Spironolactone is associated with reduced mitotane levels in adrenocortical carcinoma patients

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis. Mitotane, a derivative of the pesticide DDT, has been used successfully as first line chemotherapy since the 1960s, if maintained within a narrow therapeutic window. Spironolactone (SPL) is frequently used to treat glucocorticoid excess-associated adverse effects such as severe hypokalemia. Although data of a previous case report indicate a link, valid data regarding SPL use and mitotane plasma concentrations in a human cohort are lacking. This retrospective analysis includes data from 54 mitotane-receiving ACC patients (14 co-administered with SPL) treated between January 2005 and April 2020 (20 male, mean age 54.1 ± 2.2 yrs). All available mitotane concentrations, treatment doses, tumor stage and evidence of hormone activity were collected. Primary outcomes included mitotane levels and concentration/dose-ratios as well as time-in-range in patients with and without additional SPL treatment. The SPL group was characterized by higher glucocorticoid secretion. Other features such as tumor stage, size and anthropometrics were similar between groups. Interestingly, the SPL group had significantly lower mitotane levels despite higher doses. Mitotane time-in-range was significantly reduced in the SPL group, as was time-in-range to progression. These data provide first evidence in a human cohort for potential SPL-mitotane interactions (beyond mentioned case report), which affect dose response and may modulate treatment outcomes. This should caution clinicians to carefully adjust mitotane doses during SPL treatment in ACC patients or choose alternative therapeutic options.

Interleukin 20 receptor A expression in colorectal cancer and its clinical significance

Background Interleukin 20 receptor A (IL20RA) has been shown to play a role in the establishment and progression of multiple tumors. However, the expression of this protein in colorectal cancer (CRC) and its correlation with the clinicopathological parameters of CRC have remained unclear. Methods A total of 323 paraffin sections including CRC tissues and adjacent normal tissues after surgery were collected. IL20RA protein expression was detected by immunohistochemical staining. The difference expression of IL20RA mRNA between CRC and normal tissues was also explored in the Oncomine and GEO databases. In addition, the IL20RA-related differentially expressed genes were analyzed in TCGA database and enrichment analysis was conducted to explore the cell functions and pathways related to IL20RA expression. Results There was increased IL20RA expression in CRC compared with that in normal tissues. High IL20RA expression was associated with greater tumor diameter, lymph node metastasis, and poor TNM stage in CRC, while also being suggestive of poor prognosis. The main pathways of IL20RA-related differentially expressed genes in TCGA were protein heterodimerization activity, oxygen binding, oxygen transporter activity, hormone activity, and lipid transporter activity. Meanwhile, IL20RA-related differentially expressed genes were mainly enriched in peroxidase, nucleotide stimulant repair, fatty acid metabolism, basal transcription factor, and RNA degradation. Conclusions IL20RA might have a role as a biomarker for CRC. Its upregulation might contribute to an aggressive phenotype in CRC. IL20RA’s involvement in the development and progression of CRC might occur through it affecting fatty acid metabolism, oxygen binding, oxygen transport, and hormone activity.

The Variations of Insulin-like Growth Factor 1 Measured between Siemens Immulite, DiaSorin Liaison and IDS iSYS

Introduction/Objective Insulin-like Growth Factor 1 (IGF-1) is a biomarker for the evaluation of growth hormone activity in the hypothalamic-pituitary axis. The current most common methodology for IGF-1 measurement is automated immunometric assays. In this study, we compared the IGF-1 on Siemens Immulite 2000, DiaSorin Liaison XL and IDS iSYS. Methods/Case Report Residual 30-110 serum specimens were randomly selected from routine hospital orders. IGF- 1 was measured on these three platforms and compared with Passing-Bablok regression. Bias was evaluated using the Bland-Altman method. Results (if a Case Study enter NA) Weighted Deming regression analysis showed approximately 80% and 56% positive bias on IDS iSYS and DiaSorin Liaison, compared with Siemens Immulite (iSYS=1.81*Immulite-117.65, r=0.91; Liaison=1.56*Immulite-4.58, r=0.98). There was approximately 8% positive bias on Liaison, compared with iSYS (Liaison=1.08*iSYS+0.56, r=0.99). The Passing-Bablok regression analysis revealed approximately 67% and 54% positive bias (iSYS=1.67*Immulite-75, r=0.91; Liaison=1.54*Immulite-3.44, r=0.91). Approximately 8% positive bias on Liaison was observed, compared with iSYS (Liaison=1.08*iSYS+5.65, r=0.99). The Bland-Altman plot showed the agreement between iSYS and Immulite IGF-1 was on average 129.6±123.3 ng/mL, 98.6±148.8 ng/mL between Liaison and Immulite and 37.0±46.5 ng/mL between Liaison and iSYS. Conclusion Immunoassays rely on the specificity of antibodies. There are wide variations between different immunoassay platforms for IGF-1 measurement. The standardization of IGF-1 assay is lack. It would be a challenge for clinicians to monitor IGF-1 or treat the patients with pituitary disorders, when switching to another platform. The potential impact of the variations in IGF-1 measurement between different immunoassay platforms should be aware.

Association between thyroid cysts and hypertension by atherosclerosis status: a cross-sectional study

Our recent studies indicate that thyroid cysts have clinical implications. Thyroid cysts could have a positive effect on the supply of thyroid hormones. Both hyperthyroidism and hypothyroidism cause hypertension. Hypothyroidism, but not hyperthyroidism, is a risk factor for atherosclerosis. Therefore, thyroid cysts could be associated with hypertension, and atherosclerosis might influence the association between thyroid cysts and hypertension. To evaluate the clinical significance of thyroid cysts, a cross-sectional study was conducted with 1801 Japanese aged 40–74 years. Thyroid cysts were significantly positively associated with hypertension in participants without atherosclerosis. However, there was a significant inverse association in those with atherosclerosis. The potential confounding factor adjusted odd ratios and 95% confidence intervals (95% CIs) were 1.49 (95% CI 1.17–1.90) for participants without atherosclerosis and 0.49 (95% CI 0.24–0.98) for those with atherosclerosis. The present study demonstrates that thyroid cysts have clinical implications because thyroid cysts support thyroid hormone activity. Our findings provide sufficient evidence to develop a risk assessment for hypertension for the general population, even though further research is required.

Melatonin influences the early growth stage in Zoysia japonica Steud. by regulating plant oxidation and genes of hormones

Zoysia japonica is a commonly used turfgrass species around the world. Seed germination is a crucial stage in the plant life cycle and is particularly important for turf establishment and management. Experiments have confirmed that melatonin can be a potential regulator signal in seeds. To determine the effect of exogenous melatonin administration and explore the its potential in regulating seed growth, we studied the concentrations of several hormones and performed a transcriptome analysis of zoysia seeds after the application of melatonin. The total antioxidant capacity determination results showed that melatonin treatment could significantly improve the antioxidant capacity of zoysia seeds. The transcriptome analysis indicated that several of the regulatory pathways were involved in antioxidant activity and hormone activity. The hormones concentrations determination results showed that melatonin treatment contributed to decreased levels of cytokinin, abscisic acid and gibberellin in seeds, but had no significant effect on the secretion of auxin in early stages. Melatonin is able to affect the expression of IAA (indoleacetic acid) response genes. In addition, melatonin influences the other hormones by its synergy with other hormones. Transcriptome research in zoysia is helpful for understanding the regulation of melatonin and mechanisms underlying melatonin-mediated developmental processes in zoysia seeds.

Lupeol Accumulation Correlates with Auxin in the Epidermis of Castor

Lupeol, a natural lupane-type pentacyclic triterpene, possesses various pharmacological properties, and its production attracts attention. Significant quantities of lupeol are deposited on the castor aerial organ surface and are easily extractable as a predominant wax constituent. Thus, castor might be considered as a potential bioreactor for the production of lupeol. The lupeol biosynthesis pathway is well known, but how it is regulated remains largely unknown. Among large numbers of castor cultivars, we targeted one accession line (337) with high levels of lupeol on its stem surface and low levels thereof on its hypocotyl surface, implicating that lupeol synthesis is differentially regulated in the two organs. To explore the underlying mechanisms, we did comparative transcriptome analysis of the first internode of 337 stem and the upper hypocotyl. Our results show that large amounts of auxin-related genes are differentially expressed in both parts, implying some possible interactions between auxin and lupeol production. We also found that several auxin-responsive cis-elements are present in promoter regions of HMGR and LUS genes encoding two key enzymes involved in lupeol production. Furthermore, auxin treatments apparently induced the expression levels of RcHMGR and RcLUS. Furthermore, we observed that auxin treatment significantly increased lupeol contents, whereas inhibiting auxin transport led to an opposite phenotype. Our study reveals some relationships between hormone activity and lupeol synthesis and might provide a promising way for improving lupeol yields in castor.

Dynamic Remodeling of Membranes and Their Lipids during Acute Hormone-Induced Steroidogenesis in MA-10 Mouse Leydig Tumor Cells

Lipids play essential roles in numerous cellular processes, including membrane remodeling, signal transduction, the modulation of hormone activity, and steroidogenesis. We chose steroidogenic MA-10 mouse tumor Leydig cells to investigate subcellular lipid localization during steroidogenesis. Electron microscopy showed that cAMP stimulation increased associations between the plasma membrane (PM) and the endoplasmic reticulum (ER) and between the ER and mitochondria. cAMP stimulation also increased the movement of cholesterol from the PM compared to untreated cells, which was partially inhibited when ATPase family AAA-domain containing protein 3 A (ATAD3A), which functions in ER and mitochondria interactions, was knocked down. Mitochondria, ER, cytoplasm, PM, PM-associated membranes (PAMs), and mitochondria-associated membranes (MAMs) were isolated from control and hormone-stimulated cells. Lipidomic analyses revealed that each isolated compartment had a unique lipid composition, and the induction of steroidogenesis caused the significant remodeling of its lipidome. cAMP-induced changes in lipid composition included an increase in phosphatidylserine and cardiolipin levels in PAM and PM compartments, respectively; an increase in phosphatidylinositol in the ER, mitochondria, and MAMs; and a reorganization of phosphatidic acid, cholesterol ester, ceramide, and phosphatidylethanolamine. Abundant lipids, such as phosphatidylcholine, were not affected by hormone treatment. Our data suggested that PM–ER–mitochondria tethering may be involved in lipid trafficking between organelles and indicated that hormone-induced acute steroid production involves extensive organelle remodeling.

Skeletal muscle hormone activity and non-alcoholic fatty liver disease

Currently, a large number of studies have been published supplementing our knowledge of sarcopenia and its effect on the development of metabolic disorders, including the formation of non-alcoholic fatty liver disease (NAFLD). This data allows a new look at the pharmacological and non-pharmacological ap proaches to the treatment of NAFLD, based on basic physiological processes, including the biological axis the ′muscle – the liver′. This provides a compelling rationale for studying skeletal muscle as the main therapeutic target for NAFLD and metabolic syndrome.