17-DMAG, an Hsp90 inhibitor, ameliorates ovariectomy-induced obesity in rats

Tsai, Yao‐Chou; Leu, Sy-Ying; Chen, Shuying; Kung, Ching-Wen; Lee, Yen-Mei; Liu, Yia-Ping; Yen, Mao‐Hsiung; Cheng, Pao-Yun

doi:10.1016/j.lfs.2019.116672

Cited by 10 publications

(6 citation statements)

References 47 publications

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“…It has been reported that inhibiting HSP90 results in upregulation of HSP70 in cells ( 67 , 68 ). HSP90 inhibitors do not generally change the expression of the HSP90 protein, but they inhibit its activity by binding at the N-terminal catalytic ATP-binding site ( 36 , 37 , 54 , 69 ). To further understand the mechanism by which HSP90 inhibitors reverse the NPC1 mutant phenotype, we measured the expression of HSP90, HSP70, and HSP40 as well as the NPC1 protein.…”

Section: Resultsmentioning

confidence: 99%

HSP90 inhibitors reduce cholesterol storage in Niemann-Pick type C1 mutant fibroblasts

Pipalia

Saad

Subramanian

et al. 2021

Journal of Lipid Research

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Section: Resultsmentioning

confidence: 99%

HSP90 inhibitors reduce cholesterol storage in Niemann-Pick type C1 mutant fibroblasts

Pipalia

Saad

Subramanian

et al. 2021

Journal of Lipid Research

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“…Geldanamycin, an antibiotic associated with depression and anxiety 64 inhibits the function of Heat Shock Protein 90 (Hsp90). Hsp90 is an FKBP5 co-chaperone that works to regulate the glucocorticoid receptor’s sensitivity to cortisol 65 , and accordingly has been implicated in the pathophysiology of several psychiatric disorders 66 and in rodent models of menopause 67 . Future studies should investigate the role inhibition of Hsp90 signaling could play in PMD.…”

Section: Discussionmentioning

confidence: 99%

In vitro model of perimenopausal depression implicates steroid metabolic and proinflammatory genes

Rudzinskas

Hoffman

Martinez³

et al. 2020

Mol Psychiatry

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The estimated 20–30% of women who develop perimenopausal depression (PMD) are at an increased risk of cardiovascular and all-cause mortality. The therapeutic benefits of estradiol (E2) and symptom-provoking effects of E2-withdrawal (E2-WD) suggest that a greater sensitivity to changes in E2 at the cellular level contribute to PMD. We developed an in vitro model of PMD with lymphoblastoid cell lines (LCLs) derived from participants of a prior E2-WD clinical study. LCLs from women with past PMD (n=8) or control women (n=9) were cultured in three experimental conditions: at vehicle baseline, during E2 treatment, and following E2-WD. Transcriptome analysis revealed significant differences in transcript expression in PMD in all experimental conditions, and significant overlap in genes which were changed in PMD regardless of experimental condition. Of these, chemokine CXCL10 , previously linked to cardiovascular disease, was upregulated in women with PMD, but most so after E2-WD (P<1.55×10 −5 ). CYP7B1 , an enzyme intrinsic to DHEA metabolism, was upregulated in PMD across experimental conditions (F (1,45) =19.93, P<0.0001). These transcripts were further validated via qRT-PCR. Gene networks dysregulated in PMD included inflammatory response, early/late E2-response, and cholesterol homeostasis. Our results provide evidence that differential behavioral responsivity to E2-WD in PMD reflects intrinsic differences in cellular gene expression. Genes such as CXCL10 , CYP7B1 , and corresponding proinflammatory and steroid biosynthetic gene networks, may represent biomarkers and molecular targets for intervention in PMD. Finally, this in vitro model allows for future investigations into the mechanisms of genes and gene networks involved in the vulnerability to, and consequences of, PMD.

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“…We focused in metformin prevention of ovariectomy’s metabolic effects. To minimized the effects of obesity that naturally develops after ovariectomy in rats (8), we have chosen a short-term treatment of only 21 days with a normal diet.…”

Section: Discussionmentioning

confidence: 99%

“…In this study, we used ovariectomized animals, a model in which animals have both ovaries removed and therefore mimics the estrogen deficiency that occurs during menopause. Ovariectomy is frequently used in literature for a better understanding of metabolic disorders of menopause (6, 7), and for testing pharmacological alternatives to prevent menopause disturbances (8, 9).…”

Section: Introductionmentioning

confidence: 99%

Metformin ameliorates body mass gain and early metabolic changes in ovariectomized rats

Barthem

Rossetti

Carvalho

et al. 2019

Endocrine Connections

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Estradiol has been used to prevent metabolic diseases, bone loss and menopausal symptoms, even though it might raise the risk of cancer. Metformin is usually prescribed for type 2 diabetes mellitus and lowers food intake and body mass while improving insulin resistance and the lipid profile. Ovariectomized rats show increased body mass, insulin resistance and changes in the lipid profile. Thus, the aim of this work was to evaluate whether metformin could prevent the early metabolic dysfunction that occurs early after ovariectomy. Female Wistar rats were divided into the following groups: SHAM-operated (SHAM), ovariectomized (OVX), ovariectomized + estradiol (OVX + E2) and ovariectomized + metformin (OVX + M). Treatment with metformin diminished approximately 50% of the mass gain observed in ovariectomized animals and reduced both the serum and hepatic triglyceride levels. The hepatic levels of phosphorylated AMP-activated protein kinase (pAMPK) decreased after OVX, and the expression of the inactive form of hepatic acetyl-CoA carboxylase (ACC) was also reduced. Metformin was able to increase the levels of pAMPK in the liver of OVX animals, sustaining the balance between the inactive and total forms of ACC. Estradiol effects were similar to those of metformin but with different proportions. Our results suggest that metformin ameliorates the early alterations of metabolic parameters and rescues hepatic AMPK phosphorylation and ACC inactivation observed in ovariectomized rats.

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17-DMAG, an Hsp90 inhibitor, ameliorates ovariectomy-induced obesity in rats

Cited by 10 publications

References 47 publications

HSP90 inhibitors reduce cholesterol storage in Niemann-Pick type C1 mutant fibroblasts

HSP90 inhibitors reduce cholesterol storage in Niemann-Pick type C1 mutant fibroblasts

In vitro model of perimenopausal depression implicates steroid metabolic and proinflammatory genes

Metformin ameliorates body mass gain and early metabolic changes in ovariectomized rats

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