Steroid secreting cell organelles

Results : Autophagy took place in normal steroid-secreting cells with higher frequencies than in many other cells including the tubular cells of kidney and hepatocytes. The large number of autophagosomes or autophagic vacuoles allowed to outline the autophagic process in these cells. The C-shaped double-membrane profiles tending to demacate a portion of cytoplasm were referred to as pre-autophagosomes. So called early autophagosomes were the vacuoles enclosed completely by double delimiting membranes, containing normal-looking cellular components. The majority of sequestered organelles appeared to be mitochondria and smooth endoplasmic reticulum. The autophagosomes starting digestion were considered as late autophagosomes or autophagic vacuoles, the indications of which were the destruction of their contents or the presence of lysosomal enzymes demonstrated by a positive CMPase reaction. Residual bodies were frequently observed to be exocytosed. The quantitative assay revealed an alteration of autophagic activity in close relation with steroid-secreting states. The number of autophagosomes was one-fold higher in hyposecreting Leydig cells after 2 days testosterone administration, and three-fold higher in hyposecreting adrenocortical fasciculata cells after one dosage of dexamethasone administration. In addition, the autophagosomes showed a four-fold decrease in hypesecreting Leydig cells stimulated by LRH for 2 days.

Mitogenic function of E-ER relies on the presence of sufficient supply of nutrients such as glucose, because E-ER signaling also promotes the glycolysis and Krebs cycling [ 75 ]. A recent work, however, reported that estrogen up-regulates glycolysis via activation of PI3K-AKT signaling pathway, promotes cell proliferation under high glucose condition and represses Krebs cycle simultaneously [ 76 , 77 ]. This is similar to the situation in proliferating cancer cells that consume glucose and rely on glycolysis over Krebs cycle in generating ATP, which is termed as “Warburg effect” [ 78 ]. However, when the extracellular glucose decreases, estrogen treatment activates mitochondria respiration via up-regulating PDH (pyruvate dehydrogenase) activity and repressing glycolysis [ 76 ], suggesting estrogen's effect on cell metabolism is adaptable and is under control of glucose availability. In the scenarios of cancer prone condition, glucose is frequently enriched. Estrogen probably promotes the cell proliferation by stimulating the anabolic metabolism. In fact, release of glycolysis proteins into plasma precedes the diagnosis of ER + breast carcinoma [ 79 ], suggesting E-ER signaling promoted glycolysis is a very early event that associates with tumorigenesis. It was shown that the genes maximally induced by estrogen treatment after relatively long time (160 mins) incubation have the top hit of GO (gene ontology) term “cellular biosynthetic process” by ontology analysis [ 67 ]. These observations indicate E-ER signaling plays an important role in promoting tumor growth. But the E-ER signaling may also have its own risk management strategy because BRCA1 is responsive to E-ER signaling, and the response of BRCA1 needs to be mediated by CtBP and the cell metabolite NADH [ 65 ]. Estrogen was found to be able to activate tumor suppressor gene expression via manipulation of the cellular metabolism status globally [ 65 ]. Although BRCA1 function in regulating cell metabolism pathways has just been realized, several recent findings suggested that BRCA1 is a negative regulator of anabolic cell metabolism. BRCA1 has been shown to negatively regulate Igf-1 expression and mediate phosphorylated AKT degradation [ 80 , 81 ]. Also, BRCA1 directly inhibits ACC (acetyl-CoA carboxylase) by interacting with it [ 82 ]. ACC catalyzes the converting of Acetyl-CoA to malonyl-CoA during fatty acid synthesis which is essential for tumor cell growth [ 83 ]. Since de novo fatty acid synthesis frequently associates with cancer cell growth, and probably the EMT, it suggests BRCA1 has novel tumor repressor function by controlling fatty acids metabolism. Thus, E-ER activated BRCA1 expression forms an important negative regulatory feedback that slows down the anabolic process promoted by E-ER.

A 36-year-old woman with central diabetes insipidus (DI), diagnosed when she was 7, was referred to our Endocrine Unit in January 1993 for further hormonal investigations. Clinical and laboratory findings confirmed the diagnosis of central DI. Cranial computed tomography and magnetic resonance imaging showed only an empty sella. Moreover, we noted impaired glucose tolerance and unusual findings of subclinical adrenocortical failure, . high plasma renin activity with normal aldosterone levels, high ACTH despite normal basal and ACTH-stimulated cortisol levels. Immunological study of the patient’s serum showed the presence of arginine vasopressin (AVP)-secreting cell antibodies (Abs), steroid-producing cell Abs, adrenal and islet cell Abs. The following aspects of our case are stressed and discussed: (1) the presence of AVP-secreting cell Abs 29 years after the diagnosis of DI; (2) the association between DI, empty sella and subclinical autoimmune adrenocortical failure with unusual hormonal findings, and (3) impaired glucose tolerance with islet cell antibody positivity.

Most recently, treatment with IL-6 blockade has been gaining favor for patients with relapsing disease. Studies have documented elevated serum levels of IL-6 in patients with PMR, and these levels appear to correlate with disease activity, inflammatory markers, and response to prednisone. 11 Accordingly, use of tocilizumab, a humanized monoclonal antibody against the IL-6 receptor, has been tried and reported in four patients with pure PMR, with promising results. 22–25 At doses of 8 mg/kg once monthly, three of four patients entered clinical remission, and two achieved remission without concomitant use of prednisone. 23,25 Interestingly, one patient did not have a clinical response, despite complete normalization of inflammatory markers, with tocilizumab, and remission was subsequently achieved with reinstitution of glucocorticoids. 24 This case highlights the concern that when IL-6 is blocked for therapeutic reasons, inflammatory markers may no longer be reliable for assessment of disease activity. At this point, further study of tocilizumab in PMR is warranted.

Steroid secreting cell organelles

steroid secreting cell organelles

Most recently, treatment with IL-6 blockade has been gaining favor for patients with relapsing disease. Studies have documented elevated serum levels of IL-6 in patients with PMR, and these levels appear to correlate with disease activity, inflammatory markers, and response to prednisone. 11 Accordingly, use of tocilizumab, a humanized monoclonal antibody against the IL-6 receptor, has been tried and reported in four patients with pure PMR, with promising results. 22–25 At doses of 8 mg/kg once monthly, three of four patients entered clinical remission, and two achieved remission without concomitant use of prednisone. 23,25 Interestingly, one patient did not have a clinical response, despite complete normalization of inflammatory markers, with tocilizumab, and remission was subsequently achieved with reinstitution of glucocorticoids. 24 This case highlights the concern that when IL-6 is blocked for therapeutic reasons, inflammatory markers may no longer be reliable for assessment of disease activity. At this point, further study of tocilizumab in PMR is warranted.

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