Positive association of ethylene oxide levels with young stroke: a population-based study.

Background: Ethylene oxide (EtO), a highly reactive organic compound with extensive industrial applications, poses significant health risks. The association between EtO exposure and stroke was not well established. This study examined the association between EtO exposure and stroke among US adults using data from the 2013-2018 National Health and Nutrition Examination Survey (NHANES). Methods: We used appropriately weighted multifactorial logistic regression models to analyze the data and validated the findings with smoothed curve fitting. Stratified analysis and interaction assessments were performed to evaluate the robustness of the findings. Results: The study included 5,071 participants, balanced between men and women, with a stroke prevalence of 4.1%. Higher EtO levels were associated with rising rates of stroke (OR = 1.23, 95% CI: 1.06-1.42). Individuals in the top 25% group displayed a stroke prevalence 1.6 times higher than those in the bottom 25% group (OR = 1.60, 95%CI: 1.03-2.48). Stratified analysis demonstrated a significant positive association between EtO and stroke in individuals under 50 years (OR = 1.94, 95%CI: 1.38-2.72), while no significant association was found in those aged 50 and above (OR = 0.97, 95%CI: 0.83-1.14). Conclusion: This study identified a significant association between EtO exposure and stroke occurrence in young adults in the United States.

TGF-ß1 mediates hypoxia-preconditioned olfactory mucosa mesenchymal stem cells improved neural functional recovery in Parkinson's disease models and patients.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra (SN). Activation of the neuroinflammatory response has a pivotal role in PD. Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic approach for various nerve injuries, but there are limited reports on their use in PD and the underlying mechanisms remain unclear. METHODS: We investigated the effects of clinical-grade hypoxia-preconditioned olfactory mucosa (hOM)-MSCs on neural functional recovery in both PD models and patients, as well as the preventive effects on mouse models of PD. To assess improvement in neuroinflammatory response and neural functional recovery induced by hOM-MSCs exposure, we employed single-cell RNA sequencing (scRNA-seq), assay for transposase accessible chromatin with high-throughput sequencing (ATAC-seq) combined with full-length transcriptome isoform-sequencing (ISO-seq), and functional assay. Furthermore, we present the findings from an initial cohort of patients enrolled in a phase I first-in-human clinical trial evaluating the safety and efficacy of intraspinal transplantation of hOM-MSC transplantation into severe PD patients. RESULTS: A functional assay identified that transforming growth factor-ß1 (TGF-ß1), secreted from hOM-MSCs, played a critical role in modulating mitochondrial function recovery in dopaminergic neurons. This effect was achieved through improving microglia immune regulation and autophagy homeostasis in the SN, which are closely associated with neuroinflammatory responses. Mechanistically, exposure to hOM-MSCs led to an improvement in neuroinflammation and neural function recovery partially mediated by TGF-ß1 via activation of the anaplastic lymphoma kinase/phosphatidylinositol-3-kinase/protein kinase B (ALK/PI3K/Akt) signaling pathway in microglia located in the SN of PD patients. Furthermore, intraspinal transplantation of hOM-MSCs improved the recovery of neurologic function and regulated the neuroinflammatory response without any adverse reactions observed in patients with PD. CONCLUSIONS: These findings provide compelling evidence for the involvement of TGF-ß1 in mediating the beneficial effects of hOM-MSCs on neural functional recovery in PD. Treatment and prevention of hOM-MSCs could be a promising and effective neuroprotective strategy for PD. Additionally, TGF-ß1 may be used alone or combined with hOM-MSCs therapy for treating PD.

Curcumin-primed olfactory mucosa-derived mesenchymal stem cells mitigate cerebral ischemia/reperfusion injury-induced neuronal PANoptosis by modulating microglial polarization.

BACKGROUND: Cerebral ischemia-reperfusion (I/R) injury often leads to neuronal death through persistent neuroinflammatory responses. Recent research has unveiled a unique inflammatory programmed cell death mode known as PANoptosis. However, direct evidence for PANoptosis in ischemic stroke-induced neuronal death has not been established. Although it is widely thought that modulating the balance of microglial phenotypic polarization in cerebral I/R could mitigate neuroinflammation-mediated neuronal death, it remains unknown whether microglial polarization influences PANoptotic neuronal death triggered by cerebral I/R. Our prior study demonstrated that curcumin (CUR) preconditioning could boost the neuroprotective properties of olfactory mucosa-derived mesenchymal stem cells (OM-MSCs) in intracerebral hemorrhage. Yet, the potential neuroprotective capacity of curcumin-pretreated OM-MSCs (CUR-OM-MSCs) on reducing PANoptotic neuronal death during cerebral I/R injury through modulating microglial polarization is uncertain. METHODS: To mimic cerebral I/R injury, We established in vivo models of reversible middle cerebral artery occlusion (MCAO) in C57BL/6 mice and in vitro models of oxygen-glucose deprivation/reoxygenation (OGD/R) in HT22 neurons and BV2 microglia. RESULTS: Our findings indicated that cerebral I/R injury caused PANoptotic neuronal death and triggered microglia to adopt an M1 (pro-inflammatory) phenotype both in vivo and in vitro. Curcumin pretreatment enhanced the proliferation and anti-inflammatory capacity of OM-MSCs. The CUR-OM-MSCs group experienced a more pronounced reduction in PANoptotic neuronal death and a better recovery of neurological function than the OM-MSCs group. Bioinformatic analysis revealed that microRNA-423-5p (miRNA-423-5p) expression was obviously upregulated in CUR-OM-MSCs compared to OM-MSCs. CUR-OM-MSCs treatment induced the switch to an M2 (anti-inflammatory) phenotype in microglia by releasing miRNA-423-5p, which targeted nucleotide-binding oligomerization domain 2 (NOD2), an upstream regulator of NF-kappaB (NF-κB) and Mitogen-Activated Protein Kinase (MAPK) signaling pathways, to attenuate PANoptotic neuronal death resulting from cerebral I/R. CONCLUSION: This results provide the first demonstration of the existence of PANoptotic neuronal death in cerebral I/R conditions. Curcumin preconditioning enhanced the ameliorating effect of OM-MSCs on neuroinflammation mediated by microglia polarization via upregulating the abundance of miRNA-423-5p. This intervention effectively alleviates PANoptotic neuronal death resulting from cerebral I/R. The combination of curcumin with OM-MSCs holds promise as a potentially efficacious treatment for cerebral ischemic stroke in the future.

Mesenchymal stem cell-derived exosomes overexpressing SRC-3 protect mice from cerebral ischemia by inhibiting ferroptosis.

BACKGROUND: The treatment for cerebral ischemia remains limited, and new therapeutic strategies are urgently needed. Exosome has shown great promise for the treatment of cerebral ischemia. Steroid receptor coactivator-3 (SRC-3) was reported to be involved in neurological performances. In this study, we aimed to investigate the protective effects of mesenchymal stem cell (MSC)-derived exosomes overexpressing SRC-3 on cerebral ischemia in mice. METHODS: The mice were treated with an intracerebroventricular injection of GFP-overexpressed exosomes (GFP-exo) and SRC-3-overexpressed exosomes (SRC3-exo) in a middle cerebral artery occlusion (MCAO) model of cerebral ischemia. RESULTS: The results showed that SRC3-exo treatment significantly inhibited lipid peroxidation and ferroptosis of the neurons subjected to oxygen-glucose deprivation. It further suppressed the activation of microglia and astrocytes, and decreased the production of pro-inflammatory cytokines in the brains of MCAO mice. Furthermore, SRC3-exo treatment reduced the water content of brain tissue and infarct size, which alleviated the neurological damage and improved neurological performances in the MCAO mice. CONCLUSIONS: Our results suggest that MSC-derived exosomes expressing SRC3 can be a therapeutic strategy for cerebral ischemia by inhibiting ferroptosis.

Dual source-powered multifunctional Pt/FePc@Mn-MOF spindle-like Janus nanomotors for active CT imaging-guided synergistic photothermal/chemodynamic therapy.

Nanomaterials capable of dual therapeutic effects of chemodynamic therapy (CDT) and photothermal therapy (PTT) is an efficacious strategy in cancer treatment. It is still a challenge to achieve complete apoptosis of tumor tissue in CDT/PTT due to the poor permeability of nanomaterials in tumor tissue. Herein, we prepared a dual-source driven Pt/FePc@Mn-MOF spindle-like Janus nanomotor by a facile oriented connection growth method for computed tomography (CT) imaging-guided CDT and PTT. The high catalase (CAT)-like activity of nanomotors allows the generation of oxygen (O2) bubbles by catalyzing the decomposition of endogenous H2O2, which alleviates the hypoxic state of the tumor microenvironment (TME) and simultaneously drive nanomotors. Pt/FePc@Mn-MOF nanomotor with excellent photothermal conversion efficiency exhibited dual peroxidase (POD)-like and oxidase (OXD)-like activities, which can produce large amounts of ROS to obtain PTT enhanced CDT. Meanwhile, near-infrared light, as "optical brakes", can trigger Janus nanomotor to realize self-thermophoretic movement. Chemical/NIR-assisted autonomous propulsion can significantly improve the accumulation of Janus nanomotors in solid tumors and enhance their ability to penetrate tumor tissue, thus brings synergistic enhancement effect to PTT and CDT. Moreover, Mn-MOF in nanomotor can deplete the antioxidant GSH by redox reaction to release massive Mn2+, which introduce Mn2+-based CT imaging properties. This novel dual-source controlled Janus nanomotor offers great potential for multimodal therapeutic medical applications.

Bone marrow-derived mesenchymal stem cells overexpressed with miR-182-5p protects against brain injury in a mouse model of cerebral ischemia.

BACKGROUND: Toll-like receptor 4 (TLR4) plays a critical role in ischemic brain injury by mediating the inflammatory response. The microRNA miR-185-5p suppresses inflammatory signaling by targeting TLR4. This study investigates whether overexpressing miR-182-5p in bone marrow-derived mesenchymal stem cells (BM-MSCs) could potentiate the neuroprotective effects of BM-MSCs in a mouse model of ischemic brain injury. METHODS: We isolated BM-MSCs from mice, transfected the cells with miR-182-5p mimic, determined their MSC lineage through flow cytometry analysis of surface markers, examined miR-182-5p and TLR4 expression levels, and injected them into mice undergone middle cerebral artery occlusion (MCAO). MSC transplanted mice were subjected to behavior assays to determine cognitive and motor functions and biochemical analysis to determine neuroinflammation and TLR4/NF-κB in the ischemic hemisphere. RESULTS: We found that BM-MSCs overexpressing miR-182-5p showed reduced TLR4 expression without affecting their MSC lineage. Mice transplanted with miR-182-5p overexpressing BM-MSCs after MCAO showed significantly improved cognitive and motor functions and reduced neuroinflammation, including suppressed microglial M1 polarization, reduced inflammatory cytokines, and inhibited TLR4/ NF-κB signaling. CONCLUSION: Our findings suggest that overexpressing miR-182-5p in BM-MSCs can enhance the neuroprotective effects of BM-MSCs against ischemic brain injury by suppressing TLR4-mediated inflammatory response.

Mesenchymal stem cells-derived therapies for subarachnoid hemorrhage in preclinical rodent models: a meta-analysis.

BACKGROUND: Mesenchymal stem cells (MSCs) and MSCs-derived extracellular vesicles (EVs) have emerged as potential novel therapies for subarachnoid hemorrhage (SAH). However, their effects remain incompletely understood. We aim to comprehensively evaluate the effect of MSCs-derived therapies in rodent models of SAH. METHODS: We searched PubMed, EMBASE, and Web of Science up to September 2021 to identify studies that reported the effects of MSCs or MSCs-derived EVs in a rodent SAH model. Neurobehavioral score was extracted as the functional outcome, and brain water content was measured as the histopathological outcome. A random-effects model was used to calculate the standardized mean difference (SMD) and confidence interval (CI). RESULTS: Nine studies published from 2018 to 2021 met the inclusion criteria. Studies quality scores ranged from 5 to 10, with a mean value of 7.22. Our results revealed an overall positive effect of MSCs and MSCs-derived EVs on the neurobehavioral score with a SMD of - 2.21 (95% CI - 3.14, - 1.08; p < 0.0001). Meanwhile, we also found that MSCs and MSCs-derived EVs reduced brain water content by a SMD of - 2.09 (95% CI - 2.99, - 1.19; p < 0.00001). Significant heterogeneity among studies was observed, further stratified and sensitivity analyses did not identify the source of heterogeneity. CONCLUSIONS: Our results suggested that MSCs-derived therapies prominently improved functional recovery and reduced brain edema in the rodent models of SAH. Notably, the limitations of small sample size should be considered when interpreting the results, and large animal studies and human trials are needed for further investigation.

SRC3 Promotes the Protective Effects of Bone Marrow Mesenchymal Stem Cell Transplantation on Cerebral Ischemia in a Mouse Model.

Mesenchymal stem cells (MSCs) derived from the bone marrow (BM) are reported to protect against ischemic brain injury. This study aimed to investigate whether the steroid receptor cofactor 3 (SRC3) was involved in MSC-induced neuroprotection. BM-MSCs were isolated from wild-type (WT) and SRC3 knockout (SRC3-/-) mice and transplanted into mice with middle cerebral artery occlusion (MCAO). The MSC identification and differentiation were determined by flow cytometry and Alizarin Red S staining after osteogenic and adipogenic stimulations. The effects of MSCs on brain injury were assessed by brain water content, modified neurological severity score (mNSS), Morris water maze test, and open field test. Finally, the effects of MSCs on MCAO-induced oxidative stress were assessed by measuring the levels of malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) and mRNA levels of SOD1, SOD2, and CAT. We found that SRC3 deficiency did not impact the MSC identification or osteogenic and adipogenic differentiation. MSC-SRC3-/- transplantation in mice that underwent the MCAO procedure exhibited diminished effects on suppression of brain edema, neurological deficits, cognitive disruption, locomotor impairment, and anxiety compared to comparable levels of MSC-WT. Finally, MSC-WT transplantation inhibited MCAO-induced oxidative stress, and the effects were significantly attenuated in MCAO mice transplanted with MSC-SRC3-/-. MSCs suppressed the MCAO-induced upregulation of MDA activity and the inhibition of SOD, GSH, SOD1, SOD2, and CAT levels, and SRC3-deficient MSCs showed significantly reduced effects. Our results indicate that SRC3 plays an important role in mediating the neuroprotective effects of MSCs in mice that experienced ischemic stroke.

The Efficacy of Mesenchymal Stem Cell Therapies in Rodent Models of Multiple Sclerosis: An Updated Systematic Review and Meta-Analysis.

Studies have demonstrated the potential of mesenchymal stem cell (MSC) administration to promote functional recovery in preclinical studies of multiple sclerosis (MS), yet the effects of MSCs on remyelination are poorly understood. We wished to evaluate the therapeutic effects of MSCs on functional and histopathological outcomes in MS; therefore, we undertook an updated systematic review and meta-analysis of preclinical data on MSC therapy for MS. We searched mainstream databases from inception to July 15, 2021. Interventional studies of therapy using naïve MSCs in in vivo rodent models of MS were included. From each study, the clinical score was extracted as the functional outcome, and remyelination was measured as the histopathological outcome. Eighty-eight studies published from 2005 to 2021 met the inclusion criteria. Our results revealed an overall positive effect of MSCs on the functional outcome with a standardized mean difference (SMD) of -1.99 (95% confidence interval (CI): -2.32, -1.65; p = 0.000). MSCs promoted remyelination by an SMD of -2.31 (95% CI: -2.84, -1.79; p = 0.000). Significant heterogeneity among studies was observed. Altogether, our meta-analysis indicated that MSC administration improved functional recovery and promoted remyelination prominently in rodent models of MS.

17ß-Estradiol Attenuates Intracerebral Hemorrhage-Induced Blood-Brain Barrier Injury and Oxidative Stress Through SRC3-Mediated PI3K/Akt Signaling Pathway in a Mouse Model.

Estrogen is neuroprotective in brain injury models, and steroid receptor cofactor 3 (SRC3) mediates estrogen signaling. We aimed to investigate whether and how SRC3 is involved in the neuroprotective effects of 17ß-estradiol (E2) in a mouse model of intracerebral hemorrhage (ICH). Ovariectomized female mice were treated with E2 after autologous blood injection-induced ICH. Brain damage was assessed by neurological deficit score, brain water content, and oxidative stress levels. Blood-brain barrier (BBB) integrity was evaluated by Evan's blue extravasation and claudin-5, ZO-1, and occludin levels. SRC3 expression and PI3K/Akt signaling pathway were examined in ICH mice treated with E2. The effect of SRC3 on E2-mediated neuroprotection was determined by examining neurological outcomes in SRC3-deficient mice undergone ICH and E2 treatment. We found that E2 alleviated ICH-induced brain edema and neurological deficits, protected BBB integrity, and suppressed oxidative stress. E2 enhanced SRC3 expression and PI3K-/Akt signaling pathway. SRC3 deficiency abolished the protective effects of E2 on ICH-induced neurological deficits, brain edema, and BBB integrity. Our results suggest that E2 suppresses ICH-induced brain injury and SRC3 plays a critical role in E2-mediated neuroprotection.

SRC-3 Deficiency Exacerbates Neurological Deficits in a Mouse Model of Intracerebral Hemorrhage: Role of Oxidative Stress.

Intracerebral hemorrhage (ICH) causes long term neurological abnormality or death. Oxidative stress is closely involved in ICH mediated brain damage. Steroid receptor cofactor 3 (SRC-3), a p160 family member, is widely expressed in the brain and regulates transactivation of Nrf2, a key component of antioxidant response. Our study aims to test if SRC-3 is implicated in ICH mediated brain injury. We first examined levels of SRC-3 and oxidative stress in the brain of mice following ICH and analyzed their correlation. Then ICH was induced in wild type (WT) and SRC-3 knock out mice and how SRC-3 deletion affected ICH induced brain damage, oxidative stress and behavioral outcome was assessed. We found that SRC-3 mRNA and protein expression levels were reduced gradually after ICH induction in WT mice along with an increase in oxidative stress levels. Correlation analysis revealed that SRC-3 mRNA levels negatively correlated with oxidative stress. Deletion of SRC-3 further increased ICH induced brain edema, neurological deficit score and oxidative stress and exacerbated ICH induced behavioral abnormality including motor dysfunction and cognitive impairment. Our findings suggest that SRC-3 is involved in ICH induced brain injury, probably through modulation of oxidative stress.