Tufm lactylation regulates neuronal apoptosis by modulating mitophagy in traumatic brain injury.

Lactates accumulation following traumatic brain injury (TBI) is detrimental. However, whether lactylation is triggered and involved in the deterioration of TBI remains unknown. Here, we first report that Tufm lactylation pathway induces neuronal apoptosis in TBI. Lactylation is found significantly increased in brain tissues from patients with TBI and mice with controlled cortical impact (CCI), and in neuronal injury cell models. Tufm, a key factor in mitophagy, is screened and identified to be mostly lactylated. Tufm is detected to be lactylated at K286 and the lactylation inhibits the interaction of Tufm and Tomm40 on mitochondria. The mitochondrial distribution of Tufm is then inhibited. Consequently, Tufm-mediated mitophagy is suppressed while mitochondria-induced neuronal apoptosis is increased. In contrast, the knockin of a lactylation-deficient TufmK286R mutant in mice rescues the mitochondrial distribution of Tufm and Tufm-mediated mitophagy, and improves functional outcome after CCI. Likewise, mild hypothermia, as a critical therapeutic method in neuroprotection, helps in downregulating Tufm lactylation, increasing Tufm-mediated mitophagy, mitigating neuronal apoptosis, and eventually ameliorating the outcome of TBI. A novel molecular mechanism in neuronal apoptosis, TBI-initiated Tufm lactylation suppressing mitophagy, is thus revealed.

Using Natural Language Processing (GPT-4) for Computed Tomography Image Analysis of Cerebral Hemorrhages in Radiology: Retrospective Analysis.

BACKGROUND: Cerebral hemorrhage is a critical medical condition that necessitates a rapid and precise diagnosis for timely medical intervention, including emergency operation. Computed tomography (CT) is essential for identifying cerebral hemorrhage, but its effectiveness is limited by the availability of experienced radiologists, especially in resource-constrained regions or when shorthanded during holidays or at night. Despite advancements in artificial intelligence-driven diagnostic tools, most require technical expertise. This poses a challenge for widespread adoption in radiological imaging. The introduction of advanced natural language processing (NLP) models such as GPT-4, which can annotate and analyze images without extensive algorithmic training, offers a potential solution. OBJECTIVE: This study investigates GPT-4's capability to identify and annotate cerebral hemorrhages in cranial CT scans. It represents a novel application of NLP models in radiological imaging. METHODS: In this retrospective analysis, we collected 208 CT scans with 6 types of cerebral hemorrhages at Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, between January and September 2023. All CT images were mixed together and sequentially numbered, so each CT image had its own corresponding number. A random sequence from 1 to 208 was generated, and all CT images were inputted into GPT-4 for analysis in the order of the random sequence. The outputs were subsequently examined using Photoshop and evaluated by experienced radiologists on a 4-point scale to assess identification completeness, accuracy, and success. RESULTS: The overall identification completeness percentage for the 6 types of cerebral hemorrhages was 72.6% (SD 18.6%). Specifically, GPT-4 achieved higher identification completeness in epidural and intraparenchymal hemorrhages (89.0%, SD 19.1% and 86.9%, SD 17.7%, respectively), yet its identification completeness percentage in chronic subdural hemorrhages was very low (37.3%, SD 37.5%). The misidentification percentages for complex hemorrhages (54.0%, SD 28.0%), epidural hemorrhages (50.2%, SD 22.7%), and subarachnoid hemorrhages (50.5%, SD 29.2%) were relatively high, whereas they were relatively low for acute subdural hemorrhages (32.6%, SD 26.3%), chronic subdural hemorrhages (40.3%, SD 27.2%), and intraparenchymal hemorrhages (26.2%, SD 23.8%). The identification completeness percentages in both massive and minor bleeding showed no significant difference (P=.06). However, the misidentification percentage in recognizing massive bleeding was significantly lower than that for minor bleeding (P=.04). The identification completeness percentages and misidentification percentages for cerebral hemorrhages at different locations showed no significant differences (all P>.05). Lastly, radiologists showed relative acceptance regarding identification completeness (3.60, SD 0.54), accuracy (3.30, SD 0.65), and success (3.38, SD 0.64). CONCLUSIONS: GPT-4, a standout among NLP models, exhibits both promising capabilities and certain limitations in the realm of radiological imaging, particularly when it comes to identifying cerebral hemorrhages in CT scans. This opens up new directions and insights for the future development of NLP models in radiology. TRIAL REGISTRATION: ClinicalTrials.gov NCT06230419; https://clinicaltrials.gov/study/NCT06230419.

An injectable refrigerated hydrogel for inducing local hypothermia and neuroprotection against traumatic brain injury in mice.

BACKGROUND: Hypothermia is a promising therapy for traumatic brain injury (TBI) in the clinic. However, the neuroprotective outcomes of hypothermia-treated TBI patients in clinical studies are inconsistent due to several severe side effects. Here, an injectable refrigerated hydrogel was designed to deliver 3-iodothyronamine (T1AM) to achieve a longer period of local hypothermia for TBI treatment. Hydrogel has four advantages: (1) It can be injected into injured sites after TBI, where it forms a hydrogel and avoids the side effects of whole-body cooling. (2) Hydrogels can biodegrade and be used for controlled drug release. (3) Released T1AM can induce hypothermia. (4) This hydrogel has increased medical value given its simple operation and ability to achieve timely treatment. METHODS: Pol/T hydrogels were prepared by a low-temperature mixing method and characterized. The effect of the Pol/T hydrogel on traumatic brain injury in mice was studied. The degradation of the hydrogel at the body level was observed with a small animal imager. Brain temperature and body temperature were measured by brain thermometer and body thermometer, respectively. The apoptosis of peripheral nerve cells was detected by immunohistochemical staining. The protective effect of the hydrogels on the blood-brain barrier (BBB) after TBI was evaluated by the Evans blue penetration test. The protective effect of hydrogel on brain edema after injury in mice was detected by Magnetic resonance (MR) in small animals. The enzyme linked immunosorbent assay (ELISA) method was used to measure the levels of inflammatory factors. The effects of behavioral tests on the learning ability and exercise ability of mice after injury were evaluated. RESULTS: This hydrogel was able to cool the brain to hypothermia for 12 h while maintaining body temperature within the normal range after TBI in mice. More importantly, hypothermia induced by this hydrogel leads to the maintenance of BBB integrity, the prevention of cell death, the reduction of the inflammatory response and brain edema, and the promotion of functional recovery after TBI in mice. This cooling method could be developed as a new approach for hypothermia treatment in TBI patients. CONCLUSION: Our study showed that injectable and biodegradable frozen Pol/T hydrogels to induce local hypothermia in TBI mice can be used for the treatment of traumatic brain injury.

Intraoperative application of intelligent, responsive, self-assembling hydrogel rectifies oxygen and energy metabolism in traumatically injured brain.

In managing severe traumatic brain injury (TBI), emergency surgery involving the removal of damaged brain tissue and intracerebral hemorrhage is a priority. Secondary brain injury caused by oxidative stress and energy metabolic disorders, triggered by both primary mechanical brain damage and surgical insult, is also a determining factor in the prognosis of TBI. Unfortunately, the effectiveness of traditional postoperative intravenous neuroprotective agents therapy is often limited by the lack of targeting, timeliness, and side effects when neuroprotective agents systemically delivered. Here, we have developed injectable, intelligent, self-assembling hydrogels (P-RT/2DG) that can achieve precise treatment through intraoperative application to the target area. P-RT/2DG hydrogels were prepared by integrating a reactive oxygen species (ROS)-responsive thioketal linker (RT) into polyethylene glycol. By scavenging ROS and releasing 2-deoxyglucose (2DG) during degradation, these hydrogels functioned both in antioxidation and energy metabolism to inhibit the vicious cycle of post-TBI ROS-lactate which provoked secondary injury. In vitro and in vivo tests confirmed the absence of systemic side effects and the neuroprotective function of P-RT/2DG hydrogels in reducing edema, nerve cell apoptosis, neuroinflammation, and maintaining the blood-brain barrier. Our study thus provides a potential treatment strategy with novel hydrogels in TBI.

Dexamethasone for delayed edema after intracerebral hemorrhage： To be or not to be?

The pathogenesis of delayed cerebral edema after intracerebral hemorrhage is still unclear. In this case report, we speculate that the formation of subdural effusion or hemorrhage is associated with delayed cerebral edema. By referring to the treatment plan of chronic subdural hematoma, adding dexamethasone to routine medication, certain therapeutic effect has been achieved. Dexamethasone may maintain the stability of blood-brain barrier by directly increasing the expression of ZO-1, and reduce the neuroinflammatory response caused by NF-κB pathway by upregulating KLF2 expression, ultimately reducing nerve injury through multiple pathways.

Reactive Oxygen Species Scavenging Functional Hydrogel Delivers Procyanidins for the Treatment of Traumatic Brain Injury in Mice.

Traumatic brain injury (TBI) is accompanied by the overload of reactive oxygen species (ROS), which can result in secondary brain injury. Although procyanidins (PCs) have a powerful free radical scavenging capability and have been widely studied in the treatment of TBI, conventional systemic drug therapy cannot make the drug reach the targeted area in the early stage of TBI and will cause systemic side effects because of the presence of the blood-brain barrier (BBB). To address this tissue, we designed and fabricated a ROS-scavenging functional hydrogel loaded PC (GelMA-PPS/PC) to deliver the drug by responding to the traumatic microenvironment. In situ injection of the GelMA-PPS/PC hydrogel effectively avoided the BBB and was directly applied to the surface of brain tissue to target the traumatic area. Hydrophobic poly(propylene sulfide)60 (PPS60), an ROS quencher and H2O2-responsive substance, was covalently bound to GelMA and exposed in response to the trauma microenvironment. At the same time, the H2O2 response of PPS60 further caused the structure of the hydrogel to degrade and release the encapsulated PC. Then PC could regulate the oxidative stress response in the cells and synergistically deplete ROS to play a neurotrophic protective role. This work suggests a novel method for the treatment of secondary brain injury by inhibiting the oxidative stress response after TBI.

A Novel Targeted Nanoparticle for Traumatic Brain Injury Treatment: Combined Effect of ROS Depletion and Calcium Overload Inhibition.

Survival after severe traumatic brain injury (TBI) depends on minimizing or avoiding secondary insults to the brain. Overproduction of reactive oxygen species (ROS) and Ca2+ influx at the damaged site are the key factors that cause secondary injury upon TBI. Herein, a TBI-targeted lipid covered radical scavenger nanoparticle is developed to deliver nimodipine (Np) (CL-PPS/Np), in order to inhibit Ca2+ influx in neurons by Np and to scavenge ROS in the brain trauma microenvironment by poly(propylene sulfide)60 (PPS60 ) and thus prevent TBI-associated secondary injury. In post-TBI models, CL-PPS/Np effectively accumulates into the wound cavity and prolongs the time of systemic circulation of Np. CL-PPS/Np can markedly protect the integrity of blood-brain barrier, prevent brain edema, reduce cell death and inflammatory responses, and promote functional recovery after TBI. These findings may provide a new therapy for TBI to prevent the spread of the secondary injury.

Application of New Radiosensitizer Based on Nano-Biotechnology in the Treatment of Glioma.

Glioma is the most common intracranial malignant tumor, and its specific pathogenesis has been unclear, which has always been an unresolved clinical problem due to the limited therapeutic window of glioma. As we all know, surgical resection, chemotherapy, and radiotherapy are the main treatment methods for glioma. With the development of clinical trials and traditional treatment techniques, radiotherapy for glioma has increasingly exposed defects in the treatment effect. In order to improve the bottleneck of radiotherapy for glioma, people have done a lot of work; among this, nano-radiosensitizers have offered a novel and potential treatment method. Compared with conventional radiotherapy, nanotechnology can overcome the blood-brain barrier and improve the sensitivity of glioma to radiotherapy. This paper focuses on the research progress of nano-radiosensitizers in radiotherapy for glioma.

Correction: Injectable postoperative enzyme-responsive hydrogels for reversing temozolomide resistance and reducing local recurrence after glioma operation.

Correction for 'Injectable postoperative enzyme-responsive hydrogels for reversing temozolomide resistance and reducing local recurrence after glioma operation' by Zongren Zhao et al., Biomater. Sci., 2020, 8, 5306-5316, DOI: 10.1039/D0BM00338G.

In Situ implantable, post-trauma microenvironment-responsive, ROS Depletion Hydrogels for the treatment of Traumatic brain injury.

Traumatic brain injury (TBI) generates excess reactive oxygen species (ROS), which can exacerbate secondary injury and result in disability and death. Secondary injury cascades can trigger the release of uncontrolled ROS into the surrounding normal brain tissue, forming an extended pool of ROS, which leads to massive neuronal death. Here, we developed an injectable, post-trauma microenvironment-responsive, ROS depletion hydrogel embedded curcumin (Cur) (TM/PC) for reducing ROS levels in damaged brain tissue to promote the regeneration and recovery of neurons. Hydrogel was composed of three parts: (1) Hydrophobic poly (propylene sulfide)120 (PPS120) was synthesized, with a ROS quencher and H2O2-responsive abilities, to embed Cur. (2) Matrix metalloproteinase (MMP)-responsive triglycerol monostearate (TM) was used to cover the PPS120 to form a TM/P hydrogel. (3) Cur could further eradicate the ROS, promoting the regeneration and recovery of neurons. In two postoperative TBI models, TM/PC hydrogel effectively responded the TBI surgical environment and released drug. TM/PC hydrogel significantly depleted ROS and reduced brain edema. In addition, reactive astrocytes and activated microglia were decreased, growth-associated protein 43 (GAP43) and doublecortin (DCX) were increased, suggested that TM/PC hydrogel had the strongest anti-inflammatory effect and effectively promoted nerve regeneration after TBI. This study provides new information for the management of TBI to prevent the secondary spread of damage.

Hypoxia-Responsive Lipid-Polymer Nanoparticle-Combined Imaging-Guided Surgery and Multitherapy Strategies for Glioma.

Glioma is the most prevalent type of malignant brain tumor and is usually very aggressive. Because of the high invasiveness and aggressive proliferative growth of glioma, it is difficult to resect completely or cure with surgery. Residual glioma cells are a primary cause of postoperative recurrence. Herein, we describe a hypoxia-responsive lipid polymer nanoparticle (LN) for fluorescence-guided surgery, chemotherapy, photodynamic therapy (PDT), and photothermal therapy (PTT) combination multitherapy strategies targeting glioma. The hypoxia-responsive LN [LN (DOX + ICG)] contains a hypoxia-responsive component poly(nitroimidazole)25 [P-(Nis)25], the glioma-targeting peptide angiopep-2 (A2), indocyanine green (ICG), and doxorubicin (DOX). LN (DOX + ICG) comprises four distinct functional components: (1) A2: A2 modified nanoparticles effectively target gliomas, enhancing drug concentration in gliomas; (2) P-(Nis)25: (i) the hydrophobic component of LN (DOX + ICG) with hypoxia responsive ability to encapsulate DOX and ICG; (ii) allows rapid release of DOX from LN (DOX + ICG) after 808 nm laser irradiation; (3) ICG: (i) ICG allows imaging-guided surgery, combining PDT and PTT therapies; (ii) upon irradiation with an 808 nm laser, ICG creates a hypoxic environment; (4) DOX inhibits glioma growth. This work demonstrates that LN (DOX + ICG) might provide a novel clinical approach to preventing post-surgical recurrence of glioma.

Correction: Injectable postoperative enzyme-responsive hydrogels for reversing temozolomide resistance and reducing local recurrence after glioma operation.

Correction for 'Injectable postoperative enzyme-responsive hydrogels for reversing temozolomide resistance and reducing local recurrence after glioma operation' by Zongren Zhao et al., Biomater. Sci., 2020, DOI: .

Injectable postoperative enzyme-responsive hydrogels for reversing temozolomide resistance and reducing local recurrence after glioma operation.

Glioma is the most aggressive primary malignant brain tumor. The eradication of the gliomas by performing neurosurgery has not been successful due to the diffuse nature of malignant gliomas. Temozolomide (TMZ) is the first-line agent in treating gliomas after surgery, and its therapeutic efficacy is limited mainly due to the high activity levels of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) in glioma cells. Herein, we used an injectable matrix metalloproteinase (MMP) enzyme responsive hydrogel that loaded TMZ and O6-benzylamine (BG) (MGMT inhibitor) for eradicating residual TMZ-resistant gliomas after surgery. The hydrogels exhibited three features: (1) TMZ and BG could be encapsulated within the hydrophobic lamellae of the hydrogel to form Tm (TMZ + BG) hydrogels; (2) The hydrogels could release TMZ and BG in response to the high concentration of MMP enzymes after glioma surgery; (3) The hydrogels could increase local TMZ concentration and reduce side effects of BG. In vivo, the Tm (TMZ + BG) hydrogels inhibited the MGMT expression and sensitized TMZ-resistant glioma cells to TMZ. Moreover, the Tm (TMZ + BG) hydrogels effectively reduced the recurrence of TMZ-resistant glioma after surgery and significantly enhanced the efficiency of TMZ to inhibit glioma growth. Together, these data suggest that an MMP-responsive hydrogel is a promising localized drug delivery method to inhibit TMZ-resistant glioma recurrence after surgery.

Hypoxic Radiosensitizer-Lipid Coated Gold Nanoparticles Enhance the Effects of Radiation Therapy on Tumor Growth.

Radiotherapy (RT) has become one of the most effective treatments for malignant tumor. Intra-tumoral hypoxia is recognized as a chief reason that induces resistance to radiation. Moreover, the toxicities of RT to normal tissues limits the usage of high doses of radiation to eliminate cancer cells. Therefore, developing an effective radiosensitizer is critical for improving the curative effects of RT. In the present study, we developed angiopep-2 (A2) modified hypoxic lipid radiosensitizer (HLR) coated gold nanoparticles (GNPs) (referred to as A2-HRGNPs) to increase the RT sensitivity of tumors. The A2-HRGNPs are comprised of the following two functional components: (1) HLR enhances the RT sensitivity on hypoxic tumor cells; (2) alkylthiol modified GNPs (DGNPs) increase radiation effects by a dose enhancing effect in RT. Our findings suggest that the synergistic radiosensitizing effects of A2-HRGNPs can significantly enhance radiosensitization effects and thus, inhibit tumor growth in vivo.