The prevalence of stroke increases with age and the ability to absorb all nutrients from our diets decreases with age. Nutrition is a modifiable risk factor for stroke, which is a leading cause of ...death and disability in world-wide. Deficiencies in one‑carbon metabolism, including in methyltetrahydrofolate reductase (MTHFR), have been linked to increased risk of stroke. The Mthfr+/− mice mouse model mimic the phenotype of the MTHFR677C➔T polymorphism, such as elevated levels of homocystine. Using this mouse model, the aim of this study was to investigate the impact of dietary supplementation with 5-methylTHF, vitamin B12, and choline after ischemic stroke. Male Mthfr+/− and wildtype littermate control mice were aged (~1.5-year-old) and were placed on control diet (CD) 4-weeks prior to sensorimotor cortex damage using photothrombosis (PT), a model for ischemic stroke. Post-operatively, one group of Mthfr+/− and wildtype littermate mice were placed on 5-methylTHF, vitamin B12, and choline supplemented diet (SD). Four weeks after PT and SD motor function was assessed using the accelerating rotarod, forepaw asymmetry, and ladder beam walking tasks. Total homocysteine and cysteine levels were measured in blood. Brain tissue was processed to assess lesion volume and investigate biochemical and molecular changes. After PT and SD, Mthfr+/− mice were able to stay on the accelerating rotarod longer and used their impaired forepaw to explore more when compared to CD animals. Furthermore, total homocysteine levels in plasma and lesion volume were reduced in Mthfr+/+ and Mthfr+/− SD mice. Within the damage site, there were reduced levels of apoptotic cell death and increased neuroprotective cellular response in the brains of SD treated Mthfr+/− mice. This study reveals a critical role for one‑carbon supplementation, with 5-methylTHF, vitamin B12, and choline, in supporting improvement after ischemic stroke damage.
•In Mthfr+/−mice supplementation reduced motor impairment after stroke.•tHcy levels and lesion volumes were reduced in supplemented animals.•In brain tissue, there were reduced levels of active caspase-3 of supplemented mice.•HIF-α levels were increased in ischemic core of Mthfr+/− supplemented mice.
Nutrition is a modifiable risk factor for stroke, which is one of the leading causes of death and disability world-wide. In humans deficiencies in one-carbon metabolism, including the ...methyltetrahydrofolate reductase (MTHFR) polymorphism, have been linked to increased risk of stroke. The Mthfr+/– mice mouse model mimics the phenotype of the MTHFR677C – >T polymorphism. In our work using in vitro and in vivo models of ischemic stroke we have observed decreased recovery after stroke through reduced neuronal and astrocyte viability and increased apoptosis in MTHFR-deficient mice. In addition, we have previously shown dietary supplementation of one-carbon metabolites increases neuroplasticity and reduced oxidative stress after ischemic stroke. Using the MTHFR-deficient mouse model, the aim of this study was to investigate the impact of dietary supplementation with one-carbon metabolites on stroke outcome.
Male Mthfr+/– and wildtype littermate control mice were aged to 1.5-year-old and were placed on control diet (CD) 4-weeks prior to sensorimotor cortex damage using photothrombosis (PT), a model for ischemic stroke. Post-operatively, one group of Mthfr+/– and wildtype littermate mice were fed a supplemented diet (SD) containing 5-methylTHF, vitamin B12, and choline. Four weeks after PT damage and SD motor function was assessed and brain tissue was processed to assess lesion volume and investigate biochemical and molecular changes.
Mthfr+/– mice fed a SD after PT did not have an impaired neuroscore compared to CD Mthfr+/– mice. When compared to CD, SD Mthfr+/– mice were able to stay on the accelerating rotarod longer and travelled further, they also used their impaired forepaw more. Total homocysteine levels in plasma and lesion volume were reduced in SD Mthfr+/+ and Mthfr+/– mice. In the brain, within the damage site, there were reduced levels of apoptotic cell death and an increased neuroprotective cellular response in SD treated Mthfr+/– mice.
This study reveals a critical role for one-carbon supplementation in supporting improvement of function after ischemic stroke. Our data suggests that in stroke affected patients, nutritional supplementation maybe an important component to post-operative care, in addition to pharmacological and rehabilitation therapies.
NSERC.
Recent advances in the cervical screening programme Hawco, Sarah; Cruickshank, Margaret E.
BJOG : an international journal of obstetrics and gynaecology,
January 2023, 2023-01-00, 20230101, Letnik:
130, Številka:
2
Journal Article
The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib potentiated radiation and temozolomide (TMZ) chemotherapy in preclinical glioblastoma models but brain penetration was poor. Clinically, PARP ...inhibitors exacerbate the hematological side effects of TMZ. The OPARATIC trial was conducted to measure penetration of recurrent glioblastoma by olaparib and assess the safety and tolerability of its combination with TMZ.
Preclinical pharmacokinetic studies evaluated olaparib tissue distribution in rats and tumor-bearing mice. Adult patients with recurrent glioblastoma received various doses and schedules of olaparib and low-dose TMZ in a 3 + 3 design. Suitable patients received olaparib prior to neurosurgical resection; olaparib concentrations in plasma, tumor core and tumor margin specimens were measured by mass spectrometry. A dose expansion cohort tested tolerability and efficacy of the recommended phase II dose (RP2D). Radiosensitizing effects of olaparib were measured by clonogenic survival in glioblastoma cell lines.
Olaparib was a substrate for multidrug resistance protein 1 and showed no brain penetration in rats but was detected in orthotopic glioblastoma xenografts. Clinically, olaparib was detected in 71/71 tumor core specimens (27 patients; median, 496 nM) and 21/21 tumor margin specimens (9 patients; median, 512.3 nM). Olaparib exacerbated TMZ-related hematological toxicity, necessitating intermittent dosing. RP2D was olaparib 150 mg (3 days/week) with TMZ 75 mg/m2 daily for 42 days. Fourteen (36%) of 39 evaluable patients were progression free at 6 months. Olaparib radiosensitized 6 glioblastoma cell lines at clinically relevant concentrations of 100 and 500 nM.
Olaparib reliably penetrates recurrent glioblastoma at radiosensitizing concentrations, supporting further clinical development and highlighting the need for better preclinical models.
Innate lymphoid cells (ILCs) play strategic roles in tissue homeostasis and immunity. ILCs arise from lymphoid progenitors undergoing lineage restriction and the development of specialized ILC ...subsets. We generated “5x polychromILC” transcription factor reporter mice to delineate ILC precursor states by revealing the multifaceted expression of key ILC-associated transcription factors (Id2, Bcl11b, Gata3, RORγt, and RORα) during ILC development in the bone marrow. This approach allowed previously unattained enrichment of rare progenitor subsets and revealed hitherto unappreciated ILC precursor heterogeneity. In vivo and in vitro assays identified precursors with potential to generate all ILC subsets and natural killer (NK) cells, and also permitted discrimination of elusive ILC3 bone marrow antecedents. Single-cell gene expression analysis identified a discrete ILC2-committed population and delineated transition states between early progenitors and a highly heterogeneous ILC1, ILC3, and NK precursor cell cluster. This diversity might facilitate greater lineage potential upon progenitor recruitment to peripheral tissues.
•Five-color “polychromILC” transcription factor reporter mice define ILC precursors•ILC precursors give rise to ILC1, ILC2, and ILC3 and retain NK potential•A RorcKat allele allows resolution of extremely rare ILC3 progenitors•Detection of divergent trajectories for ILC2 and common ILC1, ILC3, and NK development
Innate lymphoid cells (ILCs) play strategic roles in tissue homeostasis and immunity. Walker et al. demonstrate via five-reporter polychrome mice the distinct divergence of ILC2 development from common ILC1, ILC3, and NK progenitors.
The complement system is vital for anti-microbial defense. In the classical pathway, pathogen-bound antibody recruits the C1 complex (C1qC1r2C1s2) that initiates a cleavage cascade involving C2, C3, ...C4, and C5 and triggering microbial clearance. We demonstrate a C4-dependent antiviral mechanism that is independent of downstream complement components. C4 inhibits human adenovirus infection by directly inactivating the virus capsid. Rapid C4 activation and capsid deposition of cleaved C4b are catalyzed by antibodies via the classical pathway. Capsid-deposited C4b neutralizes infection independent of C2 and C3 but requires C1q antibody engagement. C4b inhibits capsid disassembly, preventing endosomal escape and cytosolic access. C4-deficient mice exhibit heightened viral burdens. Additionally, complement synergizes with the Fc receptor TRIM21 to block transduction by an adenovirus gene therapy vector but is partially restored by Fab virus shielding. These results suggest that the complement system could be altered to prevent virus infection and enhance virus gene therapy efficacy.
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•Complement components C1 and C4 mediate potent neutralization of adenovirus•Deposition of C4b on the viral capsid inactivates capsid disassembly•C4 exerts direct antiviral functions independent from its role as a C3-convertase•C4 antiviral functions synergize with TRIM21-mediated virus neutralization
The complement system is pivotal to the humoral immune response. Bottermann et al. demonstrate that complement proteins C1 and C4 possess potent antiviral activity independent of downstream components. C4b is deposited on the viral capsid, preventing capsid disassembly and virus entry into the cytosol, a prerequisite for productive virus infection.
Abstract Background Depressive disorders are common and disabling among perinatal women. The rates are high in ethnic minority groups. The causes are not known in British Pakistani women. The aim of ...this study was to estimate the rates, correlates and maintaining factors of perinatal depression in a Pakistani sample in UK. The design used was a cross-sectional two phase population based survey with a prospective cohort study. Methods All women in 3rd trimester attending antenatal clinic were screened with the Edinburgh postnatal depression scale (EPDS). Women scoring 12 or more on EPDS and a random sample of low scorers were interviewed using the Schedules for Assessment in Neuropsychiatry (SCAN) and the Life Events and Difficulties schedule (LEDS). Social support was assessed with the Multidimensional Scale for Perceived Social Support (MSPSS). They were reassessed 6 months after the delivery using the same measures. Results The weighted prevalence of depression was 16.8%. Depressed mothers had more marked non health difficulties (housing, financial and marital). They had less social support and were socially isolated. Marked social isolation and marked non-health related difficulties were independent predictors of depression. Analyses of all the possible risk factors, comparing 26 persistent depressed with 27 depression resolved group showed significant differences in the MSPSS subscales between the two groups. Limitations The study lacked inter-rater reliability testing between the individuals carrying out diagnostic interviews. The study sample did not accurately represent the general population and information about the origins of depression in this group of mothers was limited. Conclusion Depression in British Pakistani mothers is associated with social isolation, poor social support and severe and persistent social difficulties. The findings will have implications in planning suitable services for this group.
Obesity impairs the relaxant capacity of adipose tissue surrounding the vasculature (PVAT) and has been implicated in resultant obesity-related hypertension and impaired glucose intolerance. Resident ...immune cells are thought to regulate adipocyte activity. We investigated the role of eosinophils in mediating normal PVAT function. Healthy PVAT elicits an anti-contractile effect, which was lost in mice deficient in eosinophils, mimicking the obese phenotype, and was restored upon eosinophil reconstitution. Ex vivo studies demonstrated that the loss of PVAT function was due to reduced bioavailability of adiponectin and adipocyte-derived nitric oxide, which was restored after eosinophil reconstitution. Mechanistic studies demonstrated that adiponectin and nitric oxide are released after activation of adipocyte-expressed β3 adrenoceptors by catecholamines, and identified eosinophils as a novel source of these mediators. We conclude that adipose tissue eosinophils play a key role in the regulation of normal PVAT anti-contractile function.
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