Dexmedetomidine promotes inflammation resolving through TGF-ß1 secreted by F4/80+Ly6G+ macrophage.

Dexmedetomidine (DEX) is a highly selective α2-adrenoceptor agonist, which can regulate inflammatory responses. However, whether DEX interferes with the inflammation resolving remains unclear. Here, we reported the effects of DEX on zymosan-induced generalized inflammation in mice during resolution. Mice were administered intraperitoneally with DEX after the initiation of sepsis. The resolution interval (Ri), a vital resolution indice, decreased from twelve hours to eight hours after the administration of DEX. The induction of peritoneal pro-inflammatory interleukin [IL] - 1ß and tumour necrosis factor-α (TNF-α) appeared to be inhibited. Of interest, the anti-inflammatory transforming growth factor-ß1 (TGF-ß1) but not IL-10 levels were up-regulated at twenty-four hours in the DEX group along with 1.0 mg/mice zymosan A (ZyA) treatment. The expression levels of multiple genes related to protective immune processes and clearance functions were detected and revealed the same trends. DEX markedly increased the F4/80+Ly6G+ macrophage population. Additionally, the adequate apoptotic neutrophil clearance from injury after DEX installation could be reverse by opsonization or co-instillation of TGF-ß1 neutralizing antibody in vivo, promoting the inflammation-resolution programs. In conclusion, DEX post-treatment, via the increase of F4/80+Ly6G+ macrophages, provokes further secretion of TGF-ß1, leading to the attenuated cytokine storm and accelerated inflammation resolving.

In utero cadmium and dibutyl phthalate combination exposure worsens the defects of fetal testis in rats.

Testicular dysgenesis syndrome might be due to the fetal testis defects caused by endocrine disruptors. Here, we report the combined effects of in utero exposure to cadmium (CdCl2, Cd) and di-n-butyl phthalate (DBP) on fetal testis development in rats. Pregnant Sprague-Dawley rats were randomly divided into four groups: control, Cd, DBP (250 mg/kg/day), and Cd + DBP. Cd (0.25 mg/kg/once) was intraperitoneally injected to the dam on gestational day 12 and DBP (250 mg/kg) was daily gavaged to the dam on gestational day 12 for 10 days. Cd, DBP, and Cd + DBP lowered serum testosterone levels in male fetuses. Cd and DBP did not alter fetal Leydig cell (FLC) number, but the combined exposure led to decreased FLC number. Cd did not affect FLC aggregation while DBP caused FLC aggregation and the combined exposure worsened FLC aggregation. Cd lowered FLC mRNA (Lhcgr, Star, Cyp11a1, and Insl3) levels and DBP lowered Lhcgr, Star, Insl3, and Nr5a1 levels. DBP up-regulated Scarb1 expression without affecting Cyp11a1 while the combined exposure antagonized DBP. These two chemicals and its combination did not affect Sertoli cell number and gene (Amh, Fshr, and Sox9) expression at current doses. In conclusion, the combined exposure of Cd and DBP exerts synergically antiandrogenic effects via targeting FLC development.

Delayed Puberty by Ziram Is Associated with Down Regulation of Testicular Phosphorylated AKT1 and SIRT1/PGC-1α Signaling.

Ziram is a dimethyldithiocarbamate fungicide, which may influence the male reproductive system as a potential endocrine disruptor. We interrogated the disruption of ziram on rat progenitor Leydig cell development. Prepubertal male Sprague-Dawley rats were orally treated with 0, 2, 4, or 8 mg/kg ziram for 2 weeks. We investigated the effects of ziram on serum testosterone levels, Leydig cell number, and Leydig and Sertoli cell gene and protein expression, SIRT1/PGC-1α levels, and phosphorylation of AKT1, ERK1/2, and AMPK in vivo. We also interrogated the effects of ziram on reactive oxidative species (ROS) level, apoptosis rate, and mitochondrial membrane potential of progenitor Leydig cells in vitro. Ziram decreased serum testosterone and follicle-stimulating hormone levels, the down-regulated Leydig cell-specific gene ( Lhcgr, Scarb1, Star, Cyp17a1, and Hsd17b3), and their protein expression. However, ziram stimulated anti-Müllerian hormone production. Ziram lowered SIRT1/PGC-1α and phosphorylated protein levels of AKT1. Ziram induced ROS and apoptosis and lowered the mitochondrial membrane potential of progenitor Leydig cells in vitro. In conclusion, ziram disrupts Leydig cell development during the prepubertal period potentially through the SIRT1/PGC-1α and phosphorylated AKT1 signaling.

Interleukin 6 inhibits the differentiation of rat stem Leydig cells.

Inflammation causes male hypogonadism. Several inflammatory cytokines, including interleukin 6 (IL-6), are released into the blood and may suppress Leydig cell development. The objective of the present study was to investigate whether IL-6 affected the proliferation and differentiation of rat stem Leydig cells. Leydig cell-depleted rat testis (in vivo) and seminiferous tubules (in vitro) with ethane dimethane sulfonate (EDS) were used to explore the effects of IL-6 on stem Leydig cell development. Intratesticular injection of IL-6 (10 and 100 ng/testis) from post-EDS day 14 to 28 blocked the regeneration of Leydig cells, as shown by the lower serum testosterone levels (21.6% of the control at 100 ng/testis dose), the down-regulated Leydig cell gene (Lhcgr, Star, Cyp11a1, Cyp17a1, and Hsd17b3) expressions, and the reduced Leydig cell number. Stem Leydig cells on the surface of the seminiferous tubules were induced to enter the Leydig cell lineage in vitro in the medium containing luteinizing hormone and lithium. IL-6 (1, 10, and 100 ng/ml) concentration-dependently decreased testosterone production and Lhcgr, Cyp11a1, Cyp17a1, Hsd17b3 and Insl3 mRNA levels. The IL-6 mediated effects were antagonized by Janus kinase 1 (JAK) inhibitor (filgotinib) and Signal Transducers and Activators of Transcription 3 (STAT3) inhibitor (S3I-201), indicating that a JAK-STAT3 signaling pathway is involved. In conclusion, our results demonstrated that IL-6 was an inhibitory factor of stem Leydig cell development.