Several studies have shown that female reproductive factors are associated with breast cancer (BC), but the results differ. We conducted two-sample MR in the present work. The raw data applied in the MR study were all from the Genome-wide association study (GWAS) database. The causal effect of reproductive factors on breast cancer were mainly estimated by the standard inverse variance weighted (IVW) method. Cochran’s Q test and I² statistics were used to assess heterogeneity. The pleiotropy was evaluated by MR-Egger intercept test and MR-PRESSO. Finally, the leave-one-out analysis was performed to evaluate the robustness of the MR results. We found that there was a negative causal effect of the age at last live birth on BC (OR = 0.687, 95%CI = 0.539–0.875, p = 0.002) and positive effect of the age at menopause on BC (OR = 1.054, 95%CI = 1.034–1.075, p = 8.010 × 10⁻⁸). Additionally, there were null effects of the age at menarche (OR = 0.977, 95%CI = 0.915–1.043, p = 0.484), the age at first sexual intercourse (OR = 1.053, 95%CI = 0.958–1.157, p = 0.284) and the age at first birth (OR = 0.981, 95%CI = 0.936–1.027, p = 0.404) on BC. All these results were reliable and stable. In conclusion, the present study showed that younger age at last birth and older age at menopause could increase the risk of BC.

Objective. We have previously demonstrated that inflammation induced by toll‐like receptors (TLRs) 2/4 exert cerebral deleterious effects after diffuse axonal injury (DAI); however, the underlying mechanisms are not fully understood. Macrophage migration inhibitory factor (MIF) is a multifunctional cytokine involved in inflammatory responses. The purpose of this study was to investigate the role of MIF in inflammation induced by TLRs in the cortices of DAI rats. Methods. The rat DAI model was established by head rotational acceleration and confirmed by β‐APP, HE, and silver staining. MIF protein expression at 3 h, 6 h, 12 h, 1 d, and 3 d after DAI was measured by western blot. The localization of MIF was measured by immunofluorescence. MIF antagonist ISO‐1 was intracerebroventricularly injected to inhibit MIF. Neuronal and axonal injury and glial responses were assessed by TUNEL, immunohistochemistry, and TEM. Expression of TLR2, TLR4, ERK, phospho‐ERK, NF‐κB, and phospho‐NF‐κB was examined by western blot. The level of IL‐1β, IL‐6, and TNF‐α was measured by ELISA. Results. MIF expression was significantly increased, peaking at 1 day after DAI, and MIF was mainly localized in microglial cells and neurons. ISO‐1 suppressed neuronal apoptosis, axonal injury, and glial responses and decreased the expression of downstream signaling molecules related to TLR2/4, including ERK, phospho‐ERK, NF‐κB, phospho‐NF‐κB, IL‐1β, IL‐6, and TNF‐α. Conclusion. MIF was involved in the neuronal and axonal damage through a TLR‐related pathway following DAI.

Objectives: We aimed to investigate the role of soluble epoxide hydrolase for hyperglycemia induced‐disruption of blood‐brain barrier (BBB) integrity after diffuse axonal injury (DAI).Methods: Rat DAI hyperglycemia model was established by a lateral head rotation device and intraperitoneal injection of 50% glucose. Glial fibrillary acidic protein, ionized calcium‐binding adapter molecule‐1, β‐amyloid precursor protein, neurofilament light chain, and neurofilament heavy chain was detected by immunohistochemistry. Cell apoptosis was examined by terminal deoxynucleotidyl transferase nick‐end labeling (TUNEL) assay. The permeability of blood‐brain barrier (BBB) was assessed by expression of tight junction proteins, leakage of Evans blue and brain water content. The soluble epoxide hydrolase (sEH) pathway was inhibited by 1‐trifluoromethoxyphenyl‐3‐(1‐propionylpiperidin‐4‐yl) urea (TPPU) and the nuclear transcription factor kappa B (NF‐κB) pathway was inhibited by pyrrolidine dithiocarbamate and activated by phorbol‐12‐myristate‐13‐acetate in vivo and/or vitro, respectively. The inflammatory factors were detected by enzyme‐linked immunosorbent assay.Results: Hyperglycemia could exacerbate axonal injury, aggravate cell apoptosis and glial activation, worsen the loss of BBB integrity, increase the release of inflammatory factors, and upregulate the expression of sEH and NF‐κB. Inhibition of sEH could reverse all these damages and protect BBB integrity by upregulating the expression of tight junction proteins and downregulating the levels of inflammatory factors in vivo and vitro, while the agonist of NF‐κB pathway abrogated the protective effects of TPPU on BBB integrity in vitro.Conclusions: sEH was involved in mediating axonal injury induced by hyperglycemia after DAI by disrupting BBB integrity through inducing inflammation via the NF‐κB pathway.