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Testosterone Replacement, Low T, HCG, & Beyond
Prostate Related Issues
Testosterone paradox of advanced prostate cancer
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<blockquote data-quote="madman" data-source="post: 241124" data-attributes="member: 13851"><p><strong>Fig. 3 | <u>Mechanisms of action of supraphysiological testosterone</u>. <u>a</u> <u>Cell-cycle regulation</u>. Supraphysiological testosterone (supraphysiological T) inhibits the transcription of MYC, which is required for cyclin and cyclin-dependent kinase-mediated passage of cells from the G1 to the S phase. Downregulation of MYC suppresses CDK2 and CyclinA activity, which prevents phosphorylation-mediated degradation of RB leading to cell-cycle arrest. Supraphysiological T also increases p21 levels through transcriptional upregulation by the androgen receptor (AR) and inhibits the expression of S-phase kinase-associated protein (SKP2), a subunit of SCF-type cullin ubiquitin ligase. Downregulation of SKP2 by supraphysiological T increases p27, which, in conjunction with p21 and p16 upregulation, causes a G1 phase arrest leading to cell death and quiescence and/or senescence. <u>b</u>, <u>Autophagy and immune activation</u>. Supraphysiological T mediates DNA double-stranded breaks (DSBs) by recruiting TOPO2B to DNA binding sites. Unrepaired DNA lesions cause apoptosis, cell-cycle arrest, or senescence. Supraphysiological T also causes induction of two parallel autophagy-mediated pathways: ferritinophagy and nucleophagy. Ferritinophagy, which involves autophagy-mediated degradation of ferritin, results in increased lipid reactive oxygen species (ROS) and ferroptotic cell death. Supraphysiological T-damaged DNA can be degraded in the autophagosomes by the process of nucleophagy. Cytoplasmic autophagosomal DNA activates a nucleic acid-sensing mechanism through STING and RIG-I. Activated STING and RIG-I signal through NF-κB and cause the release of pro-inflammatory chemokines, including CXCL10, attracting natural killer (NK) cells, T cells, macrophages, and neutrophils. DHT, dihydrotestosterone.</strong></p><p><strong>[ATTACH=full]27690[/ATTACH]</strong></p><p><strong>[ATTACH=full]27691[/ATTACH]</strong></p></blockquote><p></p>
[QUOTE="madman, post: 241124, member: 13851"] [B]Fig. 3 | [U]Mechanisms of action of supraphysiological testosterone[/U]. [U]a[/U] [U]Cell-cycle regulation[/U]. Supraphysiological testosterone (supraphysiological T) inhibits the transcription of MYC, which is required for cyclin and cyclin-dependent kinase-mediated passage of cells from the G1 to the S phase. Downregulation of MYC suppresses CDK2 and CyclinA activity, which prevents phosphorylation-mediated degradation of RB leading to cell-cycle arrest. Supraphysiological T also increases p21 levels through transcriptional upregulation by the androgen receptor (AR) and inhibits the expression of S-phase kinase-associated protein (SKP2), a subunit of SCF-type cullin ubiquitin ligase. Downregulation of SKP2 by supraphysiological T increases p27, which, in conjunction with p21 and p16 upregulation, causes a G1 phase arrest leading to cell death and quiescence and/or senescence. [U]b[/U], [U]Autophagy and immune activation[/U]. Supraphysiological T mediates DNA double-stranded breaks (DSBs) by recruiting TOPO2B to DNA binding sites. Unrepaired DNA lesions cause apoptosis, cell-cycle arrest, or senescence. Supraphysiological T also causes induction of two parallel autophagy-mediated pathways: ferritinophagy and nucleophagy. Ferritinophagy, which involves autophagy-mediated degradation of ferritin, results in increased lipid reactive oxygen species (ROS) and ferroptotic cell death. Supraphysiological T-damaged DNA can be degraded in the autophagosomes by the process of nucleophagy. Cytoplasmic autophagosomal DNA activates a nucleic acid-sensing mechanism through STING and RIG-I. Activated STING and RIG-I signal through NF-κB and cause the release of pro-inflammatory chemokines, including CXCL10, attracting natural killer (NK) cells, T cells, macrophages, and neutrophils. DHT, dihydrotestosterone. [ATTACH type="full"]27690[/ATTACH] [ATTACH type="full"]27691[/ATTACH][/B] [/QUOTE]
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Testosterone Replacement, Low T, HCG, & Beyond
Prostate Related Issues
Testosterone paradox of advanced prostate cancer
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