<b><i>Background:</i></b> Neuroinflammation subsequent to traumatic brain injury (TBI) is important for the recovery of patients and is associated with neurodegenerative changes post-TBI. The tripartite motif containing 44 (TRIM44) protein is an E3 ligase involved in the regulation of immune function with no previously known link to TBI. This study explores the connection between TRIM44 and TBI. <b><i>Methods:</i></b> After induction of TBI in rats by control cortex injury, TRIM44 expressions were determined with quantitative real-time reverse transcription polymerase chain reaction and Western blot, and Toll-like receptor 4 (TLR4)-NF-κB signaling was examined by the expression of TLR4, p65 phosphorylation, and the specific NF-κB transcription activity. The effects of TRIM44 knockdown on inflammation, neurological function, and TLR4-NF-κB signaling in TBI rats were revealed by the detection of proinflammatory cytokines and TLR4-NF-κB signaling molecules, modified neurological severity score, brain water content, and Evans blue permeability. <b><i>Results:</i></b> We found that TRIM44 expression was significantly increased following TBI induction along with TLR4-NF-κB activation. Silencing of TRIM44 suppressed proinflammatory cytokine production, improved neurological outcomes, alleviated brain edema, and inhibited TLR4-NF-κB signaling in TBI rats. <b><i>Conclusion:</i></b> Our findings suggest that suppressing TRIM44 or modulation of relevant pathways may be a therapeutic strategy for TBI.
Brain metastasis is a devastating clinical condition globally as one of the most common central nervous system malignancies. The current study aimed to assess the effect of defibrotide, an Food and Drug Administration-approved drug, against brain metastasis and the underlying molecular mechanisms. Two tumor cell lines with high brain metastasis potential, PC-9 and 231-BR, were subjected to defibrotide treatment of increasing dosage. The metastasis capacity of the tumor cells was evaluated by cell invasion and migration assays. Western blotting was employed to determine the levels of tight junction proteins in the blood–brain barrier (BBB) including Occludin, Zo-1, and Claudin-5, as well as metastasis-related proteins including CXCR4, MMP-2, and MMP-9. The in-vitro observations were further verified in nude mice, by monitoring the growth of xenograft tumors, mouse survival and brain metastasis foci following defibrotide treatment. Defibrotide inhibited proliferation, migration, invasion, and promotes lactate dehydrogenase release of brain metastatic tumor cells, elevated the levels of BBB tight junction proteins and metastasis-related proteins. Such beneficial role of defibrotide was mediated by its inhibitory action on the SDF-1/CXCR4 signaling axis both in vitro and in vivo, as CXCR4 agonist SDF1α negated the anti-tumoral effect of defibrotide on mouse xenograft tumor growth, mouse survival and brain metastasis. Defibrotide inhibits brain metastasis through activating the adenosine A2A receptors, which in turn inhibits the SDF-1/CXCR4 signaling axis. Our study hereby proposes defibrotide as a new and promising candidate drug against brain metastasis of multiple organ origins.
<b><i>Background:</i></b> Recent studies have shown that curcumin can reduce the symptoms of hydrocephalus. However, the underlying mechanisms remain unclear. Our previous studies demonstrated that E2F transcription factor 4 (E2F4) protein plays an important role in hydrocephalus; hence, we hypothesized that E2F4 may involve in curcumin mediated anti-hydrocephalus benefits. <b><i>Methods:</i></b> E2F4 expression and functions in different human tissues and cell lines were determined and analyzed using the all RNA-seq and ChIP-seq sample and signature search database and ChIP-atlas database. Hydrocephalus mouse model was established through stereotactic injection of shE2F4 into frontal cortex. Mice were treated with curcumin, and then hydrocephalus severity, the expression of E2F4, and downstream targets were analyzed. <b><i>Results:</i></b> E2F4 was highly expressed in the nervous system, which was downregulated in the bran of hydrocephalus patients. Knockdown E2F4 in mice could mimic the phenotype of human hydrocephalus. Upon curcumin administration, E2F4 expression level was increased, and the hydrocephalus severity score was significantly decreased in mouse model. Mechanistically, curcumin attenuated hydrocephalus through activating E2F4 signaling pathway. <b><i>Conclusion:</i></b> Curcumin suppresses hydrocephalus progression via activation of E2F4, which could be a target for hydrocephalus treatment.
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