Pharmacological Strategies and Surgical Management of Posthemorrhagic Hydrocephalus Following Germinal Matrix-Intraventricular Hemorrhage in Preterm Infants.

Germinal matrix-intraventricular hemorrhage (GM-IVH) is a detrimental neurological complication that occurs in preterm infants, especially in babies born before 32 weeks of gestation and in those with a very low birth weight. GM-IVH is defined as a rupture of the immature and fragile capillaries located in the subependymal germinal matrix zone of the preterm infant brain, and it can lead to detrimental neurological sequelae such as posthemorrhagic hydrocephalus (PHH), cerebral palsy, and other cognitive impairments. PHH following GM-IVH is difficult to treat in the clinic, and no levelone strategies have been recommended to pediatric neurosurgeons. Several cellular and molecular mechanisms of PHH following GM-IVH have been studied in animal models, but no effective pharmacological strategies have been used in the clinic. Thus, a comprehensive understanding of molecular mechanisms, potential pharmacological strategies, and surgical management of PHH is urgently needed. The present review presents a synopsis of the pathogenesis, diagnosis, and cellular and molecular mechanisms of PHH following GM-IVH and explores pharmacological strategies and surgical management.

Histone lactylation inhibits RARγ expression in macrophages to promote colorectal tumorigenesis through activation of TRAF6-IL-6-STAT3 signaling.

Macrophages are phenotypically and functionally diverse in the tumor microenvironment (TME). However, how to remodel macrophages with a protumor phenotype and how to manipulate them for therapeutic purposes remain to be explored. Here, we show that in the TME, RARγ is downregulated in macrophages, and its expression correlates with poor prognosis in patients with colorectal cancer (CRC). In macrophages, RARγ interacts with tumor necrosis factor receptor-associated factor 6 (TRAF6), which prevents TRAF6 oligomerization and autoubiquitination, leading to inhibition of nuclear factor κB signaling. However, tumor-derived lactate fuels H3K18 lactylation to prohibit RARγ gene transcription in macrophages, consequently enhancing interleukin-6 (IL-6) levels in the TME and endowing macrophages with tumor-promoting functions via activation of signal transducer and activator of transcription 3 (STAT3) signaling in CRC cells. We identified that nordihydroguaiaretic acid (NDGA) exerts effective antitumor action by directly binding to RARγ to inhibit TRAF6-IL-6-STAT3 signaling. This study unravels lactate-driven macrophage function remodeling by inhibition of RARγ expression and highlights NDGA as a candidate compound for treating CRC.