Inhibition of HDAC6 with CAY10603 alleviates acute and chronic kidney injury by suppressing the ATF6 branch of UPR.

BACKGROUND: Histone deacetylase 6 (HDAC6) inhibitor CAY10603 has been identified as a potential therapeutic agent for the treatment of diabetic kidney disease (DKD). The objective of this study was to investigate the therapeutic effects of CAY10603 in mice with acute kidney injury (AKI) and chronic kidney diseases (CKD). METHODS: Renal immunohistology was performed to assess the expression levels of HDAC6 in both human and mouse kidney samples. C57BL/6J mice were intraperitoneal injected with lipopolysaccharide (LPS) to induce AKI; CD-1 mice were fed with adenine diet to induce adenine-nephropathy as CKD model. Serum creatinine, blood urea nitrogen and uric acid were measured to reflect renal function; renal histology was applied to assess kidney damage. Western blot and immunohistology were used to analyze the unfolded protein response (UPR) level. RESULTS: HDAC6 was significantly upregulated in renal tubular epithelial cells (RTECs) of both AKI and CKD patients as well as mice. In the murine models of AKI induced by LPS and adenine-induced nephropathy, CAY10603 exhibited notable protective effects, including improvement in biochemical indices and pathological changes. In vivo and in vitro studies revealed that CAY10603 effectively suppressed the activation of activating transcription factor 6 (ATF6) branch of UPR triggered by thapsigargin (Tg), a commonly employed endoplasmic reticulum (ER) stressor. Consistent with these findings, CAY10603 also displayed substantial inhibition of ATF6 activation in RTECs from both murine models of LPS-induced AKI and adenine-induced nephropathy. CONCLUSIONS: Collectively, these results suggest that CAY10603 holds promise as a potential therapeutic agent for both acute and chronic kidney injury.

Similar incidence of graft glomerulonephritis in recipients with definitively diagnosed glomerulonephritis and those with unknown etiology: a retrospective observational study.

OBJECTIVE: In China, most of the patients who underwent kidney transplants have unknown causes of end-stage renal disease (uESRD). However, little is known regarding the incidence of graft glomerulonephritis (GN) and graft survival in kidney transplant recipients (KTRs) with uESRD. METHODS: In this retrospective cohort study, 473 of the 565 KTRs who underwent kidney transplantation (KTx) from 2015 to 2020 were included. We mainly observed the occurrence of graft GN between uESRD group and definitively diagnosed GN group, and repeatedly compared after propensity score matching (PSM). RESULTS: The median follow-up was 50 months in 473 KTRs, and about 75% of KTRs of native kidney disease of unknown etiology. The total cumulative incidence of graft GN was 17%, and no difference was observed between the definitively diagnosed GN group and the uESRD group (p = 0.76). Further, PSM analysis also showed no difference in the incidence of graft GN between the 2 groups. Multivariable analysis disclosed males (p = 0.001), younger age (p = 0.03), and anti-endothelial cell anti-body (AECA) positive pre-KTx (p = 0.001) were independent risk factors for graft GN. CONCLUSIONS: The incidence of graft GN was similar between uESRD and definitively diagnosed GN group. The allograft survival was also similar between two groups.

Artificial-goosebump-driven microactuation.

Microactuators provide controllable driving forces for precise positioning, manipulation and operation at the microscale. Development of microactuators using active materials is often hampered by their fabrication complexity and limited motion at small scales. Here we report light-fuelled artificial goosebumps to actuate passive microstructures, inspired by the natural reaction of hair bristling (piloerection) on biological skin. We use light-responsive liquid crystal elastomers as the responsive artificial skin to move three-dimensionally printed passive polymer microstructures. When exposed to a programmable femtosecond laser, the liquid crystal elastomer skin generates localized artificial goosebumps, resulting in precise actuation of the surrounding microstructures. Such microactuation can tilt micro-mirrors for the controlled manipulation of light reflection and disassemble capillary-force-induced self-assembled microstructures globally and locally. We demonstrate the potential application of the proposed microactuation system for information storage. This methodology provides precise, localized and controllable manipulation of microstructures, opening new possibilities for the development of programmable micromachines.

Green autofluorescence of the skin and fingernails is a novel biomarker for evaluating the risk for developing acute ischemic stroke.

The only existing approach for assessing the risk of developing acute ischemic stroke (AIS) necessitates that individuals possess a strong understanding of their health status. Our research gathered compelling evidence in favor of our hypothesis, suggesting that the likelihood of developing AIS can be assessed by analyzing the green autofluorescence (AF) of the skin and fingernails. Utilizing machine learning-based analyses of AF images, we found that the area under the curve (AUC) for distinguishing subjects with three risk factors from those with zero, one, or two risk factors was 0.79, 0.76, and 0.75, respectively. Our research has revealed that green AF serves as an innovative biomarker for assessing the risk of developing AIS. Our method is objective, non-invasive, efficient, and economic, which shows great promise to boost a technology for screening natural populations for risk of developing AIS.

Evaluation of the significance of complement-related genes mutations in atypical postinfectious glomerulonephritis: a pilot study.

BACKGROUND: Postinfectious glomerulonephritis with C3-dominant glomerular deposition (C3-PIGN) involves C3-dominant glomerular deposition without immunoglobulin. Atypical C3-PIGN involves persistent hypocomplementemia. We investigated the clinical features and explored complement-related gene mutations in atypical PIGN patients. METHODS: We enrolled atypical C3-PIGN patients and collected data regarding the clinical presentation and pathological characteristics and follow-up data. We measured the levels of complement associated antibodies and performed whole-exome sequencing (WES) to detect mutations in complement-related genes. RESULTS: The analysis included six atypical C3-PIGN patients. All patients were antistreptolysin-O (ASO) positive. All patients had varying degrees of hematuria, and four patients had proteinuria. None of the patients were positive for complement-related antibodies. All patients possessed mutations of genes related to the complement pathway, including alternative complement pathway genes-CFI, CFH, CFHR3, CFHR5; the lectin pathway gene-MASP2; and the common complement pathway gene-C8A. The rare variant of CFHR3 has been reported in C3 glomerulonephritis. During 56-73 months of follow-up, the levels of urine markers in three patients recovered within 6 months, and the remaining patients had abnormal urine test results over 12 months. Patients who received glucocorticoid therapy recovered faster. CONCLUSIONS: Our study suggested that complement-related gene mutations may be an important cause of persistent hypocomplementemia in atypical C3-PIGN patients. In addition to variations in alternate pathway-related genes, we also found variations in lectin pathway-related genes, especially MASP2 genes. Although the overall prognosis was good, atypical C3-PIGN patients exhibited a longer period for recovery. Our results suggested that atypical C3-PIGN patients should receive more medical attention and need testing for mutations in complement-related genes.

Micro- and nanofabrication of dynamic hydrogels with multichannel information.

Creating micro/nanostructures containing multi-channel information within responsive hydrogels presents exciting opportunities for dynamically changing functionalities. However, fabricating these structures is immensely challenging due to the soft and dynamic nature of hydrogels, often resulting in unintended structural deformations or destruction. Here, we demonstrate that dehydrated hydrogels, treated by a programmable femtosecond laser, can allow for a robust fabrication of micro/nanostructures. The dehydration enhances the rigidity of the hydrogels and temporarily locks the dynamic behaviours, significantly promoting their structural integrity during the fabrication process. By utilizing versatile dosage domains of the femtosecond laser, we create micro-grooves on the hydrogel surface through the use of a high-dosage mode, while also altering the fluorescent intensity within the rest of the non-ablated areas via a low-dosage laser. In this way, we rationally design a pixel unit containing three-channel information: structural color, polarization state, and fluorescent intensity, and encode three complex image information sets into these channels. Distinct images at the same location were simultaneously printed onto the hydrogel, which can be observed individually under different imaging modes without cross-talk. Notably, the recovered dynamic responsiveness of the hydrogel enables a multi-information-encoded surface that can sequentially display different information as the temperature changes.

YTHDF1 mitigates acute kidney injury via safeguarding m6A-methylated mRNAs in stress granules of renal tubules.

Acute kidney injury (AKI) presents a daunting challenge with limited therapeutic options. To explore the contribution of N6-methyladenosine (m6A) in AKI development, we have investigated m6A-modified mRNAs within renal tubular cells subjected to injuries induced by diverse stressors. Notably, while the overall level of m6A-modified RNA remains unaltered in renal tubular cells facing stress, a distinct phenomenon emerges-mRNAs bearing m6A methylation exhibit a pronounced tendency to accumulate within stress granules (SGs), structures induced in response to these challenges. Cumulation of m6A-modified mRNA in SGs is orchestrated by YTHDF1, a m6A 'reader' closely associated with SGs. Strikingly, AKI patients and various mouse AKI models showcase elevated levels of renal tubular YTHDF1. Depleting YTHDF1 within renal tubular cells leads to a marked reduction in m6A-modified mRNA accumulation within SGs, accompanied by an escalation in cell apoptosis under stress challenges. The significance of YTHDF1's protective role is further underscored by findings in AKI mouse models triggered by cisplatin or renal ischemia-reperfusion treatments. In particular, renal tubular-specific YTHDF1 knockout mice exhibit heightened AKI severity when contrasted with their wild-type counterparts. Mechanistic insights reveal that YTHDF1 fulfills a crucial function by safeguarding m6A-modified mRNAs that favor cell survival-exemplified by SHPK1-within SGs amid stress-challenged renal tubular cells. Our findings collectively shed light on the pivotal role of YTHDF1 in shielding renal tubules against AKI, through its adeptness in recruiting and preserving m6A-modified mRNAs within stress-induced SGs.

Krüppel-like Factor 15 Suppresses Ferroptosis by Activating an NRF2/GPX4 Signal to Protect against Folic Acid-Induced Acute Kidney Injury.

Acute kidney injury (AKI) is a common and serious disease with high morbidity and mortality, and its pathophysiological mechanisms are not fully understood. Increasing evidence suggests an important role of ferroptosis in AKI. Krüppel-like factor 15 (KLF15) is a transcription factor involved in several metabolic diseases, but its role in AKI and ferroptosis remains unclear. In this study, we explored the potential role of KLF15 using a folic acid-induced AKI model. Our study showed that KLF15 expression was reduced in kidney tissues of AKI mice, and KLF15 knockout exacerbated folic acid-induced ferroptosis and kidney injury. In vitro studies revealed that the ferroptosis inducer erastin significantly suppressed KLF15 expression in human tubular epithelial cells. Notably, the overexpression of KLF15 attenuated ferroptosis, as evidenced by a decrease in the lipid peroxidation marker of malondialdehyde and the upregulation of glutathione peroxidase 4 (GPX4), while KLF15 knockdown with shRNA exerted the opposite effect. Mechanistically, KLF15 stabilized the protein of nuclear factor erythroid 2-related factor 2 (NRF2) and subsequently increased the GPX4 level. Collectively, KLF15 plays an important role in the modulation of ferroptosis in AKI and may be a potential therapeutic target for treating AKI.

Edge-rich molybdenum disulfide tailors carbon-chain growth for selective hydrogenation of carbon monoxide to higher alcohols.

Selective hydrogenation of carbon monoxide (CO) to higher alcohols (C2+OH) is a promising non-petroleum route for producing high-value chemicals, in which precise regulations of both C-O cleavage and C-C coupling are highly essential but remain great challenges. Herein, we report that highly selective CO hydrogenation to C2-4OH is achieved over a potassium-modified edge-rich molybdenum disulfide (MoS2) catalyst, which delivers a high CO conversion of 17% with a superior C2-4OH selectivity of 45.2% in hydrogenated products at 240 °C and 50 bar, outperforming previously reported non-noble metal-based catalysts under similar conditions. By regulating the relative abundance of edge to basal plane, C2-4OH to methanol selectivity ratio can be overturned from 0.4 to 2.2. Mechanistic studies reveal that sulfur vacancies at MoS2 edges boost carbon-chain growth by facilitating not only C-O cleavage but also C-C coupling, while potassium promotes the desorption of alcohols via electrostatic interaction with hydroxyls, thereby enabling preferential formation of C2-4OH.

Production of carbon monoxide and hydrogen from methanol using a ruthenium pincer complex: a DFT study.

To understand the mechanism of the dehydrogenation of methanol to CO and H2 catalyzed by a ruthenium pincer complex, a density functional theory (DFT) study has been conducted on two different cycles which differ in the substances entering the cycle (methanol (cycle 1) versus methoxymethanol (cycle 2)). Our calculated results show that both cycles consist of three stages: dehydrogenation of alcohol to aldehyde (stage I); hydrogen formation (stage II); and decarbonylation with the regeneration of the catalyst (stage III). The energy barriers of the rate-determining steps for cycles 1 and 2 are 49.6 and 28.5 kcal mol-1, respectively. Thus cycle 2 is more energetically feasible. For stage III of cycle 2, our results did not support the mechanism proposed in the experiment (CO release occurs prior to decarbonylation). Instead, we suggested and examined an alternative pathway, that is, decarbonylation occurs prior to CO release. The mechanistic insights gained in the present paper could be beneficial for further designing of these kinds of reactions.

Hydrogel muscles powering reconfigurable micro-metastructures with wide-spectrum programmability.

Stimuli-responsive geometric transformations endow metamaterials with dynamic properties and functionalities. However, using existing transformation mechanisms to program a single geometry to transform into diverse final configurations remains challenging, imposing crucial design restrictions on achieving versatile functionalities. Here, we present a programmable strategy for wide-spectrum reconfigurable micro-metastructures using linearly responsive transparent hydrogels as artificial muscles. Actuated by the hydrogel, the transformation of micro-metastructures arises from the collaborative buckling of their building blocks. Rationally designing the three-dimensional printing parameters and geometry features of the metastructures enables their locally isotropic or anisotropic deformation, allowing controllable wide-spectrum pattern transformation with programmable chirality and optical anisotropy. This reconfiguration mechanism can be applied to various materials with a wide range of mechanical properties. Our strategy enables a thermally reconfigurable printed metalattice with pixel-by-pixel mapping of different printing powers and angles for displaying or hiding complex information, providing opportunities for encryption, miniature robotics, photonics and phononics applications.

Mechanisms and Stereoselectivities in the NHC-Catalyzed [4 + 2] Annulation of 2-Bromoenal and 6-Methyluracil-5-carbaldehyde.

To disclose the reaction mechanism and selectivity in the NHC-catalyzed reaction of 2-bromoenal and 6-methyluracil-5-carbaldehyde, a systematic computational study has been performed. According to DFT computations, the catalytic cycle is divided into eight elementary steps: nucleophilic attack of the NHC on 2-bromoenal, 1,2-proton transfer, C-Br bond dissociation, 1,3-proton transfer, addition to 6-methyluracil-5-carbaldehyde, [2 + 2] cycloaddition, NHC dissociation, and decarboxylation. The Bronsted acid DABCO·H+ plays a crucial role in proton transfer and decarboxylation steps. The addition to 6-methyluracil-5-carbaldehyde determines both chemoselectivity and stereoselectivity, leading to R-configured carbocycle-fused uracil, in agreement with experimental results. NCI analysis indicates that the CH···N, CH···π, and LP···π interactions should be the key factor for determining the stereoselectivity. ELF analysis shows the main role of the NHC in promoting C-Br bond dissociation. The mechanistic insights obtained in the present work may guide the rational design of potential NHC catalysts.

CD8 T Cell-Derived Exosomal miR-186-5p Elicits Renal Inflammation via Activating Tubular TLR7/8 Signal Axis.

T cells play an important role in the development of focal segmental glomerulosclerosis (FSGS). The mechanism underlying such T cell-based kidney disease, however, remains elusive. Here the authors report that activated CD8 T cells elicit renal inflammation and tissue injury via releasing miR-186-5p-enriched exosomes. Continuing the cohort study identifying the correlation of plasma level of miR-186-5p with proteinuria in FSGS patients, it is demonstrated that circulating miR-186-5p is mainly derived from activated CD8 T cell exosomes. Renal miR-186-5p, which is markedly increased in FSGS patients and mice with adriamycin-induced renal injury, is mainly delivered by CD8 T cell exosomes. Depleting miR-186-5p strongly attenuates adriamycin-induced mouse renal injury. Supporting the function of exosomal miR-186-5p as a key circulating pathogenic factor, intravenous injection of miR-186-5p or miR-186-5p-containing T cell exosomes results in mouse renal inflammation and tissue injury. Tracing the injected T cell exosomes shows their preferential distribution in mouse renal tubules, not glomerulus. Mechanistically, miR-186-5p directly activates renal tubular TLR7/8 signal and initiates tubular cell apoptosis. Mutating the TLR7-binding sequence on miR-186-5p or deleting mouse TLR7 largely abolishes renal tubular injuries induced by miR-186-5p or adriamycin. These findings reveal a causative role of exosomal miR-186-5p in T cell-mediated renal dysfunction.

NAD+ administration profoundly decreases UVC-induced skin damage by attenuating oxidative stress, inflammation, DNA damage and apoptosis.

Ultraviolet (UV) radiation is a major cause of multiple major skin diseases including skin cancer. It is crucial to discover new agents that can produce profound protective effects on UV-produced skin damage. Using a mouse model, in this study we determined the effects of NAD+ on UVC-induced skin damage and investigated the mechanisms underlying the effects, obtaining the following discoveries: First, UVC-induced skin's green autofluorescence (AF) was highly correlated with the extent of UVC-indued skin's damage; second, NAD+ administration profoundly decreased UVC-induced skin damage; third, NAD+ administration significantly attenuated UVC-induced decreases in the levels of mitochondrial superoxide dismutase and catalase; fourth, NAD+ administration significantly attenuated UVC-induced increase in the level of cyclooxygenase (COX) 2 - a marker of inflammation; fifth, NAD+ administration profoundly attenuated UVC-induced increase in double-strand DNA (dsDNA) damage; and sixth, NAD+ administration profoundly attenuated UVC-induced decreases in the ratios of Bcl-2/Bax - an index of apoptosis. Collectively, our study has found that NAD+ administration can profoundly decrease UVC-induced skin damage by attenuating oxidative stress, inflammation, DNA damage, and apoptosis, suggesting great potential of NAD+ as a protective agent for UVC-induced skin damage. Moreover, our study has further indicated that the skin's green AF is a biomarker for predicting UVC-induced skin damage.

Polynucleotide phosphorylase protects against renal tubular injury via blocking mt-dsRNA-PKR-eIF2α axis.

Renal tubular atrophy is a hallmark of chronic kidney disease. The cause of tubular atrophy, however, remains elusive. Here we report that reduction of renal tubular cell polynucleotide phosphorylase (PNPT1) causes renal tubular translation arrest and atrophy. Analysis of tubular atrophic tissues from renal dysfunction patients and male mice with ischemia-reperfusion injuries (IRI) or unilateral ureteral obstruction (UUO) treatment shows that renal tubular PNPT1 is markedly downregulated under atrophic conditions. PNPT1 reduction leads to leakage of mitochondrial double-stranded RNA (mt-dsRNA) into the cytoplasm where it activates protein kinase R (PKR), followed by phosphorylation of eukaryotic initiation factor 2α (eIF2α) and protein translational termination. Increasing renal PNPT1 expression or inhibiting PKR activity largely rescues IRI- or UUO-induced mouse renal tubular injury. Moreover, tubular-specific PNPT1-knockout mice display Fanconi syndrome-like phenotypes with impaired reabsorption and significant renal tubular injury. Our results reveal that PNPT1 protects renal tubules by blocking the mt-dsRNA-PKR-eIF2α axis.

A mouse model for X-linked Alport syndrome induced by Del-ATGG in the Col4a5 gene.

Alport syndrome (AS) is an inherited glomerular basement membrane (GBM) disease leading to end-stage renal disease (ESRD). X-linked AS (XLAS) is caused by pathogenic variants in the COL4A5 gene. Many pathogenic variants causing AS have been detected, but the genetic modifications and pathological alterations leading to ESRD have not been fully characterized. In this study, a novel frameshift variant c.980_983del ATGG in the exon 17 of the COL4A5 gene detected in a patient with XLAS was introduced into a mouse model in by CRISPR/Cas9 system. Through biochemical urinalysis, histopathology, immunofluorescence, and transmission electron microscopy (TEM) detection, the clinical manifestations and pathological alterations of Del-ATGG mice were characterized. From 16 weeks of age, obvious proteinuria was observed and TEM showed typical alterations of XLAS. The pathological changes included glomerular atrophy, increased monocytes in renal interstitial, and the absence of type IV collagen α5. The expression of Col4a5 was significantly decreased in Del-ATGG mouse model. Transcriptomic analysis showed that differentially expressed genes (DEGs) accounted for 17.45% (4,188/24003) of all genes. GO terms indicated that the functions of identified DEGs were associated with cell adhesion, migration, and proliferation, while KEGG terms found enhanced the degradation of ECM, amino acid metabolism, helper T-cell differentiation, various receptor interactions, and several important pathways such as chemokine signaling pathway, NF-kappa B signaling pathway, JAK-STAT signaling pathway. In conclusion, a mouse model with a frameshift variant in the Col4a5 gene has been generated to demonstrate the biochemical, histological, and pathogenic alterations related to AS. Further gene expression profiling and transcriptomic analysis revealed DEGs and enriched pathways potentially related to the disease progression of AS. This Del-ATGG mouse model could be used to further define the genetic modifiers and potential therapeutic targets for XLAS treatment.

In Situ Mineralizing Spinning of Strong and Tough Silk Fibers for Optical Waveguides.

Biopolymer-based optical waveguides with low-loss light guiding performance and good biocompatibility are highly desired for applications in biomedical photonic devices. Herein, we report the preparation of silk optical fiber waveguides through bioinspired in situ mineralizing spinning, which possess excellent mechanical properties and low light loss. Natural silk fibroin was used as the main precursor for the wet spinning of the regenerated silk fibroin (RSF) fibers. Calcium carbonate nanocrystals (CaCO3 NCs) were in situ grown in the RSF network and served as nucleation templates for mineralization during the spinning, leading to the formation of strong and tough fibers. CaCO3 NCs can guide the structure transformation of silk fibroin from random coils to ß-sheets, contributing to enhanced mechanical properties. The tensile strength and toughness of the obtained fibers are up to 0.83 ± 0.15 GPa and 181.98 ± 52.42 MJ·m-3, obviously higher than those of natural silkworm silks and even comparable to spider silks. We further investigated the performance of the fibers as optical waveguides and observed a low light loss of 0.46 dB·cm-1, which is much lower than natural silk fibers. We believed that these silk-based fibers with excellent mechanical and light propagation properties are promising for applications in biomedical light imaging and therapy.

Poor outcomes of proliferative glomerulonephritis with monoclonal IgG deposits in renal allografts: a retrospective multicenter study.

BACKGROUND: Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) in renal allografts is a rare, renal-limited disease. No study has reported the long-term outcomes and prognostic features of PGNMID in renal allografts in the Chinese population. METHODS: We retrospectively included transplant patients diagnosed with PGNMID who underwent renal allograft biopsy at three transplant centers from April 2012 to July 2020. We observed the clinicopathologic features, explored the long-term graft survival, and investigated the characteristics associated with the prognosis. RESULTS: A total of 13 transplant patients with PGNMID were included, out of 3821 biopsies. The mean follow-up time was 55 months since kidney transplantation (KTx). At diagnosis, all patients presented with proteinuria (100%) and most of them with hematuria (92%). IgG3κ (69%) was the main immunofluorescence (IF) subtype. The median graft survival of the total cohort was 17 months from diagnosis and 49 months from kidney transplantation. During follow-up, 9 patients needed dialysis and 2 out of 9 patients who progressed to dialysis died of infection. Primary membranoproliferative glomerulonephritis (MPGN) (P = 0.014) and MPGN pattern at diagnostic biopsy (P < 0.001) were associated with a higher risk of graft loss. CONCLUSIONS: The long-term outcome of allograft PGNMID was relatively poor in the Chinese population. Primary MPGN and MPGN pattern in renal allograft were associated with  poor outcomes.

Improving the Function of Meningeal Lymphatic Vessels to Promote Brain Edema Absorption after Traumatic Brain Injury.

Brain edema is the most common and fatal complication after traumatic brain injury (TBI). Meningeal lymphatic vessels (MLVs) are the conduits that transport cerebrospinal fluid (CSF) and macromolecules to deep extracranial cervical lymph nodes (dCLNs). After TBI, the drainage function of MLVs can become impaired. However, the scenario in which the improvement of the function of MLVs can promote brain edema absorption after TBI has not been reported. Therefore, the purpose of this study was to investigate the effects of ketoprofen, 9-cis retinoic acid (RA) and vascular endothelial cell growth factor-C (VEGF-C), which promote the proliferation of peripheral lymphatic vessels, on the cerebellar medullary cistern injection of TBI rats, as well as their mechanism of action on brain edema after TBI. In the experiment, we found that ketoprofen, 9-cisRA, and VEGF-C can improve the function of MLVs, promote the extracranial drainage of CSF and the absorption of brain edema, weaken the neuroinflammatory response, reduce reactive oxygen species (ROS) production, maintain the structural integrity of MLVs, and improve neurological function. In addition, ketoprofen, 9-cisRA, and VEGF-C upregulated the lymphatic-specific proteins VEGF receptor (VEGFR)3, PROX1, forkhead box protein C2 (FOXC2), and lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1). These results indicate that ketoprofen, 9-cisRA, and VEGF-C may maintain the integrity of the meningeal lymphatic wall and promote lymphatic proliferation by upregulating the expression of lymphatic vessel-specific proteins, improve meningeal lymphatic function after TBI, promote CSF drainage and brain edema absorption, reduce the immune response of the nervous system, and reduce ROS formation, thereby improving prognoses. These findings may provide new ideas for the treatment of brain edema after TBI.