Fangfang Li

Sleep disorders and deficiencies can up-regulate pro-inflammatory mediators, but their potential adverse impact on ovarian function remains not fully understood. In this study, we investigated the immunoregulatory mechanisms underlying sleep deprivation (SD)–induced ovarian damage and the effects on follicular development. We found that SD disrupted follicular development and compromised early embryonic developmental potential in female mice. Notably, the use of the anti-inflammatory drug acetaminophen can effectively alleviate the adverse effect. Bulk and single-cell RNA sequencing of ovarian tissues revealed a notable up-regulation of neutrophil-associated genes, including S100a8 , S100a9 , the macrophage M1 polarization gene set, and pyroptosis-related genes in granulosa, immune, and mesothelial cells. Further experiments conducted both in vivo and in vitro verified that S100A8/A9 activates the TLR4/Myd88/NF-κB pathway, which induces the polarization of M1 macrophages and leads to pyroptosis of granulosa cells. Collectively, this study provides molecular insight into strategies for fertility preservation in individuals experiencing sleep deprivation, including those with occupational circadian rhythm disruptions.

The molecular mechanisms underlying unexplained recurrent implantation failure (RIF) remain unclear. This study aimed at identifying potential biomarkers, exploring relevant signaling pathways, and analyzing the contribution of immune cell infiltration in RIF. Microarray expression datasets were extracted from the Gene Expression Omnibus database to perform bioinformatic analyses. The results showed that ten hub genes may predict RIF with high specificity and sensitivity (area under the curve = 1.000). Protein–protein interaction analysis revealed close interactions between the hub genes and the endometrial receptivity array. The real-time quantitative polymerase chain reaction further validated three potential biomarkers (RAB32, TRIB2, and FAM155B). Functional enrichment analyses indicated that immune pathways were significantly downregulated and lipid metabolism pathways were significantly upregulated in RIF compared with the controls. Significant negative correlations were observed between fatty acid biosynthesis and the immune pathways. Immune cell infiltration, including those in CD56dim natural killer, dendritic, Th1, Th2, and regulatory T cells, as well as macrophages, was significantly reduced in RIF compared with the controls used herein. This study may provide a novel perspective on the diagnosis and treatment of RIF.

Pain is a common clinical symptom among patients. Although various opioid analgesics have been developed, their side effects hinder their application. This study aimed to develop a novel opioid analgesic, HAGD (H-Tyr-D-AIa-GIy-Phe-NH₂), with limited side effects. In vivo studies on mouse models as well as in vitro studies on Chinese hamster ovary (CHO) cells expressing human mu, delta, or kappa opioid receptors (CHO_hMOP, CHO_hDOP, and CHO_hKOP, respectively) and human sperm were conducted. Compared with subcutaneous morphine (10 mg/kg), subcutaneous HAGD (10 mg/kg) produced equipotent or even greater antinociception with a prolonged duration by activating mu/delta opioid receptors in preclinical mouse pain models. The analgesic tolerance, rewarding effects (i.e., conditioned place preference and acute hyperlocomotion), and gastrointestinal transit inhibition of HAGD were significantly reduced compared with those of morphine. Both HAGD and morphine exhibited a withdrawal response and had no impacts on motor coordination. In CHO_hMOP and CHO_hDOP, HAGD showed specific and efficient intracellular Ca²⁺ stimulation. HAGD had minimal impact on human sperm motility in vitro, whereas 1 × 10⁻⁷ and 1 × 10⁻⁸ mol/L of morphine significantly declined sperm motility at 3.5 h. Overall, HAGD may serve as a promising antinociceptive compound.

ObjectivePain is a common clinical symptom. Although a variety of opioid analgesics have been developed, the side effects including negative impact on human sperm motility still hinder their application. Aim of this study is to develop a novel opioid analgesic, a multitarget peptide HAGD (H-Tyr-D-AIa-GIy-Phe-NH₂) which has less side effects and minimal impact on sperm motility.MethodsThe peripheral antinociceptive effects of HAGD were appraised in a series of preclinical mice pain models, including the tail-flick test, carrageenan-induced inflammatory pain, acetic acid-induced writhing test and formalin test. In conditioned place preference experiment, open field test, gastrointestinal transit test and rotarod test, the side effects of HAGD in mice were assessed. The impacts of HAGD on sperm motility in vitro were investigated.ResultsHAGD produced equipotent antinociception compared with morphine. HAGD was stronger in terms of analgesia intensity in chemical stimulation pain of formalin test phase I. The antinociception was mediated by mu- and delta-opioid receptors. HAGD didn’t induce conditioned place preference and hyperlocomotion, but morphine did. Both HAGD and morphine had no impacts on motor coordination. HAGD had a limited side effect in gastrointestinal transit, while morphine inhibited gastrointestinal transit to a greater extent. However, HAGD had minimal impact on human sperm motility, whereas morphine declined sperm motility at concentrations of 1 × 10^-7 mol/l and 1 × 10^-8 mol/l at 3.5 h of incubation.Conclusion HAGD may be a better candidate for future development of novel multitarget opioid analgesics with less side effects and minimal impact on human sperm motility.