Sex-Specific Differences in Autophagic Responses to Experimental Ischemic Stroke.
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ABSTRACT:
SUBMITTER: Patrizz AN
PROVIDER: S-EPMC8304137 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:We recently reported that neonatal ischemia induces microglia/macrophage activation three days post-ischemia. We also found that female mice sustained smaller infarcts than males three months post-ischemia. The objective of our current study was to examine whether differential acute neuroinflammatory response and infiltrated immune cells occurs between male and females after three days post-ischemia. Permanent middle cerebral artery occlusion was induced in male and female postnatal 9-day-old (P9) mice, and mice were sacrificed three days after ischemia. Brains were analyzed for mRNA transcription after microglia magnetic cell sorting to evaluate M1 and M2 markers. FACS analysis was performed to assess myeloid infiltration and microglial expression of CX3 chemokine receptor 1 (CX3CR1). Inflammatory cytokine expression and microglia/macrophage activation were analyzed via in situ hybridization combined with immunofluorescence techniques. Lesion volume and cell death were measured. An increase in microglia/macrophages occurred in male versus female mice. The cells exhibited amoeboid morphology, and TNFα and ptgs2 (Cox-2) genes were more expressed in males. More myeloid cell infiltration was found in male versus female brains. However, we did not observe sex-dependent differences in the injured volume or cell death density. Our data show that sex differences in the acute microglial and immune responses to neonatal ischemia are likely both gene- and region-specific.
| S-EPMC6695584 | biostudies-literature
Project description:ObjectiveWe aimed to compare quality of life (QOL) in women and men after ischemic stroke or TIA, and to determine the incremental impact of demographic, socioeconomic, clinical, and stroke-specific effects on longitudinal QOL.MethodsWe assessed QOL in patients with ischemic stroke or TIA at 3 and 12 months postdischarge in the Adherence eValuation After Ischemic stroke-Longitudinal Registry using the European Quality of Life-5 Dimensions (EQ-5D) instrument. We generated multivariable linear regression models to evaluate the association between sex and EQ-5D while sequentially adjusting for sociodemographic, clinical, and stroke-related variables. We also used a proportional odds model to assess sex differences in the change in EQ-5D scores from 3 to 12 months.ResultsA total of 1,370 patients were included, 53.7% male, median age 65 years (interquartile range 56-77 years). Women had significantly lower QOL at 3 months (unadjusted EQ-5D 0.81 in women vs 0.84 in men; p < 0.001) and 12 months (0.83 vs men 0.84; p < 0.001) poststroke. After multivariable adjustment for sociodemographic, clinical, and stroke-related factors, women continued to have lower QOL at 3 months (mean difference -0.036; p = 0.003) and at 12 months (mean difference -0.022; p = 0.046). Women fared worse in the dimensions of mobility, pain/discomfort, and anxiety/depression at 3 and 12 months. There were no sex differences in change in EQ-5D score from 3 to 12 months.ConclusionWomen have worse QOL than men up to 12 months after stroke, even after adjusting for important sociodemographic variables, stroke severity, and disability.
| S-EPMC4211921 | biostudies-literature
Project description:Background and Purpose- We determined the effect of sex on outcome after endovascular stroke thrombectomy in acute ischemic stroke, including lifelong disability outcomes. Methods- We analyzed patients treated with the Solitaire stent retriever in the combined SWIFT (Solitaire FR With the Intention for Thrombectomy), STAR (Solitaire FR Thrombectomy for Acute Revascularization), and SWIFT PRIME (Solitaire FR With the Intention for Thrombectomy as Primary Endovascular Treatment) cohorts. Ordinal and logistic regression were used to examine known factors influencing outcome after endovascular stroke thrombectomy and study the effect of sex on the association between these factors and outcomes, including age and time to reperfusion. Years of optimal life after thrombectomy were defined as disability-adjusted life years and calculated by projecting disability through adjusted poststroke life expectancy by sex. Results- Among 389 patients treated with endovascular stroke thrombectomy, 55% were females, and median National Institutes of Health Stroke Scale was 17 (interquartile range, 8-28). There were no differences between females versus males in presenting deficit severity (National Institutes of Health Stroke Scale score, 17 versus 17, P=0.21), occlusion location (69% versus 64% M1, P=0.62), presenting infarct extent (Alberta Stroke Program Early CT Score 8 versus 8, P=0.24), rate of substantial reperfusion (Thrombolysis in Cerebral Infarction 2b/3, 87% versus 83%, P=0.37), onset to reperfusion time (294 versus 302 minutes, P=0.46). Despite older ages (69 versus 64, P<0.001) and higher rate of atrial fibrillation (45% versus 30%, P=0.002) for females compared with males, adjusted rates of functional independence at 90 days were similar (odds ratio, 1.0; 95% CI, 0.6-1.6). After adjusting for age at presentation and stroke severity, females had more years of optimal life (disability-adjusted life year) after endovascular stroke thrombectomy, 10.6 versus 8.5 years (P<0.001). Conclusions- Despite greater age and higher rate of atrial fibrillation, females experienced comparable functional outcomes and greater years of optimal life after intervention compared with males.
| S-EPMC6710145 | biostudies-literature
Project description:Minocycline is neuroprotective in clinical and experimental stroke studies, due in part to its ability to inhibit poly (ADP-ribose) polymerase. Previous preclinical data have shown that interference with poly (ADP-ribose) polymerase signaling leads to sex-specific neuroprotection, reducing stroke injury only in males. In this study, we show that minocycline is ineffective at reducing ischemic damage in females after middle cerebral artery occlusion, likely due to effects on poly (ADP-ribose) polymerase signaling. Clinical trials must consider possible sex differences in the response to neuroprotective agents, if we hope to translate promising therapies to stroke patients of both sexes.
| S-EPMC2855881 | biostudies-literature
Project description:IntroductionStroke is a disease that presents with well-known sex differences. While women account for more stroke deaths, recent data show that after adjusting for age and pre-stroke functional status, mortality is higher in men. Immune responses are key determinants of stroke outcome and may differ by sex. This study examined sex differences in central and peripheral T cell immune responses, systemic effects on gut permeability and microbiota diversity and behavioral outcomes after stroke in aged mice. We hypothesized that there are sex differences in the immune response to stroke in aged animals.MethodsC57BL/6CR mice (20-22 months) were subjected to 60 min middle cerebral artery occlusion, or sham surgery. T cells were quantified in brain and blood at 3, 7 and 15 days (d) post-stroke by flow cytometry. Peripheral effects on gut permeability and microbiota diversity, as well as neurological function were assessed up to 14 d, and at 21 d (cognitive function) post-stroke. Brain glial fibrillary acidic protein (GFAP) expression was evaluated at 42 d post-stroke.Results and discussionMortality (50% vs 14%, p < 0.05) and hemorrhagic transformation (44% vs 0%) were significantly higher in males than in females. No difference in infarct size at 3d were observed. Peripherally, stroke induced greater gut permeability of FITC-dextran in males at d3 (p < 0.05), and non-reversible alterations in microbiota diversity in males. Following the sub-acute phase, both sexes demonstrated a time-dependent increase of CD4+ and CD8+ T cells in the brain, with significantly higher levels of CD8+ T cells and Regulatory T cells in males at d15 (p < 0.01). Aged males demonstrated greater neurological deficits up to d5 and impaired sensorimotor function up to d15 when assessed by the corner asymmetry test (p < 0.001 and p < 0.01, respectively). A trend in greater cognitive decline was observed at d21 in males. Increased GFAP expression in the ischemic hemisphere, indicating astroglial activation and gliosis, was demonstrated in both males and females 42d post-stroke. Our findings indicate that despite a similar initial ischemic brain injury, aged male mice experience greater peripheral effects on the gut and ongoing central neuroinflammation past the sub-acute phase after stroke.
| S-EPMC7590503 | biostudies-literature
Project description:Background The association between systemic hypertension and cerebrovascular disease is well documented. However, the impact of pulmonary hypertension (PH) on acute ischemic stroke outcomes is unknown despite PH being recognized as a risk factor for acute ischemic stroke. We aimed to determine the association between PH and adverse in-hospital outcomes after acute ischemic stroke, as well as whether there are sex differences in this association. Methods and Results Acute ischemic stroke admissions from the US National Inpatient Sample between October 2015 and December 2017 were included. The relationship between PH and outcomes (mortality, prolonged hospitalization >4 days, and routine home discharge) was analyzed using logistic regressions adjusting for demographics, comorbidities, and revascularization therapies. Interaction terms between PH and sex and age groups were also included. A total of 221 249 records representative of 1 106 045 admissions were included; 2.9% of patients had co-morbid PH, and 35.34% of those were male. PH was not associated with in-hospital mortality (odds ratio [OR], 0.96; 95% CI, 0.86-1.09) but was associated with increased odds of prolonged hospitalization (OR, 1.15; 95% CI, 1.09-1.22) and decreased odds of routine discharge (OR, 0.87; 95% CI, 0.81-0.94) for both sexes. Older patients with PH were significantly less likely to be discharged routinely (P=0.028) than their younger counterparts. Compared with female patients with PH, men were 31% more likely to die in hospital (P=0.024). Conclusions PH was not significantly associated with in-hospital mortality but was associated with prolonged hospitalization and adverse discharge status. Male patients with PH were more likely to die in hospital than female patients.
| S-EPMC8174217 | biostudies-literature
Project description:ObjectiveHigh-risk intracranial arterial plaques are the most common cause of ischemic stroke and their characteristics vary between male and female patients. However, sex differences in intracranial plaques among symptomatic patients have rarely been discussed. This study aimed to evaluate sex differences in intracranial atherosclerotic plaques among Chinese patients with cerebral ischemia.MethodsOne hundred and ten patients who experienced ischemic events underwent 3T cardiovascular magnetic resonance vessel wall scanning for the evaluation of intracranial atherosclerotic disease. Each plaque was classified according to its likelihood of causing a stroke (as culprit, uncertain, or non-culprit). The outer wall area (OWA) and lumen area of the lesion and reference sites were measured, and the wall and plaque areas, remodeling ratio, and plaque burden (characterized by a normalized wall index) were further calculated. The composition (T1 hyperintensity, enhancement) and morphology (surface irregularity) of each plaque were analyzed. Sex differences in intracranial plaque characteristics were compared between male and female patient groups.ResultsOverall, 311 plaques were detected in 110 patients with ischemic stroke (81 and 29 male and female patients, respectively). The OWA (P < 0.001) and wall area (P < 0.001) of intracranial arterial lesions were significantly larger in male patients. Regarding culprit plaques, the plaque burden in male patients was similar to that in female patients (P = 0.178, odds ratio [OR]: 0.168, 95% confidence interval [CI]: -0.020 to 0.107). However, the prevalence of plaque T1 hyperintensity was significantly higher than that in female patients (P = 0.005, OR: 15.362, 95% CI: 2.280-103.49). In the overall ischemic stroke sample, intracranial T1 hyperintensity was associated with male sex (OR: 13.480, 95% CI: 2.444-74.354, P = 0.003), systolic blood pressure (OR: 1.019, 95% CI: 1.002-1.036, P = 0.031), and current smoker (OR: 3.245, 95% CI: 1.097-9.598, P = 0.033).ConclusionFor patients with ischemic stroke, the intracranial plaque burden in male patients was similar to that in female patients; however, the plaque characteristics in male patients are associated with higher risk, especially in culprit plaques.
| S-EPMC9280275 | biostudies-literature
Project description:Ischemic stroke (IS) is a complex disease with sex differences in epidemiology, presentations, and outcomes. However, the sex-specific mechanism underlying IS remains unclear. The purpose of this study was to identify key genes contributing to biological differences between sexes. First, we downloaded the gene expression data of GSE22255 from Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) were identified using R software and related packages. Second, DEGs were separately analyzed by Gene Ontology enrichment and pathways analyses. Third, protein-protein interaction (PPI) network was constructed to further investigate the interactions of DEGs. A total of 123 DEGs were identified between sexes, including 8 upregulated and 115 downregulated genes. In the PPI network, ten key genes were identified, including IL1α, IL1β, IL6, IL8, CXCL1, CXCL2, CXCL20, CCL4, ICAM1, and PTGS2. Functional enrichment analysis revealed that these genes were mainly enriched in biological processes of immune response and apoptotic process, also in pathways of TNF and NOD-like receptor signaling. In conclusion, the above ten genes may have a protective effect on IS females through their direct or indirect involvement in biological processes of immune response and apoptotic process, as well as in TNF and NOD-like receptor signaling pathways. The results of this study may help to gain new insights into the sex-specific mechanisms underlying IS females and may suggest potential therapeutic targets for disease treatment.
| S-EPMC6515108 | biostudies-literature
Project description:Neonatal hypoxic-ischemic encephalopathy (HIE) is increasingly recognized as a sexually dimorphic disease. Male infants are not only more vulnerable to ischemic insult; they also suffer more long-term cognitive deficits compared with females with comparable brain damage. The innate immune response plays a fundamental role in mediating acute neonatal HIE injury. However, the mechanism underlying the sex difference in chronic HIE is still elusive. The present study investigated the sex difference in HIE outcomes and inflammatory response in the chronic stage (30 days after HIE). Postnatal day 10 (P10) male and female C57BL/6 pups were subjected to 60-min Rice-Vanucci model (RVM) to induce HIE. Brain atrophy and behavioral deficits were analyzed to measure stroke outcomes at 30 days of HIE. Flow cytometry (FC) was performed to examine central (microglial activation) and peripheral immune responses. Serum levels of cytokines and sex hormones were determined by enzyme-linked immunosorbent assay (ELISA). Neurogenesis was quantified by 5-Bromo-2'-deoxyuridine (BrdU) incorporation with neurons. Results showed males had worse HIE outcomes than females at the endpoint. Female microglia exhibited a more robust anti-inflammatory response that was corresponding to an enhanced expression of CX3C chemokine receptor 1 (CX3CR1) than males. More infiltration of peripheral lymphocytes was seen in male vs. female HIE brains. Cytokine levels of tumor necrosis factor (TNF)-α and interleukin (IL)-10 were more upregulated in males and females respectively than their counterparts. Neurogenesis was more highly induced in females vs. males. No significant difference in circulating hormonal level was found between males and females after HIE. We conclude that a sex dichotomy in pro- and anti-inflammatory response underlies the sex-specific chronic HIE outcomes, and an enhanced neurogenesis in females also contribute to the sex difference.
| S-EPMC6168990 | biostudies-literature
Project description:Background Studies suggest the presence of sex differences in hypertension prevalence and its associated outcomes in atherosclerosis and stroke. We hypothesized a higher intracranial atherosclerosis burden among men with hypertension and acute ischemic stroke compared with women. Methods and Results A multicenter retrospective study was performed from a prospective database identifying patients with hypertension presenting with intracranial atherosclerosis-related acute ischemic stroke and imaged with intracranial vessel wall magnetic resonance imaging. Proximal and distal plaques on vessel wall magnetic resonance imaging were scored. Negative binomial models assessed the associations between plaque-count and sex and the interaction between sex and treatment. Covariates were selected by a least absolute shrinkage and selection operator procedure. Sixty-one patients (n=42 men) were included. There were no significant differences in demographic or cardiovascular risk factors except for smoking history (P=0.002). Adjusted total and proximal plaque counts for men were 1.6 (95% CI, 1.2-2.1; P<0.01) and 1.4 (95% CI, 1.0-1.9; P=0.03) times as high as women, respectively. Female sex was more protective for proximal plaque if treated for hypertension. The risk ratio of men versus women was 1.5 (95% CI, 1.0-2.1) for treated patients. The risk ratio of men versus women was 0.7 (95% CI, 0.4-1.3) for untreated patients. The relative difference between these 2 risk ratios was 2.0 (95% CI, 1.1-3.9), which was statistically significant from the interaction test, P=0.04. Conclusions Men with hypertension with acute ischemic stroke have significantly higher total and proximal plaque burdens than women. Women with hypertension on anti-hypertensive medication showed a greater reduction in proximal plaque burden than men. Further confirmation with a longitudinal cohort study is needed and may help evaluate whether different treatment guidelines for managing hypertension by sex can help reduce intracranial atherosclerosis burden and ultimately acute ischemic stroke risk.
| S-EPMC9238545 | biostudies-literature