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Parthanatos is a form of regulated cell death (RCD) that is closely linked to DNA damage, which is a common consequence of oxidative stress due to central nervous trauma, such as spinal cord injury (SCI). The mechanism by which apoptosis-inducing factor (AIF) mediates DNA strand breaks in parthanatos was not clear until the discovery of the nuclease function of MIF. A previous study suggested that observed results may not be reliable if the oxidative stress induced in cells observed under experimental pathological conditions does not accurately replicate the specific pathologies being studied. According to an earlier direct measurement of extracellular oxidative stress in a rat SCI model, post-SCI oxidative stress was approximately the same as exposure to 150 μM H 2 O 2. However, this concentration has been reported as sublethal oxidative stress in other cell types related to senescence, apoptosis, and parthanatos. Using sublethal H 2 O 2 concentrations to induce oxidative stress is equivocal. Also, different cell types have diverse tolerances and responses to oxidative stress, and, therefore, exposure to H 2 O 2. To avoid these limitations, the present study explored the mechanism of neuronal death under this simulated post-SCI oxidative stress and determined the effects of MIF knockdown in parthanatos associated with SCI. Immunofluorescence and flow cytometry were used to reveal typical characteristics of parthanatos that were blocked by PARP-1 inhibitors but not caspase inhibitors. In addition to classic features like PARP-1 and caspase-3 cleavage that were absent, we determined that parthanatos instead of apoptosis played a major role in the cell death caused by oxidative stress following SCI. Flow cytometry analysis of cells transfected by adenovirus with MIF-shRNA then exposed to H 2 O 2 showed a significant decrease in cell death for MIF knockdown cells, even after AIF nuclear translocation. The comet assay also displayed significantly fewer DNA strand breaks after MIF knockdown. This is the first study has verified that MIF knockdown enables to protect neurons from parthanatos under a simulated in vivo oxidative stress following SCI. It suggests that MIF knockdown is a promising therapy to rescue neurons suffering from oxidative stress-induced SCI pathology. • Spinal cord injury may inflict sublethal oxidative stress on neurons. • Long-term sublethal oxidative stress exposure induced neurons parthanatos. • MIF Knockdown decreases DNA fragmentation in parthanatos to protect neurons. [ABSTRACT FROM AUTHOR]

Abstract: Advanced glycation endproducts (AGEs) and the receptor for AGEs (RAGE) have been linked to the pathogenesis of diabetic complications, such as retinopathy, neuropathy, and nephropathy. AGEs may induce β-cell dysfunction and apoptosis, another complication of diabetes. However, the role of AGE-RAGE interaction in AGE-induced pancreatic β-cell failure has not been fully elucidated. In this study, we investigated whether AGE–RAGE interaction could mediate β-cell failure. We explored the potential mechanisms in insulin secreting (INS-1) cells from a pancreatic β-cell line, as well as primary rat islets. We found that glycated serum (GS) induced apoptosis in pancreatic β-cells in a dose- and time-dependent manner. Treatment with GS increased RAGE protein production in cultured INS-1 cells. GS treatment also decreased bcl-2 gene expression, followed by mitochondrial swelling, increased cytochrome c release, and caspase activation. RAGE antibody and knockdown of RAGE reversed the β-cell apoptosis and bcl-2 expression. Inhibition of RAGE prevented AGE-induced pancreatic β-cell apoptosis, but could not restore the function of glucose stimulated insulin secretion (GSIS) in rat islets. In summary, the results of the present study demonstrate that AGEs are integrally involved in RAGE-mediated apoptosis and impaired GSIS dysfunction in pancreatic β-cells. Inhibition of RAGE can effectively protect β-cells against AGE-induced apoptosis, but cannot reverse islet dysfunction in GSIS. [ABSTRACT FROM AUTHOR]

• Brain androgen (Testosterone and 11-Ketotestosterone) levels are significantly decreased in cyp17a1 KO zebrafish. • Androgens are crucial for male-typical mating behaviors in zebrafish. • Different genes and signaling pathways are altered in cyp17a1 KO zebrafish. • We have identified genes that could be crucial for zebrafish brain sex differentiation, such as cyp19a1b , dio2 , pgr , etc. Brain sex differentiation is a complex process, wherein genes and steroid hormones act to induce specific gender brain differentiation. Testosterone (T) derived from the gonads has been linked to neural circuit modeling in a sex-specific manner. Previously, we have shown that cyp17a1 knockout (KO) zebrafish have low plasma androgen levels, and display compromised male-typical mating behaviors. In this study, we demonstrated that treatment of cyp17a1 KO males with T or 11-ketotestosterone (11-KT) is sufficient to rescue mating impairment by restoring the male-typical secondary sex characters (SSCs) and mating behaviors, confirming an essential role of androgen in maintaining SSCs and mating behaviors. Brain steroid hormone analysis revealed that cyp17a1 KO fish have reduced levels of T and 11-KT. We performed RNA sequencing on brain samples of control and cyp17a1 KO male zebrafish to get insights regarding the impact of cyp17a1 KO on gene expression pattern, and to correlate it with the observed disruption of male-typical mating behaviors. Transcriptome analysis of cyp17a1 KO males showed a differential gene expression when compared to control males. In total, 358 genes were differentially regulated between control males and KO males. Important genes including brain aromatase (cyp19a1b), progesterone receptor (pgr), deiodinase (dio2), and insulin-like growth factor 1 (igf1) that are involved in brain functions, as well as androgen response genes including igf1 , frem1a , elovl1a , pax3a , mmp13b , hsc70 , ogg1 were regulated. RT-qPCR analysis following rescue of cyp17a1 KO with T and 11-KT further suggested that androgen-mediated signaling is disrupted in the cyp17a1 KO fish. Our results indicated that cyp17a1 KO fish have an incomplete masculinization and altered brain gene expression, which could be due to decreased androgen levels. [ABSTRACT FROM AUTHOR]

• Revealed the role of kisspeptin in the reproductive function in the vivo and vitro levels of the Dabry's sturgeon for the first time. • In the Dabry's sturgeon, kisspeptin can not only act on hypothalamic cells, but also directly act on pituitary cells. • Both isoforms of kisspeptin can promote the expression of GnRH and gonadotropin in Dabry's sturgeon at appropriate doses. Kisspeptin, a kind of neuropeptide, is involved in various physiological processes such as tumor metastasis inhibition and reproductive regulation due to its ability to interact with Kisspeptin receptor-Kissr. In teleost, Kisspeptin/Kissr system stimulates the hypothalamus-pituitary–gonadal axis (HPG axis), which is crucial for the reproductive regulation. Compared to one Kisspeptin protein Kiss1 was existed in mammals, two Kisspeptin were identified in sturgeon species, including Kiss1 and Kiss2, with specific receptors of Kissr1 and Kissr2, respectively. However, few reports described the effects of the two isoforms of Kisspeptin on the reproductive regulation in sturgeon. The core peptides of Kiss1 and Kiss2 (Kiss1-10 and Kiss2-10) of Dabry's sturgeon were successfully synthesized to explore the functional influence of Kisspeptin on the sturgeon HPG axis in the present study. The present findings suggested that intraperitoneal injection of Kiss1-10 and Kiss2-10 could significantly up-regulate the mRNA expression of Gnrh、Fsh and Lh in the hypothalamus and pituitary and the content of Lh protein in the serum. Assays of Kisspeptin-treated cells demonstrated that Kiss1-10 and Kiss2-10 can significantly promote the expression of Gnrh in hypothalamus cells and Lh and Fsh in pituitary cells of Dabry's sturgeon, indicating their direct-acting effect on pituitary cells and regulatory function on the reproductive development of sturgeon. This study described the reproductive function of the Kisspeptin in the Dabry's sturgeon for the first time, and provided supportive reference for the development of high-efficiency ripening technologies of artificially breeding sturgeon. [ABSTRACT FROM AUTHOR]

Abstract: Cyclooxygenase-2 (COX-2) plays important roles in the development of many disease conditions, including pancreatic β-cell dysfunction. Although the processes involved in the transcriptional regulation of COX-2 are well documented, some key elements, especially inhibitory elements, are still unknown. In our previous study, we identified a novel repressor element located in promoter region of mouse COX-2. In this study, we isolated several DNA-binding proteins from NIT-1 cells via DNA affinity chromatography; the most prominent among these proteins was poly (ADP-ribose) polymerase-1 (PARP-1). In this study, gel-supershift assays and chromatin immunoprecipitation assays showed that PARP-1 can bind to the inhibitory element −655/−632 in the promoter region of mouse COX-2 both in vitro and in vivo. Furthermore, overexpression of PARP-1 significantly inhibited promoter activity and decreased COX-2 expression. Conversely, repression of PARP-1 by RNAi upregulated COX-2 expression. These data suggest that PARP-1 plays an important role in the regulation of COX-2 expression via binding to the inhibitory element. Collectively, our findings provide new important information on the transcriptional regulation of COX-2 in pancreatic β-cells. [ABSTRACT FROM AUTHOR]