Dataset Information

Nano-Plumber Reshapes Glymphatic-Lymphatic System to Sustain Microenvironment Homeostasis and Improve Long-Term Prognosis after Traumatic Brain Injury.

ABSTRACT: Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Long-term changes in the microenvironment of the brain contribute to the degeneration of neurological function following TBI. However, current research focuses primarily on short-term modulation during the early phases of TBI, not on the critical significance of long-term homeostasis in the brain microenvironment. Notably, dysfunction of the glymphatic-lymphatic system results in the accumulation of danger/damage-associated molecular patterns (DAMPs) in the brain, which is regarded as the leading cause of long-term microenvironmental disturbances following TBI. Here, a nanostructure, Nano-plumber, that co-encapsulates the microenvironment regulator pro-DHA and the lymphatic-specific growth factor VEGF-C is developed, allowing for a sustainable and orderly regulation of the microenvironment to promote long-term neurological recovery. Nano-plumber reverses the injury microenvironment by suppressing microglia and astrocytes activation and maintaining reduced activation via enhanced glymphatic-lymphatic drainage, and significantly improves the neurological function of rodents with TBI. This study demonstrates that glymphatic-lymphatic system reconstruction is essential for enhancing long-term prognosis following TBI, and that the Nano-plumber developed here may serve as a clinically translatable treatment option for TBI.

SUBMITTER: Tong S

PROVIDER: S-EPMC10700187 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Nano-Plumber Reshapes Glymphatic-Lymphatic System to Sustain Microenvironment Homeostasis and Improve Long-Term Prognosis after Traumatic Brain Injury.

Tong Shiqiang S Xie Laozhi L Xie Xiaoying X Xu Jianpei J You Yang Y Sun Yinzhe Y Zhou Songlei S Ma Chuchu C Jiang Gan G Ma Fenfen F Wang Zhihua Z Gao Xiaoling X Chen Jun J

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20231022 34

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Long-term changes in the microenvironment of the brain contribute to the degeneration of neurological function following TBI. However, current research focuses primarily on short-term modulation during the early phases of TBI, not on the critical significance of long-term homeostasis in the brain microenvironment. Notably, dysfunction of the glymphatic-lymphatic system results in the accumulation of danger/damage- ...[more]

PMID: 37867233

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Project description:Subarachnoid hemorrhage (SAH) induced acute impairment of the glymphatic system, but few have investigated the dysfunction of the meningeal lymphatic system and their contribution to the pathophysiology of SAH. In addition, most studies were conducted in rodent animals. We aimed to investigate the impact of SAH on glymphatic and meningeal lymphatic function in a large animal model using beagles and to evaluate the effects of intermittent cistern magna CSF drainage on these systems. Methods: The SAH model was created in beagles via endovascular perforation using a digital subtraction angiography machine. Intermittent cistern magna CSF drain was performed daily from 1 d to 3 d after SAH. We examined CSF pressure, neuronal death, enlargement of perivascular space (PVS), hydrocephalus, and neurological and cognitive deficits before and after SAH. The dynamics of glymphatic and meningeal lymphatic functions were analyzed by quantifying the signal intensity of dimeglumine gadopentetate (Gd-DTPA) using T1-weighted magnetic resonance imaging (MRI). Measurements were taken before SAH and at 1 h, 1 week, and 2 weeks post-SAH. Results: SAH in beagles caused significant blood clots, neuronal death, increased CSF pressure, hydrocephalus, and neurological and cognitive deficits. MRI revealed dilated ventricles and enlarged PVS post-SAH. The glymphatic system's function, assessed by Gd-DTPA distribution, showed reduced CSF influx and glymphatic impairment after SAH, particularly in the ipsilateral hemisphere, persisting for a week with partial recovery at 2 weeks. For lymphatic clearance, Gd-DTPA rapidly filled the olfactory bulbs, optic nerves, facial and vestibulocochlear nerves, and spinal nerves under normal conditions. SAH caused delayed and reduced Gd-DTPA efflux outflow in these areas, disrupting lymphatic clearance. Despite initial dysfunction, increased hemoglobin levels in cervical lymph nodes indicated active blood clearance post-SAH, with recovery by 2 weeks. Treatment with intermittent cistern magna CSF drain significantly ameliorated the glymphatic and meningeal lymphatic dysfunction after SAH. Conclusion: SAH impaired both glymphatic and meningeal lymphatic functions in beagles, with better restoration of lymphatic function post-SAH, which may contribute to functional recovery after SAH. External CSF drain is an effective therapeutic approach to facilitate the recovery of glymphatic and meningeal lymphatic function following SAH.

Project description:Human mitochondrial 12S ribosomal RNA (rRNA) 1555A>G mutation has been associated with aminoglycoside-induced and nonsyndromic deafness in many families worldwide. Our previous investigation revealed that the m.1555A>G mutation impaired mitochondrial translation and oxidative phosphorylation (OXPHOS). However, the mechanisms by which mitochondrial dysfunctions induced by m.1555A>G mutation regulate intracellular signaling for mitochondrial and cellular integrity remain poorly understood. Here, we demonstrated that the m.1555A>G mutation downregulated the expression of nucleus-encoded subunits of complexes I and IV but upregulated the expression of assemble factors for OXPHOS complexes, using cybrids derived from one hearing-impaired Chinese subject bearing the m.1555A>G mutation and from one hearing normal control lacking the mutation. These alterations resulted in the aberrant assembly, instability, and reduced activities of respiratory chain enzyme complexes I, IV, and V, rate of oxygen consumption, and diminished ATP production. Furthermore, the mutant cell lines carrying the m.1555A>G mutation exhibited decreased membrane potential and increased the production of reactive oxygen species. The aberrant assembly and biogenesis of OXPHOS impacted mitochondrial quality controls, including the imbalance of mitochondrial dynamics via increasing fission with abnormal mitochondrial morphology and impaired mitophagy. Strikingly, the cells bearing the m.1555A>G mutation revealed the upregulation of both ubiquitin-dependent and independent mitophagy pathways, evidenced by increasing levels of Parkin, Pink, BNIP3 and NIX, respectively. The m.1555A>G mutation-induced deficiencies ameliorate the cell homeostasis via elevating the autophagy process and upregulating apoptotic pathways. Our findings provide new insights into pathophysiology of mitochondrial deafness arising from reshaping mitochondrial and cellular homeostasis due to 12S rRNA 1555A>G mutation.

Dataset Information

Nano-Plumber Reshapes Glymphatic-Lymphatic System to Sustain Microenvironment Homeostasis and Improve Long-Term Prognosis after Traumatic Brain Injury.

Publications

Nano-Plumber Reshapes Glymphatic-Lymphatic System to Sustain Microenvironment Homeostasis and Improve Long-Term Prognosis after Traumatic Brain Injury.

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