RAGE Suppresses ABCG1-Mediated Macrophage Cholesterol Efflux in Diabetes. Daffu Gurdip,Shen Xiaoping,Senatus Laura,Thiagarajan Devi,Abedini Andisheh,Hurtado Del Pozo Carmen,Rosario Rosa,Song Fei,Friedman Richard A,Ramasamy Ravichandran,Schmidt Ann Marie Diabetes Diabetes exacerbates cardiovascular disease, at least in part through suppression of macrophage cholesterol efflux and levels of the cholesterol transporters ATP binding cassette transporter A1 (ABCA1) and ABCG1. The receptor for advanced glycation end products (RAGE) is highly expressed in human and murine diabetic atherosclerotic plaques, particularly in macrophages. We tested the hypothesis that RAGE suppresses macrophage cholesterol efflux and probed the mechanisms by which RAGE downregulates ABCA1 and ABCG1. Macrophage cholesterol efflux to apolipoprotein A1 and HDL and reverse cholesterol transport to plasma, liver, and feces were reduced in diabetic macrophages through RAGE. In vitro, RAGE ligands suppressed ABCG1 and ABCA1 promoter luciferase activity and transcription of ABCG1 and ABCA1 through peroxisome proliferator-activated receptor-γ (PPARG)-responsive promoter elements but not through liver X receptor elements. Plasma levels of HDL were reduced in diabetic mice in a RAGE-dependent manner. Laser capture microdissected CD68(+) macrophages from atherosclerotic plaques of Ldlr(-/-) mice devoid of Ager (RAGE) displayed higher levels of Abca1, Abcg1, and Pparg mRNA transcripts versus Ager-expressing Ldlr(-/-) mice independently of glycemia or plasma levels of total cholesterol and triglycerides. Antagonism of RAGE may fill an important therapeutic gap in the treatment of diabetic macrovascular complications. 10.2337/db15-0575

Metabolic differences in women with premature ovarian insufficiency: a systematic review and meta-analysis. Journal of ovarian research OBJECTIVE:This review aimed to investigate the metabolic profile of women with premature ovarian insufficiency (POI) compared relative to women with normal ovarian functioning. METHODS:A systematic search of PubMed, EMBASE, and the Web of Science for observational studies published up until the 6 of July 2021 that compared the metabolic profile of POI women with a healthy control group were assessed. Mean differences (MD) and 95% confidence interval (CI) were pooled using the fixed or random effect models. RESULTS:A total of 21 studies involving 1573 women with POI and 1762 control women were included. POI patients presented significantly higher waist circumference, total cholesterol, low-density lipoprotein, high-density lipoprotein, triglycerides, and fasting glucose. Additionally, POI patients had marginally higher insulin level. However, the differences in systolic, and diastolic blood pressure were non-significant relative to the control group. CONCLUSIONS:POI is associated with alterations in certain metabolic parameters compared to control women. This finding highlights the importance of early screening and the lifelong management of metabolic health for women with POI. 10.1186/s13048-022-01041-w

Transcriptome analysis reveals that cyclophosphamide induces premature ovarian failure by blocking cholesterol biosynthesis pathway. Li Qi,An Xinglan,Man Xiaxia,Chu Meiran,Zhao Tianchuang,Yu Hao,Li Ziyi Life sciences AIMS:The present study aimed to investigate the effects of cyclophosphamide (Cytoxan, CTX) on premature ovarian failure (POF) in mice and its regulatory mechanisms by transcriptome analysis. MAIN METHODS:Female C57BL/6 mice were treated with a single intraperitoneal injection of 70 mg/kg CTX. Serum levels of estradiol (E) and follicle stimulating hormone (FSH) were measured by enzyme-linked immunosorbent assay (ELISA), and follicular structure differences were observed by hematoxylin and eosin (H&E) staining. The main mechanism of POF was investigated by RNA-seq data, protein-protein interaction (PPI) networks and qPCR analysis. KEY FINDINGS:The serum levels of E were significantly decreased and those of FSH were significantly increased compared to the control group. The ovarian weights of the mice in the CTX group were reduced, and abnormal follicular structures were also observed in the CTX group. The RNA-seq data show that the downregulated genes were related to the cholesterol biosynthesis pathway. The PPI network and qPCR analyses further confirm that the PPAR signaling pathway and the ovarian infertility genes were also involved in blocking the cholesterol biosynthesis pathway. The differences were statistically significant. SIGNIFICANCE:Our results indicate that CTX may exert its anti-tumor effects by inactivating the cholesterol biosynthesis pathway, and simultaneously reducing the supply of estrogen precursor materials, ultimately leading to the occurrence of POF. Our data provided a preliminary theoretical basis for resolving the clinical toxicity and side effects of CTX. 10.1016/j.lfs.2019.116999