A new
type of chiral super Brønsted C–H acids, BINOL-derived
phosphoryl bis((trifluoromethyl)sulfonyl) methanes (BPTMs),
were developed. As compared to widely utilized BINOL-derived chiral
phosphoric acids (BPAs) and N-triflyl phosphoramides
(NTPAs), BPTMs displayed much higher Brønsted acidity, resulting
in dramatically improved activity and excellent enantioselectivity
as demonstrated in catalytic asymmetric Mukaiyama–Mannich reaction,
allylic amination, three-component coupling of allyltrimethylsilane
with 9-fluorenylmethyl carbamate and aldehydes, and protonation of
silyl enol ether. These new strong Brønsted C–H acids
have provided a platform for expanding the chemistry of asymmetric
Brønsted acid catalysis.
Surgical brain injury (SBI) triggers microglia to release numerous inflammatory factors, leading to brain edema and neurological dysfunction. Reducing neuroinflammation and protecting the blood-brain barrier (BBB) are key factors to improve the neurological function and prognosis after SBI. Na+-K+-Cl– cotransporter 1 (NKCC1) and nuclear factor κB (NF-κB) have been implicated in the secretion of inflammatory cytokines by microglia in brain injury. This study aimed to establish the role of NKCC1 in inducing inflammation in SBI, as well as to determine whether NKCC1 controls the release of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) via phosphorylation of NF-κB in microglia, thus affecting BBB permeability and neuronal cell apoptosis. Male Sprague-Dawley (SD) rats were used to establish an SBI model. This study revealed that compared with the sham group, the expression levels of p-NKCC1, p-p65-NF-κB, and related inflammatory factor proteins in SBI model group significantly increased. After p-NKCC1 was inhibited, p-p65-NF-κB, IL-6, IL-1β, and TNF-α were downregulated, and nerve cell apoptosis and BBB permeability were significantly reduced. These findings suggest that the SBI-induced increase in p-NKCC1 exacerbates neuroinflammation, brain edema, and nerve function injury, which may be mediated by regulating the activity of p65-NF-κB that in turn influences the release of inflammatory factors.
Surgical brain injury (SBi) can disrupt the function of the blood-brain barrier (BBB), leading to brain edema and neurological dysfunction. Thus, protecting the BBB and mitigating cerebral edema are key factors in improving the neurological function and prognosis of patients with SBI. The inhibition of WNK lysine deficient protein kinase/STe20/SPS1-related proline/alanine-rich kinase (SPaK) signaling ameliorates cerebral edema, and this signaling pathway regulates the phosphorylation of the downstream na + -K + -clcotransporter 1 (nKcc1). Therefore, the purpose of the present study was to investigate the role of SPaK in SBi-induced cerebral edema and to determine whether the SPaK/nKcc1 signaling pathway was involved in SBi via regulating phosphorylation. an SBi model was established in male Sprague-dawley rats, and the effects of SPaK on the regulation of the nKcc1 signaling pathway on BBB permeability and nerve cell apoptosis by western blotting analysis, immunofluorescence staining, TUNEL staining, Fluoro-Jade c staining, and brain edema and nervous system scores. The results demonstrated that, compared with those in the sham group, phosphorylated (p)-SPaK and p-nKcc1 protein expression levels were significantly increased in the SBi model group. after inhibiting p-SPaK, the expression level of p-nKcc1, neuronal apoptosis and BBB permeability were significantly reduced in SBI model rats. Taken together, these findings suggested that SBi-induced increases in p-SPaK and p-nKcc1 expression exacerbated post-traumatic neural and BBB damage, which may be mediated via the ion-transport-induced regulation of cell edema.
Blood-brain barrier (BBB) damage is closely related to morbidity and mortality in patients with traumatic brain injury (TBI). Inhibition of VEGF effectively protects BBB integrity in clinical ischemic stroke. Protecting BBB integrity, reducing brain edema and alleviating post-TBI secondary brain injury are key to a favorable patient prognosis. MMP-9 affects BBB integrity by destroying the tight junction of vascular endothelial cells and inhibiting the transport and enzymatic systems. The present study aimed to examine the possible interplay between VEGF and MMP-9 in TBI. A TBI model was established in 87 male Sprague-Dawley rats. Reverse transcription-quantitative PCR, western blotting, wet-dry brain edema assessment, TUNEL and Fluoro-Jade C staining were performed to analyze the brain tissue samples of the rats. The results showed that compared with in the Sham group rats, the mRNA and protein expression levels of VEGF and MMP-9 were increased at 24 h post-TBI. After bevacizumab treatment, BBB permeability and nerve cell apoptosis were markedly reduced. In conclusion, the present study revealed a potential role for TBI-associated VEGF and MMP-9 upregulation in BBB disruption and nerve damage post-TBI.
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