D-mannose alleviates intervertebral disc degeneration through glutamine metabolism.

BACKGROUND: Intervertebral disc degeneration (IVDD) is a multifaceted condition characterized by heterogeneity, wherein the balance between catabolism and anabolism in the extracellular matrix of nucleus pulposus (NP) cells plays a central role. Presently, the available treatments primarily focus on relieving symptoms associated with IVDD without offering an effective cure targeting its underlying pathophysiological processes. D-mannose (referred to as mannose) has demonstrated anti-catabolic properties in various diseases. Nevertheless, its therapeutic potential in IVDD has yet to be explored. METHODS: The study began with optimizing the mannose concentration for restoring NP cells. Transcriptomic analyses were employed to identify the mediators influenced by mannose, with the thioredoxin-interacting protein (Txnip) gene showing the most significant differences. Subsequently, small interfering RNA (siRNA) technology was used to demonstrate that Txnip is the key gene through which mannose exerts its effects. Techniques such as colocalization analysis, molecular docking, and overexpression assays further confirmed the direct regulatory relationship between mannose and TXNIP. To elucidate the mechanism of action of mannose, metabolomics techniques were employed to pinpoint glutamine as a core metabolite affected by mannose. Next, various methods, including integrated omics data and the Gene Expression Omnibus (GEO) database, were used to validate the one-way pathway through which TXNIP regulates glutamine. Finally, the therapeutic effect of mannose on IVDD was validated, elucidating the mechanistic role of TXNIP in glutamine metabolism in both intradiscal and orally treated rats. RESULTS: In both in vivo and in vitro experiments, it was discovered that mannose has potent efficacy in alleviating IVDD by inhibiting catabolism. From a mechanistic standpoint, it was shown that mannose exerts its anti-catabolic effects by directly targeting the transcription factor max-like protein X-interacting protein (MondoA), resulting in the upregulation of TXNIP. This upregulation, in turn, inhibits glutamine metabolism, ultimately accomplishing its anti-catabolic effects by suppressing the mitogen-activated protein kinase (MAPK) pathway. More importantly, in vivo experiments have further demonstrated that compared with intradiscal injections, oral administration of mannose at safe concentrations can achieve effective therapeutic outcomes. CONCLUSIONS: In summary, through integrated multiomics analysis, including both in vivo and in vitro experiments, this study demonstrated that mannose primarily exerts its anti-catabolic effects on IVDD through the TXNIP-glutamine axis. These findings provide strong evidence supporting the potential of the use of mannose in clinical applications for alleviating IVDD. Compared to existing clinically invasive or pain-relieving therapies for IVDD, the oral administration of mannose has characteristics that are more advantageous for clinical IVDD treatment.

Risk factors involved in the formation of multiple intracranial aneurysms.

BACKGROUND: Although several risk factors of the multiple intracranial aneurysms (MIAs) formation has been reported, the results are controversial. We aimed to find out the risk factors of MIAs formation by analyzing our clinic data combined with a meta-analysis. MATERIAL AND METHODS: A retrospective review work of medical records for the patients with aneurysms was undertaken. Univariate analysis was used to examine all mentioned variables. Binary logistic regression analysis was used to identify the risk factors of MIAs formation. RESULTS: In the retrospective review work, a total of 565 patients with aneurysm were included in this study. Of these 565 participants, 449 patients suffered SIAs and 116 patients suffered MIAs. Univariate analysis showed a significant difference in terms of female, cigarette smoking, family history of hypertension, and primary hypertension between the SIAs and MIAs group. The binary logistic regression analysis showed that the female (OR = 1.624), primary hypertension (OR = 1.563), and family history of hypertension (OR = 2.496) were independent risk factors of the formation of MIAs (for each P < 0.05). With regard to the meta-analysis results, it revealed that there was significant difference in the rates of female (P < 0.001), cigarette smoking (P < 0.001), primary hypertension (P = 0.001), and higher age (P = 0.011) among the MIAs patients. CONCLUSIONS: A higher rate of the formation of MIAs is closely associated with the elder and female. Patients with hypertension history, cigarette smoking, and family primary hypertension history also affected the formation of MIAs, these risk factors should be a guard against.

Decreased numbers of circulating endothelial progenitor cells are associated with hyperglycemia in patients with traumatic brain injury.

Hyperglycemia reduces the number of circulating endothelial progenitor cells, accelerates their senescence and impairs their function. However, the relationship between blood glucose levels and endothelial progenitor cells in peripheral blood of patients with traumatic brain injury is unclear. In this study, 101 traumatic brain injury patients admitted to the Department of Neurosurgery, Tianjin Medical University General Hospital or the Department of Neurosurgery, Tianjin Huanhu Hospital, China, were enrolled from April 2005 to March 2007. The number of circulating endothelial progenitor cells and blood glucose levels were measured at 1, 4, 7, 14 and 21 days after traumatic brain injury by flow cytometry and automatic biochemical analysis, respectively. The number of circulating endothelial progenitor cells and blood sugar levels in 37 healthy control subjects were also examined. Compared with controls, the number of circulating endothelial progenitor cells in traumatic brain injury patients was decreased at 1 day after injury, and then increased at 4 days after injury, and reached a peak at 7 days after injury. Compared with controls, blood glucose levels in traumatic brain injury patients peaked at 1 day and then decreased until 7 days and then remained stable. At 1, 4, and 7 days after injury, the number of circulating endothelial progenitor cells was negatively correlated with blood sugar levels (r = -0.147, P < 0.05). Our results verify that hyperglycemia in patients with traumatic brain injury is associated with decreased numbers of circulating endothelial progenitor cells. This study was approved by the Ethical Committee of Tianjin Medical University General Hospital, China (approval No. 200501) in January 2015.

Dynamic changes in growth factor levels over a 7-day period predict the functional outcomes of traumatic brain injury.

Traumatic brain injury (TBI) can result in poor functional outcomes and death, and overall outcomes are varied. Growth factors, such as angiopoietin-1 (Ang-1), vascular endothelial growth factor (VEGF), and granulocyte-colony stimulating factor (G-CSF), play important roles in the neurological functions. This study investigated the relationship between serum growth factor levels and long-term outcomes after TBI. Blood samples from 55 patients were collected at 1, 3 and 7 days after TBI. Blood samples from 39 healthy controls were collected as a control group. Serum Ang-1, G-CSF, and VEGF levels were measured using ELISA. Patients were monitored for 3 months using the Glasgow Outcome Scale-Extended (GOSE). Patients having a GOSE score of > 5 at 3 months were categorized as a good outcome, and patients with a GOSE score of 1-5 were categorized as a bad outcome. Our data demonstrated that TBI patients showed significantly increased growth factor levels within 7 days compared with healthy controls. Serum levels of Ang-1 at 1 and 7 days and G-CSF levels at 7 days were significantly higher in patients with good outcomes than in patients with poor outcomes. VEGF levels at 7 days were remarkably higher in patients with poor outcomes than in patients with good outcomes. Receiver operating characteristic analysis showed that the best cut-off points of serum growth factor levels at 7 days to predict functional outcome were 1,333 pg/mL for VEGF, 447.2 pg/mL for G-CSF, and 90.6 ng/mL for Ang-1. These data suggest that patients with elevated levels of serum Ang-1, G-CSF, and decreased VEGF levels had a better prognosis in the acute phase of TBI (within 7 days). This study was registered with the Chinese Clinical Trial Registry (registration number: ChiCTR1800018251) on September 7, 2018.

[Molecular mechanism of AtGA3OX1 and AtGA3OX2 genes affecting secondary wall thickening in stems in Arabidopsis].

Bioactive gibberellins (GAs) are a type of important plant growth regulators, which play the key roles in multiple processes, such as seed germination, leaf expansion, flowering, fruit bearing, and stem development. Its biosynthesis is regulated by a variety of enzymes including gibberellin 3-oxidase that is a key rate-limiting enzyme. In Arabidopsis, gibberellin 3-oxidase consists of four members, of which AtGA3OX1 and AtGA3OX2 are highly expressed in stems, suggesting the potential roles in the stem development played by the two genes. To date, there are few studies on AtGA3OX1 and AtGA3OX2 regulating secondary wall thickening in stems. In this study, we used the atga3ox1atga3ox2 double mutant as the materials to study the effects of AtGA3OX1 and AtGA3OX2 genes on secondary wall thickening in stems. The results indicated that simulations repression of AtGA3OX1 and AtGA3OX2 genes resulted in significantly reduction of secondary wall thickening of fiber cells, but not that of vessel cells. Three main components (cellulose, hemicelluloses, and lignin) were also dramatically suppressed in the double mutants. qRT-PCR analysis demonstrated that the expressions of secondary wall biosynthetic genes and the associated transcription factors were obviously affected in AtGA3OX1 and AtGA3OX2 double mutant. Therefore, we presume that Arabidopsis AtGA3OX1 and AtGA3OX2 genes might activate the expression of these transcription factors, thus regulate secondary wall thickening in stems. Together, our results provide a theoretical basis for enhancing the lodging resistance of food crops and improving the biomass of energy plants by genetically engineering Arabidopsis AtGA3OX homologs.

[Intraoperative magnetic resonance imaging-guided functional neuronavigation plus intraoperative neurophysiological monitoring for microsurgical resection of lesions involving hand motor area].

OBJECTIVE: To explore the methods and applications of intraoperative magnetic resonance imaging (iMRI)-guided functional neuronavigation plus intraoperative neurophysiological monitoring (IONM) for microsurgical resection of lesions involving hand motor area. METHODS: A total of 16 patients with brain lesions adjacent to hand motor area were recruited from January 2011 to April 2012. All of them underwent neuronavigator-assisted microsurgery. Also IONM was conducted to further map hand motor area and epileptogenic focus. High-field iMRI was employed to update the anatomical and functional imaging date and verify the extent of lesion resection. RESULTS: Brain shifting during the functional neuronavigation was corrected by iMRI in 5 patients. Finally, total lesion resection was achieved in 13 cases and subtotal resection in 3 cases. At Months 3-12 post-operation, hand motor function improved (n = 10) or remained unchanged (n = 6). None of them had persistent neurological deficit. The postoperative seizure improvement achieved Enge II level or above in 9 cases of brain lesions complicated with secondary epilepsy. CONCLUSION: Intraoperative MRI, functional neuronavigation and neurophysiological monitoring technique are complementary in microsurgery of brain lesions involving hand motor area. Combined use of these techniques can obtain precise location of lesions and hand motor functional structures and allow a maximum resection of lesion and minimization of postoperative neurological deficits.

[Application of high-field intraoperative magnetic resonance imaging in stereotactic aspiration and drainage of hypertensive hematomas].

OBJECTIVE: To explore the application values of high-field intraoperative magnetic resonance imaging (MRI) in stereotactic aspiration and drainage of hypertensive hematomas. METHODS: During a period of August 2011 to January 2012, 11 patients with hypertensive hemorrhage were examined preoperatively by conventional MRI and diffusion tensor imaging (DTI) with 1.5T intraoperative MRI system (Signa HDi, GE, USA) at Tianjin Medical University General Hospital. The anatomic relationship of corticospinal tract (CST) and hematoma was used for the operative planning with the neuronavigation planning workstation (iPlan Cranial 3.0 software, BrainLab, Germany) for 3D reconstruction. During stereotactic surgery, intraoperative MRI scan was performed. According to the clearance rate of hematomas, the operators decided to finish the operation or update the operative planning to continue hematoma removal. All patients were reexamined by conventional MRI and DTI at Week 3 postoperation. Then comparative analysis was performed for the preoperative and postoperative integrity of CST. RESULTS: No death or severe complications occurred. All patients showed improvement of motor function and the postoperative integrity of CST. CONCLUSION: The intracranial condition may be monitored effectively by intraoperative MRI throughout surgery so as to increase the rate of hematoma removal and reduce the postoperative complications.

[Positron emission tomography plus VEEG in the localization of epileptic foci in negative-MRI interact epilepsy].

OBJECTIVE: To explore the application value of positron emission tomography (PET) in the localization of magnetic resonance imaging (MRI)-negative epileptogenic focus. METHODS: Brain images of 18fluoro-2-deoxy-D-glucose (18F-FDG) and 13N-NH3·H2O-PET, MRI and video electroencephalography (VEEG) were obtained in 65 patients. Preoperative and postoperative localizations were compared in MRI-negative patients. And the results of PET and VEEG were compared between the MRI-positive and MRI-negative groups. RESULTS: MRI scans were normal in 26 cases and abnormal in 35 cases. Sixty-one patients had interictal epileptiform discharge on VEEG (brain regions, n = 12; multiple brain areas, n = 16; hemisphere, n = 13; unspecified location, n = 20) and interictal PET imaging (brain regions, n = 23; multiple brain areas, n = 28; hemisphere, n = 5; unspecified location, n = 6). And 17 MRI-negative patients underwent operations and 12 of them reached the Engels I-II level standard. Both PET and VEEG were compared between the MRI-positive and MRI-negative groups. No significant differences existed between two group (P < 0.05). A comparison of PET and VEEG showed statistical significance in two group (P > 0.05). CONCLUSIONS: PET imaging is both sensitive and effective in the detection and localization of epileptogenic foci. Especially for MRI-negative cases, it is an indispensable tool of localizing epileptogenic foci.

[Applications of blood oxygenation level dependent-functional magnetic resonance imaging, diffusion tensor imaging and intraoperative neurophysiology monitoring in secondary epileptic surgery in M1 area].

OBJECTIVE: To explore the applications of blood oxygenation level dependent-functional magnetic resonance imaging (BOLD-fMRI), diffusion tensor imaging (DTI) and cortical somatosensory evoked potentials (Co-SEP), motor evoked potentials (MEP) and electrocorticogram (ECoG) in secondary epileptic surgery of primary motor area (M1). METHODS: In 19 patients, preoperative BOLD-fMRI were performed to display the relationship between active zone, fiber bundle and epileptogenic lesions. Besides, Co-SEP, MEP and ECoG were also carried out intra-operatively to direct the resection of epileptogenic lesion and epileptogenic focus. At the same time, the nervous functions were protected as much as possible. Then fMRI was performed again to ensure that the post-operative nervous function was excellent. RESULTS: In preoperative BOLD-fMRI and DTI examinations, active zone and fiber bundle could be seen at the edge of lesions (n = 12); range reduced, become deformed or removed (n = 6); glioma epileptogenic lesion was close-up with M1 (n = 1). The central sulcus was confirmed by Co-SEP in all cases. And two cases were inconsistent with anatomical location; Stimulating precentral gyrus, MEP were elicited post-operatively from orbicularis oris, muscle of thenar, hypothenar muscle or flexor digitorum brevis. Under the monitoring of ECoG, spike-wave was monitored in all cases. Of these, epileptogenic focus was in M1 (n = 15). After treatment, spike-wave were reduced significantly or disappeared. At a post-operative follow-up of 6 - 12 months, seizure improvement has achieved Engel III level or above (n = 18). On re-examinations of BOLD-fMRI and DTI, active zone became bigger than before and fiber bundle was symmetric with opposite side. Two of 19 cases had transient motor aphasia incompletely or hemiparesis. No permanent neurological dysfunction occurred. There was no relapse in cases of glioma. CONCLUSION: BOLD-fMRI and Co-SEP, MEP and ECoG are complementary in M1 of secondary epilepsy surgery. It is effective to preserve nervous functions and enhance the quality of life for patients with epilepsy.

[Localization of epileptic foci in frontal lobe epilepsy and its surgical therapy].

OBJECTIVE: To analyze the clinical data and pre-operative examination results of frontal lobe epilepsy and combine with intra-operative intracranial electrical record in order to localize epileptic foci and to direct surgical therapy. METHODS: Preoperative EEG record and MRI scan were performed in 23 patients with refractory frontal lobe epilepsy. Among them, 17 patients received interictal 18F-FDG-PET-CT, 11 received MEG examination, 2 received functional MRI, 10 received surgical operation and intra-operative intracranial electrical record. RESULTS: The positive predictive value of clinical features of epileptic seizure, interictal EEG, ictal EEG, MRI and PET-CT were 56.52%, 56.52%, 60.87%, 54.55% and 94.12% respectively. Their consistent results helped to confirm the epileptogenic zone. MEG was more accurate than EEG. ECoE and VEEG monitoring was significant for operative guidance. CONCLUSION: A series of examinations is necessary for the diagnosis of epileptogenic zone of frontal lobe epilepsy. The surgical outcome is related to the accuracy of epileptic foci localization and the removal of epileptogenic zone.

[Stereotactic resection of small intracerebral lesions in motor cortex using blood oxygen level depended functional magnetic resonance imaging and diffusion tensor imaging fusion guidance].

OBJECTIVE: To explore the effect of stereotactic resection of small intracerebral lesions located in the motor cortex using blood oxygen level depended functional magnetic resonance imaging (BOLD-fMRI) and diffusion tensor imaging (DTI) fusion guidance. METHODS: Fifteen patients with lesions in posterior frontal lobe to anterior central gyrus, 1.5-3 cm in diameter, underwent combined three-dimensional (3D) enhancement MRI with BOLD-fMRI, and DTI. Computer procedure was used to perform the images fusion to show directly the lesions, motor cortex, and corticospinal tract, and to confirm their position relationship and design the operative approach so as to guide the stereotactic resection of the small intracerebral lesions. RESULTS: The images fusion demonstrated that the motor cortex and corticospinal tract were located in the lateral-posterior side of the lesions, and were both compressed, reformatted and displaced. Total removal of the lesions under microscope was achieved in 12 cases, and subtotal removal in 3 cases. Histological examination showed 3 cases of meningeoma, 3 cases of astrocytoma of grade II, 2 cases of astrocytoma of grade III, 2 cases of abscess, and 2 cases of cavernous angioma. No complication was found postoperatively. CONCLUSION: Mutual complementarity can be achieved by combining 3D-enhancement MRI, BOLD-fMRI, and DTI. Stereotactic resection of the small intracerebral lesions is safe, accurate and effective under the images fusion guidance.

Therapeutic effect of nimodipine on experimental brain injury.

OBJECTIVE: To study the therapeutic effect of nimodipine on experimental brain injury. METHODS: Experimental and control rabbits were subjected to a closed head injury. In one group nimodipine was given intravenously and the effect evaluated by electron microscopy, brain water content, calcium levels, transcranial Doppler, and intracranial pressure monitoring. RESULTS: In rabbits treated with nimodipine the level of neuronal cytosolic free calcium was markedly decreased. There were less cellular damage and less spasm of the middle cerebral artery seen on electron microscopy. No difference regarding intracranial pressure changes between the two groups was noted. CONCLUSIONS: Nimodipine has a protective action on brain injury by blocking a series of pathological reactions induced by neuronal calcium overload, and by reducing the spasm of brain vessels and improving cerebral blood flow.