Design and Experiment of Combined Infrared and Hot-Air Dryer Based on Temperature and Humidity Control with Sea Buckthorn (Hippophae rhamnoides L.).

A drying device based on infrared radiation heating technology combined with temperature and humidity process control technology was created to increase the drying effectiveness and quality of sea buckthorn. Based on the conventional k-turbulence model, the velocity field in the air distribution chamber was simulated using COMSOL 6.0 software. The airflow of the drying medium in the air distribution chamber was investigated, and the accuracy of the model was verified. Given that the inlet of each drying layer in the original model had a different velocity, the velocity flow field was improved by including a semi-cylindrical spoiler. The results showed that installation of the spoiler improved the homogeneity of the flow field for various air intakes, as the highest velocity deviation ratio dropped from 26.68% to 0.88%. We found that sea buckthorn dried more rapidly after being humidified, reducing the drying time by 7.18% and increasing the effective diffusion coefficient from 1.12 × 10-8 to 1.23 × 10-8 m2/s. The L*, rehydration ratio, and vitamin C retention rate were greater after drying with humidification. By presenting this hot-air drying model as a potential high-efficiency and high-quality preservation technology for sea buckthorn, we hope to advance the development of research in the sea buckthorn drying sector.

Metabolomics provide a novel interpretation of the changes in flavonoids during sea buckthorn (Hippophae rhamnoides L.) drying.

Flavonoids are major nutrients in sea buckthorn berries. However, the effects of drying methods on flavonoids in sea buckthorn berries are unclear. In this study, ultra-performance liquid chromatography and metabolomics were adopted to analyse the effects of hot air drying (HAD) and infrared drying (IRD) on flavonoid compounds and antioxidant capacity in sea buckthorn berries. In total, 97 metabolites belonging to 12 classes were identified, including 26 flavones, 23 flavonols, and 11 flavanones. Additionally, 32 differential metabolites were identified among groups. Isorhamnetin and quercetin contents increased in response to HAD and IRD, while (-)-epigallocatechin and (-)-gallocatechin contents decreased. Differential metabolism of flavonoid compounds occurred mainly via the flavonoid biosynthesis and secondary metabolite biosynthesis pathways. Flavonoid compound degradation might be associated with antioxidant activity during drying. This study elucidated the effect of drying on nutritional components of sea buckthorn berries and may guide the improvement of quality during food processing.

Drying sea buckthorn berries (Hippophae rhamnoides L.): Effects of different drying methods on drying kinetics, physicochemical properties, and microstructure.

Sea buckthorn berries are important ingredients in Chinese medicine and food processing; however, their high moisture content can reduce their shelf life. Effective drying is crucial for extending their shelf life. In the present study, we investigated the effects of hot-air drying (HAD), infrared drying (IRD), infrared-assisted hot-air drying (IR-HAD), pulsed-vacuum drying (PVD), and vacuum freeze-drying (VFD) on the drying kinetics, microstructure, physicochemical properties (color, non-enzyme browning index, and rehydration ratio), and total phenol, total flavonoid, and ascorbic acid contents of sea buckthorn berries. The results showed that the IR-HAD time was the shortest, followed by the HAD, IRD, and PVD times, whereas the VFD time was the longest. The value of the color parameter L* decreased from 53.44 in fresh sea buckthorn berries to 44.18 (VFD), 42.60 (PVD), 37.58 (IRD), 36.39 (HAD), and 36.00 (IR-HAD) in dried berries. The browning index also showed the same trend as the color change. Vacuum freeze-dried berries had the lowest browning index (0.24 Abs/g d.m.) followed by that of pulsed-vacuum-(0.28 Abs/g d.m.), infrared- (0.35 Abs/g d.m.), hot-air-(0.42 Abs/g d.m.), and infrared-assisted hot-air-dried berries (0.59 Abs/g d.m.). The ascorbic acid content of sea buckthorn berries decreased by 45.39, 53.81, 74.23, 77.09, and 79.93% after VFD, PVD, IRD, IR-HAD, and HAD, respectively. The vacuum freeze-dried and pulsed-vacuum-dried sea buckthorn berries had better physicochemical properties than those dried by HAD, IRD, and IR-HAD. Overall, VFD and PVD had the highest ascorbic acid and total phenolic contents, good rehydration ability, and bright color. Nonetheless, considering the high cost of VFD, we suggest that PVD is an optimal drying technology for sea buckthorn berries, with the potential for industrial application.

Visual Detection of Water Content Range of Seabuckthorn Fruit Based on Transfer Deep Learning.

To realize the classification of sea buckthorn fruits with different water content ranges, a convolution neural network (CNN) detection model of sea buckthorn fruit water content ranges was constructed. In total, 900 images of seabuckthorn fruits with different water contents were collected from 720 seabuckthorn fruits. Eight classic network models based on deep learning were used as feature extraction for transfer learning. A total of 180 images were randomly selected from the images of various water content ranges for testing. Finally, the identification accuracy of the network model for the water content range of seabuckthorn fruit was 98.69%, and the accuracy on the test set was 99.4%. The program in this study can quickly identify the moisture content range of seabuckthorn fruit by collecting images of the appearance and morphology changes during the drying process of seabuckthorn fruit. The model has a good detection effect for seabuckthorn fruits with different moisture content ranges with slight changes in characteristics. The migration deep learning can also be used to detect the moisture content range of other agricultural products, providing technical support for the rapid nondestructive testing of moisture contents of agricultural products.

Sea Buckthorn Pretreatment, Drying, and Processing of High-Quality Products: Current Status and Trends.

Sea buckthorn is a kind of berry rich in nutritional and industrial value. Due to its thin skin, juicy pulp, and short shelf life, it is usually preserved via freezing methods or directly processed into sea buckthorn puree after harvest. It can also be dried and processed into products such as dried sea buckthorn fruit, freeze-dried sea buckthorn powder, and sea buckthorn oil. This review, therefore, provides an overview of the existing state of drying and high-quality processing of sea buckthorn. The effects of different pretreatment and drying techniques on the drying characteristics and quality of sea buckthorn and the existing problems of superior-quality processing of sea buckthorn products are summarised. The development trend of sea buckthorn drying methods and the ways to achieve high-quality processing of sea buckthorn products are indicated. These ways are mainly related to the following: (1) The application of combined pretreatment and drying techniques to find a balance between economy, ecology, and efficiency; (2) Introducing new online measurement and control technology into drying equipment; (3) Optimising the existing process to form a complete sea buckthorn industrial chain and develop the sea buckthorn deep-processing industry.

Hot Air Drying of Seabuckthorn (Hippophae rhamnoides L.) Berries: Effects of Different Pretreatment Methods on Drying Characteristics and Quality Attributes.

Seabuckthorn berries are difficult to dry because the outermost surface is covered with a dense wax layer, which prevents moisture transfer during the drying process. In this study, uses of ultrasonic-assisted alkali (UA), pricking holes in the skin (PH) and their combination (UA + PH) as pretreatment methods prior to hot air drying and their effects on drying characteristics and quality attributes of seabuckthorn berries were investigated. Selected properties include color, microstructure, rehydration capacity, as well as total flavonoids, phenolics and ascorbic acid contents. Finally, the coefficient of variation method was used for comprehensive evaluation. The results showed that all pretreatment methods increased the drying rate; the combination of ultrasonic-assisted alkali (time, 15 min) and pricking holes (number, 6) (UA15 + PH6) had the highest drying rate that compared with the control group, the drying time was shortened by 33.05%; scanning electron microscopy images revealed that the pretreatment of UA could dissolve the wax layer of seabuckthorn berries, helped to form micropores, which promoted the process of water migration. All the pretreatments reduced the color difference and increased the lightness. The PH3 samples had the highest value of vitamin C content (54.71 mg/100 g), the UA5 and PH1 samples had the highest value of total flavonoid content (11.41 mg/g) and total phenolic content (14.20 mg/g), respectively. Compared to other pretreatment groups, UA15 + PH6 achieved the highest quality comprehensive score (1.013). Results indicate that UA15 + PH6 treatment is the most appropriate pretreatment method for improving the drying characteristics and quality attributes of seabuckthorn berries.

Prediction of Apple Slices Drying Kinetic during Infrared-Assisted-Hot Air Drying by Deep Neural Networks.

The effects of temperature, air velocity, and infrared radiation distances on the drying characteristics and quality of apple slices were investigated using infrared-assisted-hot air drying (IRAHAD). Drying temperature and air velocity had remarkable effects on the drying kinetics, color, total phenol content, total flavonoid content, and vitamin C content (VCC) of apple slices. Infrared radiation distance demonstrated similar results, other than for VCC and color. The shortest drying time was obtained at 70 °C, air velocity of 3 m/s and infrared radiation distance of 10 cm. A deep neural network (DNN) was developed, based on 4526 groups of apple slice drying data, and was applied to predict changes in moisture ratio (MR) and dry basis moisture content (DBMC) of apple slices during drying. DNN predicted that the coefficient of determination (R2) was 0.9975 and 1.0000, and the mean absolute error (MAE) was 0.001100 and 0.000127, for MR and DBMC, respectively. Furthermore, DNN obtained the highest R2 and lowest MAE values when compared with multilayer perceptron (MLP) and support vector regression (SVR). Therefore, DNN can provide new ideas for the rapid detection of apple moisture and guide apple processing in order to improve quality and intelligent control in the drying process.

Corrigendum: Risk of urinary bladder cancer in patients with inflammatory bowel diseases: A meta-analysis.

[This corrects the article DOI: 10.3389/fsurg.2021.636791.].

Tislelizumab: A Modified Anti-tumor Programmed Death Receptor 1 Antibody.

Tislelizumab is an anti-programmed death receptor 1 (PD-1) monoclonal immunoglobulin G 4 antibody developed by BeiGene. The structure of tislelizumab has been modified to maximally inhibit the binding of PD-1 to programmed death ligand 1 (PD-L1) and minimize the binding of tislelizumab to Fcγ receptors. In clinical studies, tislelizumab has shown preliminary anti-tumor effects in various solid tumors, such as Hodgkin's lymphoma, urothelial carcinoma, lung cancer, gastric and esophageal cancer, liver cancer, nasopharyngeal carcinoma, colorectal cancer, and microsatellite instability-high/mismatch repair-deficient tumors. In addition, it also showed new promise in solid tumor treatment in combination with ociperlimab. Due to its satisfactory anti-tumor effects, tislelizumab has received approvals in China for the treatment of classical Hodgkin's lymphoma, urothelial carcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, and hepatocellular carcinoma, and it is now under investigation for a new indication in microsatellite instability-high/mismatch repair-deficient tumors. Moreover, it has been granted orphan designations in hepatocellular carcinoma, esophageal cancer, and gastric cancer, including cancer of the gastroesophageal junction, by the US Food and Drug Administration. Tislelizumab has an acceptable safety profile; the most common adverse effects include fatigue, anemia, and decreased neutrophil count, while the most fatal events have been related to respiratory infection or failure, and hepatic injury. Tislelizumab has an economic advantage compared with other well-studied PD-1/PD-L1 inhibitors; thus, the introduction of it could provide clinical oncologists with an effective weapon against tumors and may alleviate the burden of cancer patients.

Pulsed Vacuum Drying of Pepper (Capsicum annuum L.): Effect of High-Humidity Hot Air Impingement Blanching Pretreatment on Drying Kinetics and Quality Attributes.

With a high moisture content, fresh peppers are perishable and rot easily. Drying is essential for shelf-life extension. The natural thin wax layer on the pepper surface hinders moisture transfer. Traditionally, chemical dipping or mechanical pricking is used to remove this wax layer. However, in chemical dipping, chemical residues can trigger food-safety issues, while the low efficiency of mechanical pricking hinders its industrial application. Feasible pretreatment methods are advantageous for industrial use. Here, an emerging pretreatment technique (high-humidity hot-air impingement blanching, HHAIB) was used for peppers before drying and its effects on drying characteristics, microstructure, and polyphenol oxidase (PPO) activity were explored. The impact of drying temperature on color parameters and red pigment content of pulsed-vacuum-dried peppers was also evaluated. PPO activity was reduced to less than 20% after blanching at 110 °C for 60 s. HHAIB reduced drying time and PPO activity and promoted chemical-substance release. Effective water diffusivity was highest (5.01 × 10-10 m2/s) after blanching at 110 °C for 90 s, and the brightness value and red pigment content were highest (9.94 g/kg) at 70 °C. HHAIB and pulsed vacuum drying are promising pretreatment and drying methods for enhancing the drying rate and quality of red peppers.

Risk of Urinary Bladder Cancer in Patients With Inflammatory Bowel Diseases: A Meta-Analysis.

A systematic search of the PubMed, Cochrane, Embase, and Web of Science databases was conducted to investigate the risk of urinary bladder cancer (BC) in patients with inflammatory bowel disease (IBD). We identified 168 articles, of which 11 met the inclusion and exclusion criteria. Our analysis included 165,176 patients with IBD, 491 of whom had BC. Overall, the pooled standardized incidence ratio (SIR) was 0.99 (95% CI: 0.87-1.12; I 2 = 0%). Further subgroup analysis showed that BC risk was neither statistically higher for Crohn's disease (CD) (SIR: 1.19; 95% CI: 0.94-1.44; I 2 = 0%) nor for patients with ulcerative colitis (UC) (SIR: 0.92; 95% CI: 0.77-1.06; I 2 = 0%). In the analysis of two case-control studies providing data on BC in UC and CD combined, IBD patients seemed to have a higher risk of BC than non-IBD patients (relative risk: 1.25; 95% CI: 0.77-2.03; I 2 = 37.5%). Although the overall risk of BC was not significantly increased among patients with IBD, there was a weak trend for the risk to be elevated in CD patients, indicating marginal significance. These findings may primarily be explained by the opposite effects of smoking on CD and UC as well as the immunosuppressive drugs these patients often take.

Toripalimab: the First Domestic Anti-Tumor PD-1 Antibody in China.

Toripalimab (Tuoyi™) is a selective, recombinant, humanized monoclonal antibody against programmed death protein 1 (PD-1) developed by Shanghai Junshi Bioscience Co., Ltd. Toripalimab is able to bind to PD-1 and block the interaction with its ligands. The binding of toripalimab to PD-1 is mainly attributed to the heavy chain of the former and the FG loop of the latter. Toripalimab received a conditional approval in China for the treatment of melanoma (second-line) in December, 2018. It has also received approvals to treat nasopharyngeal carcinoma (first-line and third-line) and urothelial carcinoma (second-line) in 2021. Additionally, several orphan drug designations were granted to toripalimab by the US Food and Drug Administration. Toripalimab has exhibited primary anti-tumor effects in tumors such as melanoma, lung cancer, digestive tract tumors, hepatobiliary and pancreatic tumors, neuroendocrine neoplasms, nasopharyngeal carcinoma and urothelial carcinoma. It showed a satisfactory anti-tumor effect and long-term survival benefits in Chinese melanoma patients, while the combination of axitinib with toripalimab exhibited an impressive result in metastatic mucosal melanoma. As a checkpoint inhibitor, toripalimab was generally well-tolerated in the enrolled patients. Due to different study populations, comparisons could not be made directly between toripalimab and other drugs in most cases. Nevertheless, the introduction of toripalimab may offer a valuable choice for decision-making in the treatment of tumors in the future.

Short-term Efficacy of the Percutaneous Vertebroplasty Using a Curved Versus Straight Vertebroplasty Needle in Osteoporotic Vertebral Compression Fractures.

The purpose of this study was to compare the efficacy of the curved puncture approach with 2 conventional approaches in percutaneous vertebroplasty (PVP) for the treatment of single-level osteoporotic vertebral compression fractures. Ninety-six patients with a single-level thoracolumbar vertebral fracture were surgically treated in the authors' department from February 2016 to February 2018. Patients were randomly divided into 3 groups, including 25 patients who had PVP punctured with a curved vertebroplasty needle (group C), 40 patients with unipedicular PVP with a straight vertebroplasty needle (group U), and 31 patients with bipedicular PVP with a straight vertebroplasty needle (group B). The short-term efficacies of PVP using different vertebroplasty needles were compared. Significant differences were tested preoperatively and postoperatively in vertebral body height variation, visual analog scale score, and Oswestry Disability Index in each of the 3 groups (P<.05). There was no significant difference among the groups in terms of Cobb angle correction and bone cement leakage. Group C and group U were superior to group B in terms of operative time and injected cement volume (P<.05). Twenty-four (96.0%) patients in group C and 29 (93.5%) patients in group B had centered cement distribution without significant differences (P>.05), which was superior to group U (P<.05). Curved puncture PVP achieved a satisfactory clinical outcome for osteoporotic vertebral compression fractures, with the advantages of less operative time, less injected cement volume, and more reasonable cement distribution for stabilization of the affected vertebrae. [Orthopedics. 2021;44(1):e131-e138.].

Complex N-glycosylation stabilizes surface expression of transient receptor potential melastatin 4b protein.

N-glycosylation is important for the function and regulation of ion channels. We examined the role of N-glycosylation of transient receptor potential melastatin (Trpm) 4b, a membrane glycoprotein that regulates calcium influx. Trpm4b was expressed in vivo in all rat tissues examined. In each tissue, Trpm4b had a different molecular mass, between ∼129 and ∼141 kDa, but all reverted to ∼120 kDa following treatment with peptide:N-glycosidase F, consistent with N-glycosylation being the principal form of post-translational modification of Trpm4b in vivo. In six stable isogenic cell lines that express different levels of Trpm4b, two forms were found, high mannose, core-glycosylated and complex, highly glycosylated (HG), with HG-Trpm4b comprising 85% of the total Trpm4b expressed. For both forms, surface expression was directly proportional to the total Trpm4b expressed. Complex N-glycosylation doubled the percentage of Trpm4b at the surface, compared with high mannose N-glycosylation. Mutation of the single N-glycosylation consensus sequence at Asn-988 (Trpm4b-N988Q), located near the pore-forming loop between transmembrane helices 5 and 6, prevented glycosylation, but did not prevent surface expression, impair formation of functional membrane channels, or alter channel conductance. In transfection experiments, the time courses for appearance of HG-Trpm4b and Trpm4b-N988Q on the surface were similar. In experiments with cycloheximide inhibition of protein synthesis, the time course for disappearance of HG-Trpm4b from the surface was much slower than that for Trpm4b-N988Q. We conclude that N-glycosylation is not required for surface expression or channel function, but that complex N-glycosylation plays a crucial role in stabilizing surface expression of Trpm4b.

Does inhibiting Sur1 complement rt-PA in cerebral ischemia?

Hemorrhagic transformation (HT) associated with recombinant tissue plasminogen activator (rt-PA) complicates and limits its use in stroke. Here, we provide a focused review on the involvement of matrix metalloproteinase 9 (MMP-9) in rt-PA-associated HT in cerebral ischemia, and we review emerging evidence that the selective inhibitor of the sulfonylurea receptor 1 (Sur1), glibenclamide (U.S. adopted name, glyburide), may provide protection against rt-PA-associated HT in cerebral ischemia. Glyburide inhibits activation of MMP-9, ameliorates edema formation, swelling, and symptomatic hemorrhagic transformation, and improves preclinical outcomes in several clinically relevant models of stroke, both without and with rt-PA treatment. A retrospective clinical study comparing outcomes in diabetic patients with stroke treated with rt-PA showed that those who were previously on and were maintained on a sulfonylurea fared significantly better than those whose diabetes was managed without sulfonylureas. Inhibition of Sur1 with injectable glyburide holds promise for ameliorating rt-PA-associated HT in stroke.

Sequential activation of hypoxia-inducible factor 1 and specificity protein 1 is required for hypoxia-induced transcriptional stimulation of Abcc8.

Cerebral ischemia causes increased transcription of sulfonylurea receptor 1 (SUR1), which forms SUR1-regulated NC(Ca-ATP) channels linked to cerebral edema. We tested the hypothesis that hypoxia is an initial signal that stimulates transcription of Abcc8, the gene encoding SUR1, via activation of hypoxia-inducible factor 1 (HIF1). In the brain microvascular endothelial cells, hypoxia increased SUR1 abundance and expression of functional SUR1-regulated NC(Ca-ATP) channels. Luciferase reporter activity driven by the Abcc8 promoter was increased by hypoxia and by coexpression of HIF1α. Surprisingly, a series of luciferase reporter assays studying the Abcc8 promoter revealed that binding sites for specificity protein 1 (Sp1), but not for HIF, were required for stimulation of Abcc8 transcription by HIF1α. Luciferase reporter assays studying Sp1 promoters of three species, and chromatin immunoprecipitation analysis in rats after cerebral ischemia, indicated that HIF binds to HIF-binding sites on the Sp1 promoter to stimulate transcription of the Sp1 gene. We conclude that sequential activation of two transcription factors, HIF and Sp1, is required to stimulate transcription of Abcc8 following cerebral ischemia. Sequential gene activation in cerebral ischemia provides a plausible molecular explanation for the prolonged treatment window observed for inhibition of the end-target gene product, SUR1, by glibenclamide.

Glibenclamide reduces hippocampal injury and preserves rapid spatial learning in a model of traumatic brain injury.

Cognitive disturbances after traumatic brain injury (TBI) are frequent, even when neuroimaging shows no overt hemorrhagic or other abnormality. Sulfonylurea receptor 1 (SUR1) plays a key role in various forms of CNS injury, but its role in hippocampal dysfunction after mild to moderate TBI is unknown. To assess the hypothesis that postinjury SUR1 upregulation in the hippocampus is associated with a later disturbance in learning, we studied a rat model of cortical impact TBI calibrated to avoid primary and secondary hemorrhage in the underlying hippocampus. The transcription factor, specificity protein 1, which regulates expression of SUR1 and caspase-3, was activated in the hippocampus 15 minutes after injury. Upregulation of SUR1 protein and of Abcc8 (which encodes SUR1) messenger RNA was evident by 6 hours. To assess the role of SUR1, injured rats were administered vehicle or a low dose of the specific sulfonylurea inhibitor glibenclamide for 1 week. At 2 weeks, the increase in activated caspase-3 in the hilus of glibenclamide-treated rats was half of that in vehicle-treated rats. Testing for rapid learning in a Morris water maze at 4 weeks showed significantly better performance in glibenclamide-treated rats; performance inversely correlated with Fluoro-Jade staining for degenerated neurons in the hilus. We conclude that glibenclamide may have long-term protective effects on the hippocampus after mild-to-moderate TBI.

De novo expression of Trpm4 initiates secondary hemorrhage in spinal cord injury.

The role of transient receptor potential M4 (Trpm4), an unusual member of the Trp family of ion channels, is poorly understood. Using rodent models of spinal cord injury, we studied involvement of Trpm4 in the progressive expansion of secondary hemorrhage associated with capillary fragmentation, the most destructive mechanism of secondary injury in the central nervous system. Trpm4 mRNA and protein were abundantly upregulated in capillaries preceding their fragmentation and formation of petechial hemorrhages. Trpm4 expression in vitro rendered COS-7 cells highly susceptible to oncotic swelling and oncotic death following ATP depletion. After spinal cord injury, in vivo gene suppression in rats treated with Trpm4 antisense or in Trpm4(-/-) mice preserved capillary structural integrity, eliminated secondary hemorrhage, yielded a threefold to fivefold reduction in lesion volume and produced a substantial improvement in neurological function. To our knowledge, this is the first example of a Trp channel that must undergo de novo expression for manifestation of central nervous system pathology.

Glibenclamide reduces inflammation, vasogenic edema, and caspase-3 activation after subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) causes secondary brain injury due to vasospasm and inflammation. Here, we studied a rat model of mild-to-moderate SAH intended to minimize ischemia/hypoxia to examine the role of sulfonylurea receptor 1 (SUR1) in the inflammatory response induced by SAH. mRNA for Abcc8, which encodes SUR1, and SUR1 protein were abundantly upregulated in cortex adjacent to SAH, where tumor-necrosis factor-alpha (TNFalpha) and nuclear factor (NF)kappaB signaling were prominent. In vitro experiments confirmed that Abcc8 transcription is stimulated by TNFalpha. To investigate the functional consequences of SUR1 expression after SAH, we studied the effect of the potent, selective SUR1 inhibitor, glibenclamide. We examined barrier permeability (immunoglobulin G, IgG extravasation), and its correlate, the localization of the tight junction protein, zona occludens 1 (ZO-1). SAH caused a large increase in barrier permeability and disrupted the normal junctional localization of ZO-1, with glibenclamide significantly reducing both effects. In addition, SAH caused large increases in markers of inflammation, including TNFalpha and NFkappaB, and markers of cell injury or cell death, including IgG endocytosis and caspase-3 activation, with glibenclamide significantly reducing these effects. We conclude that block of SUR1 by glibenclamide may ameliorate several pathologic effects associated with inflammation that lead to cortical dysfunction after SAH.

Endothelial sulfonylurea receptor 1-regulated NC Ca-ATP channels mediate progressive hemorrhagic necrosis following spinal cord injury.

Acute spinal cord injury (SCI) causes progressive hemorrhagic necrosis (PHN), a poorly understood pathological process characterized by hemorrhage and necrosis that leads to devastating loss of spinal cord tissue, cystic cavitation of the cord, and debilitating neurological dysfunction. Using a rodent model of severe cervical SCI, we tested the hypothesis that sulfonylurea receptor 1-regulated (SUR1-regulated) Ca(2+)-activated, [ATP](i)-sensitive nonspecific cation (NC(Ca-ATP)) channels are involved in PHN. In control rats, SCI caused a progressively expansive lesion with fragmentation of capillaries, hemorrhage that doubled in volume over 12 hours, tissue necrosis, and severe neurological dysfunction. SUR1 expression was upregulated in capillaries and neurons surrounding necrotic lesions. Patch clamp of cultured endothelial cells exposed to hypoxia showed that upregulation of SUR1 was associated with expression of functional SUR1-regulated NC(Ca-ATP) channels. Following SCI, block of SUR1 by glibenclamide or repaglinide or suppression of Abcc8, which encodes for SUR1 by phosphorothioated antisense oligodeoxynucleotide essentially eliminated capillary fragmentation and progressive accumulation of blood, was associated with significant sparing of white matter tracts and a 3-fold reduction in lesion volume, and resulted in marked neurobehavioral functional improvement compared with controls. We conclude that SUR1-regulated NC(Ca-ATP) channels in capillary endothelium are critical to development of PHN and constitute a major target for therapy in SCI.