| 31. |
- Velentza, Lilly, et al.
(författare)
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Humanin Treatment Protects Against Venetoclax-Induced Bone Growth Retardation in Ex Vivo Cultured Rat Bones
- 2024
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Ingår i: JOURNAL OF THE ENDOCRINE SOCIETY. - 2472-1972. ; 8:3
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Tidskriftsartikel (refereegranskat)abstract
- Context Recent preclinical studies reported that the BCL-2 inhibitor venetoclax can impair bone growth. A strategy to prevent such a side effect of this promising anticancer drug is highly desired. Earlier in vitro and in vivo studies suggested that the mitochondrial peptide humanin has the potential to prevent drug-induced growth impairment.Objective We hypothesized that co-treatment with the humanin analog HNG may prevent venetoclax-induced bone growth impairment.Methods Ex vivo studies were performed in fetal rat metatarsal bones and human growth plate samples cultured for 12 and 2 days, respectively, while in vivo studies were performed in young neuroblastoma mice being treated daily for 14 days. The treatment groups included venetoclax, HNG, venetoclax plus HNG, or vehicle. Bone growth was continuously monitored and at the end point, histomorphometric and immunohistochemical analyses were performed in fixed tissues.Results Venetoclax suppressed metatarsal bone growth and when combined with HNG, bone growth was rescued and all histological parameters affected by venetoclax monotherapy were normalized. Mechanistic studies showed that HNG downregulated the pro-apoptotic proteins Bax and p53 in cultured metatarsals and human growth plate tissues, respectively. The study in a neuroblastoma mouse model confirmed a growth-suppressive effect of venetoclax treatment. In this short-term in vivo study, no significant bone growth-rescuing effect could be verified when testing HNG at a single dose. We conclude that humanin dose-dependently protects ex vivo cultured metatarsal bones from venetoclax-induced bone growth impairment by restoring the growth plate microstructure.
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| 32. |
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| 33. |
- Wide, Leif, et al.
(författare)
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Low- and Fully N-Glycosylated Gonadotropins Circulating in Women With Polycystic Ovary Syndrome
- 2021
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Ingår i: Journal of the Endocrine Society. - : ENDOCRINE SOC. - 2472-1972. ; 5:7
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Tidskriftsartikel (refereegranskat)abstract
- Context: A preponderance of basic luteinizing hormone (LH) molecules having elevated bioactivity was detected in the circulation of women with polycystic ovary syndrome (PCOS). Subsequent studies have shown that LH and follicle-stimulating hormone (FSH) both circulate as glycoforms differing in number of glycans: low-N-glycosylated glycoforms, LHdi and FSHtri, with high in vitro bioactivity, and fully glycosylated glycoforms, LHtri and FSHtetra, with high in vivo bioactivity.Objective: This work aims to characterize the glycosylation patterns on circulating gonadotropin glycoforms in women with PCOS.Methods: Serum samples, collected from 8 women with PCOS were included. The concentration, sulfonation, and sialylation of each glycoform were determined and compared with values of serum samples from healthy women: 22 women at follicular phase, 16 at midcycle, and 15 after menopause.Results: All the women with PCOS had higher LHdi serum levels compared with those in the follicular-phase group. Median LHdi and median LHtri levels were significantly elevated in PCOS women. The percentage of LHdi was increased from 37 to 49 and that of FSHtri was decreased from 41 to 33. The LHdi, LHtri, and FSHtetra glycoforms were more sialylated and both LH glycoforms less sulfonated in women with PCOS.Conclusion: All women with PCOS had increased serum levels of LHdi, compared with those in the follicular phase. The percentage of LHdi was increased and that of FSHtri decreased in women with PCOS. The increased LHdi leads to maintenance of the abnormal early follicular development of the polycystic ovary, and the decreased FSHtri contributes to the arrested follicle growth.
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| 34. |
- Wide, Leif, et al.
(författare)
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Thyrotropin N-glycosylation and Glycan Composition in Severe Primary Hypothyroidism
- 2021
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Ingår i: Journal of the Endocrine Society. - : Endocrine Society. - 2472-1972. ; 5:4
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Tidskriftsartikel (refereegranskat)abstract
- Context: In severe primary hypothyroidism (sPH), the serum thyrotropin (TSH) levels are elevated with an increased degree of sialylation. The circulating TSH comprises 2 different TSH glycoforms: TSHdi with 2 and TSHtri with 3 N-glycans and methods have developed to determine their contents of anionic monosaccharides (AMS), that is, sialic acid (SA) and sulfonated N-acetylglactosamine (SU) residues.Objective: Characterize N-glycosylation and glycan composition of circulating TSH molecules and determine the effects during levothyroxine treatment in patients with sPH.Methods: Serum samples were obtained from 25 patients with sPH, from 159 euthyroid individuals, and from 12 women during treatment with levothyroxine for sPH. Degrees of N-glycosylation and concentrations of TSHdi and TSHtri as well as their contents of AMS, SA, and SU residues were determined. Results: The circulating TSH molecules in sPH patients had lower degrees of N-glycosylation, higher degrees of sialylation, and lower degrees of sulfonation than in euthyroid individuals. Levothyroxin restored sialylation and sulfonation of the glycans already at low free thyroxine (FT4) levels, while degree of N-glycosylation was not restored until the FT4 levels were normal.Conclusions: The majority of TSH molecules in severe primary hypothyroidism were less N- glycosylated, more sialylated, and less sulfonated compared with euthyroid individuals. This glycan pattern favors a prolonged half-life in the circulation combined with lower in vitro biopotency at the target cells. During levothyroxine treatment of sPH patients, the sialylation and sulfonation of glycans were restored already at low FT4 levels, while N-glycosylation of TSH was not restored until the FT4 levels were normal.
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| 35. |
- Yuan, Shuai, et al.
(författare)
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Physical Activity, Sedentary Behavior, and Type 2 Diabetes : Mendelian Randomization Analysis
- 2023
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Ingår i: Journal of the Endocrine Society. - : Endocrine Society. - 2472-1972. ; 7:8
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Tidskriftsartikel (refereegranskat)abstract
- Context The causality and pathways of the associations between physical activity and inactivity and the risk of type 2 diabetes remain inconclusive. Objective We conducted an updated mendelian randomization (MR) study to explore the associations of moderate-to-vigorous physical activity (MVPA) and leisure screen time (LST) with type 2 diabetes mellitus (T2DM). Methods Genetic variants strongly associated with MVPA or LST with low linkage disequilibrium were selected as instrumental variables from a genome-wide meta-analysis including more than 600 000 individuals. Summary-level data on T2DM were obtained from the DIAbetes Genetics Replication And Meta-analysis consortium including 898 130 individuals. Data on possible intermediates (adiposity indicators, lean mass, glycemic traits, and inflammatory biomarkers) were extracted from large-scale genome-wide association studies (n = 21 758-681 275). Univariable and multivariable MR analyses were performed to estimate the total and direct effects of MVPA and LST on T2DM. Methylation MR analysis was performed for MVPA in relation to diabetes. Results The odds ratio of T2DM was 0.70 (95% CI, 0.55-0.88; P = .002) per unit increase in the log-odds ratio of having MVPA and 1.45 (95% CI, 1.30-1.62; P = 7.62 x 10(-11)) per SD increase in genetically predicted LST. These associations attenuated in multivariable MR analyses adjusted for genetically predicted waist-to-hip ratio, body mass index, lean mass, and circulating C-reactive protein. The association between genetically predicted MVPA and T2DM attenuated after adjusting for genetically predicted fasting insulin levels. Two physical activity-related methylation biomarkers (cg17332422 in ADAMTS2 and cg09531019) were associated with the risk of T2DM (P < .05). Conclusion The study suggests causal associations of MVPA and LST with T2DM that appear to be mediated by obesity, lean mass, and chronic low-grade inflammation.
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| 36. |
- Zoeller, R. Thomas, 1952-, et al.
(författare)
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European Medicines Agency Conflicts With the European Food Safety Authority (EFSA) on Bisphenol A Regulation
- 2023
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Ingår i: Journal of the Endocrine Society. - : Oxford University Press. - 2472-1972. ; 7:9
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Tidskriftsartikel (refereegranskat)abstract
- The European Food Safety Authority (EFSA) has revised their estimate of the toxicity of bisphenol A (BPA) and, as a result, have recommended reducing the tolerable daily intake (TDI) by 20 000-fold. This would essentially ban the use of BPA in food packaging such as can liners, plastic food containers, and in consumer products. To come to this conclusion, EFSA used a systematic approach according to a pre-established protocol and included all guideline and nonguideline studies in their analysis. They found that Th-17 immune cells increased with very low exposure to BPA and used this endpoint to revise the TDI to be human health protective. A number of regulatory agencies including the European Medicines Agency (EMA) have written formal disagreements with several elements of EFSA's proposal. The European Commission will now decide whether to accept EFSA's recommendation over the objections of EMA. If the Commission accepts EFSA's recommendation, it will be a landmark action using knowledge acquired through independent scientific studies focused on biomarkers of chronic disease to protect human health. The goal of this Perspective is to clearly articulate the monumental nature of this debate and decision and to explain what is at stake. Our perspective is that the weight of evidence clearly supports EFSA's proposal to reduce the TDI by 20 000-fold.
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