursor protein (APP) gene (APP 5'UTR) as a therapeutic drug target for Alzheimer's disease (AD) (Figure 11.1) (Rogers et al., 1999). Interleukin-1 and iron regulate APP gene expression at the translational level through the APP 5'UTR, similar to the iron-storage protein, ferritin (Rogers, 1996, 1999). This finding is consistent with the fact that the secreted ectodomain of the precursor (APPs) binds (and probably sequesters) the neurotoxic metals, copper, and iron.