Guiqian Huang

Triple negative breast cancer (TNBC) is a diverse and highly aggressive cancer characterized by a strong tendency to metastasize, poor prognosis, and a lack of effective therapeutic targets. S-equol, an active metabolinte produced by gut microbiota through the conversion of daidzein, has been proven to possess anticancer activity. This study aims to investigate the anticancer effects of S-equol on TNBC and to elucidate key targets and potential mechanisms. In vitro experiments utilized the TNBC cell lines, while in vivo experiments employed a nude mouse xenograft tumor model. By means of using CCK-8, colony formation, scratch, and transwell invasion assays, the biological function of S-equol was evaluated. In addition, bioinformatics methods were employed to explore the potential signaling pathways and target genes of S-equol. The in vitro results substantiated that S-equol significantly suppressed both the proliferation and metastatic capacity of TNBC cells. Moreover, the prediction results indicated that S-equol may exert its anti-TNBC effects through ferroptosis via the PI3K/AKT signaling pathway, with PPARγ identified as the key gene. In vitro and in vivo results collectively verified that S-equol triggers ferroptosis by influencing lipid peroxidation and Fe²⁺ levels, thereby suppressing the proliferation of TNBC. In terms of mechanism, the result that S-equol enhanced the sensitivity of TNBC to ferroptosis ensued from inhibiting the PI3K/AKT/mTOR pathway. This inhibition suppressed the reduction in lipid peroxidation mediated by PPARγ and GPX4, while promoting an increase in intracellular Fe²⁺ levels mediated by NCOA4, which were respectively reversed by PPARγ and STAT3 agonists, as well as autophagy inhibitor ULK101. The results of NCOA4 knockdown or PPARγ overexpression further verified the previous mechanism of S-equol. In conclusion, these findings revealed that S-equol promotes ferroptosis in TNBC by suppressing PPARγ-mediated lipid metabolism and promoting NCOA4-mediated ferritinophagy, which was largely dependent on the regulation of the PI3K/AKT/mTOR signaling pathways.

Glioblastoma (GBM) cells are highly heterogeneous and invasive, leading to treatment resistance and relapse. However, the molecular regulation in and distal to tumors remains elusive. Here, we collected paired tissues from the tumor core (TC) and peritumoral brain (PTB) for integrated snRNA-seq and snATAC-seq analyses. Tumor cells infiltrating PTB from TC behave more like oligodendrocyte progenitor cells than astrocytes at the transcriptome level. Dual-omics analyses further suggest that the distal regulatory regions in the tumor genome and specific transcription factors are potential determinants of regional heterogeneity. Notably, while activator protein 1 (AP-1) is active in all GBM states, its activity declines from TC to PTB, with another transcription factor, BACH1, showing the opposite trend. Combined inhibition of AP-1 and BACH1 more efficiently attenuates the tumor progression in mice and prolongs survival than either single-target treatment. Together, our work reveals marked molecular alterations of infiltrated GBM cells and a synergy of combination therapy targeting intratumor heterogeneity in and distal to GBM.

Background Post-stroke dysphagia (PSD) is a severe complication of stroke. Cerebral small-vessel disease (CSVD) is a major risk factor for stroke and is associated with swallowing difficulties. Accumulating evidence suggests that enlarged perivascular spaces (ePVSs) are a feature of CSVD. We explored whether ePVSs affect swallowing function in patients with acute ischemic stroke.Methods This was a retrospective analysis of 395 patients with acute ischemic stroke who underwent swallowing examination after stroke who had a cerebral MRI at baseline. Swallowing function was ranked based on Functional Oral Intake Scale (FOIS) score, and ePVSs were rated using a 4-level severity score according to the number of ePVSs in the basal ganglia (BG-ePVS).Results Post-stroke dysphagia was detected in 57.4% of the patients and was related to the presence of BG-ePVS. The degree of ePVS was associated with a strong increase in the risk for incident dysphagia, independent of other standard risk factors for dysphagia. A Spearman correlation analysis showed that an increased FOIS score correlated positively with an increase in the BGPS grade.Conclusions: BG-ePVS are associated with swallowing dysfunction in patients with acute ischemic stroke. The larger the number of BG-ePVS, the more severe the post-stroke dysfunction in swallowing. Accordingly, ePVS should be considered a factor in the prediction of PSD.

Background: Hemorrhagic transformation (HT) is a severe complication in patients with acute ischemic stroke (AIS). This study was performed to explore and validate the relation between bilirubin levels and spontaneous HT (sHT) and HT after mechanical thrombectomy (tHT). Methods: The study population consisted of 408 consecutive AIS patients with HT and age- and sex-matched patients without HT. All patients were divided into quartiles according to total bilirubin (TBIL) level. HT was classified as hemorrhagic infarction (HI) and parenchymal hematoma (PH) based on radiographic data. Results: In this study, the baseline TBIL levels were significantly higher in the HT than non-HT patients in both cohorts (p < 0.001). Furthermore, the severity of HT increased with increasing TBIL levels (p < 0.001) in sHT and tHT cohorts. The highest quartile of TBIL was associated with HT in sHT and tHT cohorts (sHT cohort: OR = 3.924 (2.051–7.505), p < 0.001; tHT cohort: OR = 3.557 (1.662–7.611), p = 0.006). Conclusions: Our results suggest that an increased TBIL is associated with a high risk of patients with sHT and tHT, and that TBIL is more suitable as a predictor for sHT than tHT. These findings may help to identify patients susceptible to different types and severity of HT.

Corrigendum: Age-Dependent Association Between Elevated Homocysteine and Cognitive Impairment in a Post-stroke Population: A Prospective Study

Background and Purpose: The results regarding the independent association between homocysteine (Hcy) levels and post-stroke cognitive impairment (PSCI) were inconsistent. The effect of age on this association has yet to be explored. This study aims to determine the relationship between Hcy levels, age, and cognitive impairment in a post-stroke population.Methods: A total of 592 patients with acute ischemic stroke (AIS) completed follow-up. Serum Hcy levels were measured enzymatically by spectrophotometry within 24 h of admission. Cognitive function was evaluated by the Mini-Mental State Examination (MMSE) 1 month after stroke, and the scores ≤ 24 were considered as cognitive impairment. Our study was dichotomized into two groups by a cut-off of 65 years. Multivariate logistic regression models were used to determine the association between baseline Hcy levels and cognitive impairment.Results: According to the MMSE score, 317 (53.5%) patients had cognitive impairment. Patients with higher levels of Hcy were more prone to have cognitive impairment 1 month after stroke than patients with lower levels of Hcy (p < 0.001). The optimal cut-off points of Hcy level (μmol/L) were (T1) ≤ 8, (T2) 8–12, and (T3) ≥ 12. After adjusting for confounding factors, the multivariate regression analysis showed that the third Hcy tertile was independently associated with cognitive impairment [odds ratio (OR) = 2.057, 95% confidence interval (CI) = 1.133–3.735, p = 0.018). A stronger association [T2 (OR = 2.266, 95% CI = 1.042–4.926, p = 0.039); T3 (OR =3.583, 95% CI = 1.456–8.818, p = 0.005)] was found in the younger group. However, the independent association was not confirmed in the older group.Conclusions: Elevated Hcy levels in the acute phase of ischemic stroke were independently associated with cognitive impairment in a post-stroke population. Furthermore, the association was age-dependent and more meaningful in a younger population aged below 65. So, Hcy levels in patients with stroke should be well-monitored, especially in younger patients.

Objective: To explore whether poor sleep is associated with post‐stroke anxiety (PSA) in Chinese patients with acute ischemic stroke (AIS) and to verify whether poor sleep is a predictor of PSA.Methods: A total of 327 patients with AIS were enrolled and followed up for 1 month. Sleep quality within 1 month before stroke was evaluated using the Pittsburgh Sleep Quality Index (PSQI) at admission. The patients were divided into the poor sleep group (PSQI > 7, n = 76) and good sleep group (PSQI ≤ 7, n = 251). One month after stroke, patients with obvious anxiety symptoms and a Hamilton Anxiety Scale score >7 were diagnosed with PSA.Results: Eighty‐seven patients (26.6%) were diagnosed with PSA. Compared to the good sleep quality group, the incidence of PSA in patients with poor sleep quality was higher (42.1% vs. 21.9%, p = .001). Poor sleep quality is more common in patients with PSA (35.6% vs. 18.8%, p = .001). A logistic regression analysis indicated that poor sleep quality was significantly associated with PSA (OR: 2.265, 95% CI: 1.262–4.067, p = .003). After adjusting for conventional and identified risk factors, poor sleep quality was found to be independently associated with PSA (OR: 2.676, 95% CI: 1.451–4.936, p = .001).Conclusions: Poor sleep quality before stroke was associated with PSA and may be an independent risk factor of PSA 1 month after AIS onset.