Therapeutic Effect of Donepezil on Neuroinflammation and Cognitive Impairment after Moderate Traumatic Brain Injury.

BACKGROUND: Despite the important clinical issue of cognitive impairment after moderate traumatic brain injury (TBI), there is currently no suitable treatment. Here, we used in vitro and in vivo models to investigate the effect of Donepezil-an acetylcholinesterase (AChE) inhibitor-on cognitive impairment in the acute period following injury, while focusing on neuroinflammation and autophagy- and mitophagy-related markers. METHODS: The purpose of the in vitro study was to investigate potential neuroprotective effects in TBI-induced cells after donepezil treatment, and the in vivo study, the purpose was to investigate therapeutic effects on cognitive impairment in the acute period after injury by analyzing neuroinflammation and autophagy- and mitophagy-related markers. The in vitro TBI model involved injuring SH-SY5Y cells using a cell-injury controller and then investigating the effect of donepezil at a concentration of 80 µM. The in vivo TBI model was made using a stereotaxic impactor for male C57BL/6J mice. Immuno-histochemical markers and cognitive functions were compared after 7 days of donepezil treatment (1 mg/kg/day). Mice were divided into four groups: sham operation with saline treatment, sham operation with donepezil treatment, TBI with saline treatment, and TBI with donepezil treatment (18 mice in each group). Donepezil treatment was administered within 4 h post-TBI. RESULTS: In vitro, donepezil was found to lead to increased cell viability and 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimi-dazolylcarbocyanine iodide (JC-1), along with decreased reactive oxygen species (ROS), lactate-dehydrogenase (LDH), 2'-7'-dichlorodihydrofluorescein diacetate (DCFH-DA)-positive cells, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells. The mRNA and protein expressions of neuroinflammation (Cyclooxygenase-2, COX-2; NOD-like receptor protein 3, NLRP3; Caspase-1; and Interleukin-1 beta, IL-1ß), as well as autophagy- and mitophagy-related markers (death-associated protein kinase 1, DAPK1; PTEN-induced kinase 1, PINK1; BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like, BNIP3L; Beclin-1, BECN1; BCL2-associated X protein, BAX; microtubule-associated protein 1A/1B-light chain 3B (LC3B); Sequestosome-1; and p62) were all found to decrease after donepezil treatment. The in vivo study also showed that donepezil treatment resulted in decreased levels of cortical tissue losses and brain swelling in TBI compared to the TBI group without donepezil treatment. Donepezil treatment was also shown to decrease the mRNA and Western blotting expressions of all markers, and especially COX-2 and BNIP3L, which showed the most significant decreases. Moreover, TBI mice showed an decreased escape latency, increased alteration rate, and improved preference index, altogether pointing to better cognitive performance after donepezil treatment. CONCLUSIONS: Donepezil treatment may be beneficial in improving cognitive impairment in the early phase of moderate traumatic brain injury by ameliorating neuroinflammation, as well as autophagy and mitophagy.

Modeling of the brain-lung axis using organoids in traumatic brain injury: an updated review.

Clinical outcome after traumatic brain injury (TBI) is closely associated conditions of other organs, especially lungs as well as degree of brain injury. Even if there is no direct lung damage, severe brain injury can enhance sympathetic tones on blood vessels and vascular resistance, resulting in neurogenic pulmonary edema. Conversely, lung damage can worsen brain damage by dysregulating immunity. These findings suggest the importance of brain-lung axis interactions in TBI. However, little research has been conducted on the topic. An advanced disease model using stem cell technology may be an alternative for investigating the brain and lungs simultaneously but separately, as they can be potential candidates for improving the clinical outcomes of TBI.In this review, we describe the importance of brain-lung axis interactions in TBI by focusing on the concepts and reproducibility of brain and lung organoids in vitro. We also summarize recent research using pluripotent stem cell-derived brain organoids and their preclinical applications in various brain disease conditions and explore how they mimic the brain-lung axis. Reviewing the current status and discussing the limitations and potential perspectives in organoid research may offer a better understanding of pathophysiological interactions between the brain and lung after TBI.

Comparison of the Clinical Efficacy of Anabolic Agents and Bisphosphonates in the Patients With Osteoporotic Vertebral Fracture: Systematic Review and Meta-analysis of Randomized Controlled Trials.

OBJECTIVE: We investigated the clinical efficacy of anabolic agents compared with bisphosphonates (BPs) for the incidence of new osteoporotic vertebral fracture (OVF) and fracture healing of OVF in the patients with OVF via meta-analyses of randomized controlled trials (RCTs). METHODS: Electronic databases, including PubMed, Embase, and Cochrane Library were searched for published RCTs till December 2022. The RCTs that recruited participants with osteoporosis at high-/very high-risk of fracture (a history of osteoporotic vertebral or hip fracture) or fresh OVF were included in this study. We assessed the risk of bias on every included RCTs, estimated relative risk (RR) for the incidence of new OVF and fracture healing of OVF, and overall certainty of evidence. Meta-analyses were performed by Cochrane review manager (RevMan) ver. 5.3. Cochrane risk of bias 2.0 and GRADEpro/GDT were applied for evaluating methodological quality and overall certainty of evidence, respectively. RESULTS: Five hundred eighteen studies were screened, and finally 6 eligible RCTs were included in the analysis. In the patients with prevalent OVF, anabolic agents significantly reduced the incidence of new OVF (teriparatide and romosozumab vs. alendronate and risedronate [RR, 0.57; 95% confidence interval, 0.45-0.71; p < 0.00001; high-certainty of evidence]; teriparatide vs. risedronate [RR, 0.50; 95% confidence interval, 0.37-0.68; p < 0.0001; high-certainty of evidence]). However, there was no evidence of teriparatide compared to alendronate in fracture healing of OVF (RR, 1.23; 95% confidence interval, 0.95-1.60; p = 0.12; low-certainty of evidence). CONCLUSION: In the patients with prevalent OVF, anabolic agents showed a significant superiority for preventing new OVF than BPs, with no significant evidence for promoting fracture healing of OVF. However, considering small number of RCTs in this study, additional studies with large-scale data are required to obtain more robust evidences.

Lordosis distribution index for predicting mechanical complications after long-level fusion surgery: comparison of Global Alignment and Proportion score and Roussouly classification.

OBJECTIVE: Both the Global Alignment and Proportion (GAP) score and Roussouly classification account for the lordosis distribution index (LDI), but the LDI of the GAP score (G-LDI) is typically set to 50%-80%, while the LDI of the Roussouly classification (R-LDI) varies depending on the degree of pelvic incidence (PI). The objective of this study was to validate the ability of the G-LDI to predict mechanical complications and compare it with the predictive probability of R-LDI in patients with long-level fusion surgery. METHODS: A total of 171 patients were divided into two groups: 93 in the nonmechanical complication group (non-MC group) and 78 in the mechanical complication group (MC group). The mean age of the participants was 66.79 ± 8.56 years (range 34-83 years), and the mean follow-up period was 45.49 ± 16.20 months (range 24-62 months). The inclusion criteria for the study were patients who underwent > 4 levels of fusion and had > 2 years of follow-up. The predictive models for mechanical complications using the G-LDI and R-LDI were analyzed using binomial logistic regression and receiver operating characteristic analyses. RESULTS: There was a significant correlation between R-LDI and PI (r = -0.561, p < 0.001), while there was no correlation between G-LDI and PI (r = 0.132, p = 0.495). In reference to G-LDI, most patients in the non-MC group were classified as having alignment (72, 77.4%), while the MC group had an inhomogeneous composition (aligned: 34, 43.6%; hyperlordosis: 37, 47.4%). The agreement between the G-LDI and R-LDI was moderate (κ = 0.536, p < 0.001) to fair (κ = 0.383, p = 0.011) for patients with average or large PI, but poor (κ = -0.255, p = 0.245) for those with small PI. The areas under the curve for the G-LDI and R-LDI were 0.674 (95% CI, 0.592-0.757) and 0.745 (95% CI, 0.671-0.820), respectively. CONCLUSIONS: The R-LDI, which uses a PI-based proportional parameter, enables individual quantification of LL for all PI sizes and has been shown to have a higher accuracy in classifying cases and a stronger correlation with the risk of mechanical complications compared with G-LDI.

Effectiveness of single-session therapy for adult common mental disorders: a systematic review.

BACKGROUND: Common mental disorders (CMDs) impose significant socioeconomic impacts on the global community. Nevertheless, over 50% of individuals with CMDs do not receive proper treatment, indicating that the current treatment modalities do not adequately tackle this issue. Since single-session therapy (SST) is a potential method for reducing the treatment gap, it is crucial to evaluate its effectiveness. Therefore, this systematic review aimed to evaluate the effectiveness of SST on CMD symptoms in adults. METHODS: This systematic review included randomised and non-randomised studies assessing the clinical effectiveness of SST on CMD symptoms in adults. English-written, peer-reviewed studies or dissertations were included, while grey literature was excluded. MEDLINE, Embase, PsycINFO, and Cochrane's CENTRAL were searched on December 13, 2022, from their inception dates. The risk of bias in the included studies was evaluated using RoB 2 and ROBINS-I. A narrative synthesis was performed. This systematic review was registered in the PROSPERO database on July 6, 2022 (CRD42022343925). RESULTS: Six randomised and three non-randomised studies were included after screening 2,130 records. Three non-randomised studies with a "critical" or "serious" risk of bias were excluded from the synthesis. Therefore, six randomised trials involving 298 participants were included in the synthesis. Four out of six studies had a "high" risk of bias. The participants had non-severe symptoms at baseline, and three intervention types (behavioural activation, DBT, and solution-focused psychotherapy) were evaluated. Five of six studies showed positive results for depression, with only one reporting a positive result for anxiety. CONCLUSIONS: SST may be effective in improving CMD symptoms in adults, particularly depression. However, there is a limit to deriving definite conclusions due to a high risk of bias in included studies, insufficient sample size and research volume. Further research exploring the characteristics of clients who can benefit from SST is required to facilitate its widespread use.

Autophagy and mitophagy-related extracellular mitochondrial dysfunction of cerebrospinal fluid cells in patients with hemorrhagic moyamoya disease.

We aimed to investigate whether mitochondrial dysfunction in extracellular cerebrospinal fluid (CSF), which is associated with autophagy and mitophagy, might be involved in neurological outcomes in adult patients with hemorrhagic moyamoya disease (MMD) whose pathogenesis related to poor outcomes is not well-known. CSF samples were collected from 43 adult MMD patients and analyzed according to outcomes at 3 months. Fluorescence-activated cell sorter analysis (FACS) and the JC-1 red/green ratio were used to assess mitochondrial cells and intact mitochondrial membrane potential (MMP). We performed quantitative real-time polymerase chain reaction and Western blotting analyses of autophagy and mitophagy-related markers, including HIF1α, ATG5, pBECN1, BECN1, BAX, BNIP3L, DAPK1, and PINK1. Finally, FACS analysis with specific fluorescence-conjugated antibodies was performed to evaluate the potential cellular origin of CSF mitochondrial cells. Twenty-seven females (62.8%) with a mean age of 47.4 ± 9.7 years were included in the study. Among 43 patients with hemorrhagic MMD, 23 (53.5%) had poor outcomes. The difference in MMP was evident between the two groups (2.4 ± 0.2 in patients with poor outcome vs. 3.5 ± 0.4 in patients with good outcome; p = 0.02). A significantly higher expression (2-ΔCt) of HIF1α, ATG5, DAPK1 followed by BAX and BNIP3L mRNA and protein was also observed in poor-outcome patients compared to those with good outcomes. Higher percentage of vWF-positive mitochondria, suggesting endothelial cell origins, was observed in patients with good outcome compared with those with poor outcome (25.0 ± 1.4% in patients with good outcome vs. 17.5 ± 1.5% in those with poor outcome; p < 0.01). We observed the association between increased mitochondrial dysfunction concomitant with autophagy and mitophagy in CSF cells and neurological outcomes in adult patients with hemorrhagic MMD. Further prospective multicenter studies are needed to determine whether it has a diagnostic value for risk prediction.

Oxiracetam alleviates anti-inflammatory activity and ameliorates cognitive impairment in the early phase of traumatic brain injury.

BACKGROUND: We aimed to investigate the effects of oxiracetam on cognitive impairment in the early phase of traumatic brain injury (TBI), for which no specific treatment is currently available. METHODS: The in vitro study used a cell injury controller to damage SH-SY5Y cells and evaluate the effect of oxiracetam at a dosage of 100 nM. The in vivo study used a stereotaxic impactor to induce a TBI model in C57BL/6 J mice and analyzed immunohistochemical changes and cognitive function after an intraperitoneal injection of oxiracetam (30 mg/kg/day) for 5 days. The number of mice used in this study was 60. They were divided into three groups (sham, TBI, and TBI with oxiracetam treatment) (20 mice in each group). RESULTS: The in vitro study showed that oxiracetam treatment resulted in increased superoxide dismutase (SOD)1 and SOD2 mRNA expression. The mRNA and protein expression of COX-2, NLRP3, caspase-1, and interleukin (IL)-1 ß were decreased after oxiracetam treatment, along with decreases in intracellular reactive oxygen species production and apoptotic effects. TBI mice treated with oxiracetam exhibited the loss of fewer cortical damaged lesions, less brain edema, and fewer Fluoro-Jade B (FJB)-positive and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL)-positive cells compared to those without oxiracetam treatment. The mRNA and protein expression of COX-2, NLRP3, caspase-1, and IL-1ß were decreased significantly after oxiracetam treatment. These inflammation-related markers, which colocalized with Iba-1-positive or GFAP-positive cells after TBI, were also decreased after oxiracetam treatment. TBI mice treated with oxiracetam had a smaller decrease in preference and more latency time than those not treated with oxiracetam, suggesting the amelioration of impaired cognitive impairment. CONCLUSIONS: Oxiracetam may be helpful in restoring cognitive impairment by ameliorating neuroinflammation in the early phase of TBI.

Therapeutic effect of a hydrogel-based neural stem cell delivery sheet for mild traumatic brain injury.

OBJECTIVE: There are no effective clinically applicable treatments for neuronal dysfunction after mild traumatic brain injury (TBI). Here, we evaluated the therapeutic effect of a new delivery method of mouse neural stem cell (mNSC) spheroids using a hydrogel, in terms of improvement in damaged cortical lesions and cognitive impairment after mild TBI. METHODS: mNSCs were isolated from the subventricular zone and subgranular zone by a hydrogel-based culture system. GFP-transduced mNSCs were generated into spheroids and wrapped into a sheet for transplantation. Male C57BL/6J mice were randomly divided into four groups: sham operation, TBI, TBI with mNSC spheroids, and TBI with mNSC spheroid sheet transplantation covering the damaged cortex. Histopathological and immunohistochemical features and cognitive function were evaluated 7, 14, and 28 days after transplantation following TBI. RESULTS: Hydrogel-based culture systems and mNSC isolation were successfully established from the adult mice. Essential transcription factors for NSCs, such as SOX2, PAX6, Olig2, nestin, and doublecortin (DCX), were highly expressed in the mNSCs. A transplanted hydrogel-based mNSC spheroid sheet showed good engraftment and survival ability, differentiated into TUJ1-positive neurons, promoted angiogenesis, and reduced neuronal degeneration. Also, TBI mice treated with mNSC spheroid sheet transplantation exhibited a significantly increased preference for a new object, suggesting improved cognitive function compared to the mNSC spheroids or no treatment groups. CONCLUSION: Transplantation with a hydrogel-based mNSC spheroid sheet showed engraftment, migration, and stability of delivered cells in a hostile microenvironment after TBI, resulting in improved cognitive function via reconstruction of the damaged cortex. STATEMENT OF SIGNIFICANCE: This study presents the therapeutic effect of a new delivery method of mouse neural stem cells spheroids using a hydrogel, in terms of improvement in damaged cortical lesions and cognitive impairment after traumatic brain injury. Collagen/fibrin hydrogel allowed long-term survival and migratory ability of NSCs spheroids. Furthermore, transplanted hydrogel-based mNSCs spheroids sheet showed good engraftment, migration, and stability of delivered cells in a hostile microenvironment, resulting in reconstruction of the damaged cortex and improved cognitive function after TBI. Therefore, we suggest that a hydrogel-based mNSCs spheroids sheet could help to improve cognitive impairment after TBI.

Updated Trans-Ethnic Meta-Analysis of Associations between Inflammation-Related Genes and Intracranial Aneurysm.

OBJECTIVE: We performed an expanded multi-ethnic meta-analysis to identify associations between inflammation-related loci with intracranial aneurysm (IA) susceptibility. This meta-analysis possesses increased statistical power as it is based on the most data ever evaluated. METHODS: We searched and reviewed relevant literature through electronic search engines up to August 2022. Overall estimates were calculated under the fixed- or random-effect models using pooled odds ratio (OR) and 95% confidence intervals (CIs). Subgroup analyses were performed according to ethnicity. RESULTS: Our meta-analysis enrolled 15 studies and involved 3070 patients and 5528 controls including European, Asian, Hispanic, and mixed ethnic populations. Of 17 inflammation-related variants, the rs1800796 locus (interleukin [IL]-6) showed the most significant genome-wide association with IA in East-Asian populations, including 1276 IA patients and 1322 controls (OR, 0.65; 95% CI, 0.56-0.75; p=3.24×10-9) under a fixed-effect model. However, this association was not observed in the European population (OR, 1.09; 95% CI, 0.80-1.47; p=0.5929). Three other variants, rs16944 (IL-1ß), rs2195940 (IL-12B), and rs1800629 (tumor necrosis factor-α) showed a statistically nominal association with IA in both the overall, as well as East-Asian populations (0.01

WITHDRAWN: Effect of Therapeutic Hypothermia on Cognitive Impairment in a Mouse Model of Ischemia-Reperfusion Injury.

Ahead of Print article withdrawn by publisher.

KLK6/PAR1 Axis Promotes Tumor Growth and Metastasis by Regulating Cross-Talk between Tumor Cells and Macrophages.

Kallikrein-related peptidase (KLK)6 is associated with inflammatory diseases and neoplastic progression. KLK6 is aberrantly expressed in several solid tumors and regulates cancer development, metastatic progression, and drug resistance. However, the function of KLK6 in the tumor microenvironment remains unclear. This study aimed to determine the role of KLK6 in the tumor microenvironment. Here, we uncovered the mechanism underlying KLK6-mediated cross-talk between cancer cells and macrophages. Compared with wild-type mice, KLK6-/- mice showed less tumor growth and metastasis in the B16F10 melanoma and Lewis lung carcinoma (LLC) xenograft model. Mechanistically, KLK6 promoted the secretion of tumor necrosis factor-alpha (TNF-α) from macrophages via the activation of protease-activated receptor-1 (PAR1) in an autocrine manner. TNF-α secreted from macrophages induced the release of the C-X-C motif chemokine ligand 1 (CXCL1) from melanoma and lung carcinoma cells in a paracrine manner. The introduction of recombinant KLK6 protein in KLK6-/- mice rescued the production of TNF-α and CXCL1, tumor growth, and metastasis. Inhibition of PAR1 activity suppressed these malignant phenotypes rescued by rKLK6 in vitro and in vivo. Our findings suggest that KLK6 functions as an important molecular link between macrophages and cancer cells during malignant progression, thereby providing opportunities for therapeutic intervention.

Human embryonic stem cell-derived cerebral organoids for treatment of mild traumatic brain injury in a mouse model.

OBJECTIVE: There are no effective treatments for relieving neuronal dysfunction after mild traumatic brain injury (TBI). Here, we evaluated therapeutic efficacy of human embryonic stem cell-derived cerebral organoids (hCOs) in a mild TBI model, in terms of repair of damaged cortical regions, neurogenesis, and improved cognitive function. METHODS: Male C57BL/6 J mice were randomly divided into sham-operated, mild TBI, and mild TBI with hCO groups. hCOs cultured at 8 weeks were used for transplantation. Mice were sacrificed at 7 and 14 days after transplantation followed by immunofluorescence staining, cytokine profile microarray, and novel object recognition test. RESULTS: 8W-hCOs transplantation significantly reduced neuronal cell death, recovered microvessel density, and promoted neurogenesis in the ipsilateral subventricular zone and dentate gyrus of hippocampus after mild TBI. In addition, increased angiogenesis into the engrafted hCOs was observed. Microarray results of hCOs revealed neuronal differentiation potential and higher expression of early brain development proteins associated with neurogenesis, angiogenesis and extracellular matrix remodeling. Ultimately, 8W-hCO transplantation resulted in reconstruction of damaged cortex and improvement in cognitive function after mild TBI. CONCLUSION: hCO transplantation may be feasible for treating mild TBI-related neuronal dysfunction via reconstruction of damaged cortex and neurogenesis in the hippocampus.

Impact of C3 Involvement on Postoperative Kyphosis Following Cervical Laminoplasty: A Comparison Between High and Low T1 Slope.

BACKGROUND: The goal of the present study was to investigate the impact of C3 involvement on the postoperative kyphosis following cervical laminoplasty in patients with high and low T1S. METHODS: The data from ossification of the posterior longitudinal ligament patients who had undergone laminoplasty between January 2016 and December 2019 were retrospectively reviewed. Patients were divided into low-and high-T1S groups according to preoperative T1S, and the postoperative alignment change was compared between the groups. The relationships between postoperative cervical kyphosis and preoperative variables, including gender, C3 laminoplasty, T1S, cervical lordosis (CL), C2-7 Sagittal Vertical Axis, and T1S minus CL (T1S-CL) were investigated. RESULTS: Eighty-six patients were divided into 2 groups above and below median preoperative T1S (23.70). There were thirty-three patients (38.3%) in low-T1S group and fifty-three patients (61.7%) in high-T1S group. Twenty-three patients (26.7%) were performed with C3 involved laminoplasty. C3 laminoplasty (odds ratio [OR], 9.67; 2.82-33.16; P = 0.000), high T1S (OR, 4.89; 1.54-15.49; P = 0.007), and mismatched T1S-CL (OR, 5.96; 1.83-19.43; P = 0.003) were significantly associated with postoperative kyphosis. In high-T1S group, the loss of CL was significant (P = 0.017) when C3 laminoplasty was performed, whereas, in low-T1S group, the C3 laminoplasty did not show the statistically significant difference. (P = 0.194). CONCLUSIONS: C3 laminoplasty, mismatched T1S-CL, and high T1S were found to increase the risk of postoperative kyphosis following cervical laminoplasty. Patients with high T1 slope tended to exhibit a greater loss of CL when the laminoplasty was performed extending to C3 segment.

Anti-obesity Effects of Dark Tea Extracts by Down-regulation of C/EBPα and PPARγ.

BACKGROUND/AIM: Dark tea, made by fermentation of tea leaves using microorganisms, is well known for its antiobesity effect; however, studies to identify this effect have not been sufficiently conducted. Herein, the anti-obesity effects of post-fermented dark tea were studied in high-fat diet mouse. MATERIALS AND METHODS: Obesity was induced through a high-fat diet in C57BL/6 mice, and then dark tea extract powder (DTP) was orally administered daily for 12 weeks to evaluate the body and organ weights. Changes in the biochemical markers of obesity were evaluated to study the mechanism of the anti-obesity effects of DTP. RESULTS: When DTP was administered to obesity mice, the weight and food intake reduced, blood aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C) decreased, whereas high-density lipoprotein cholesterol (HDL-C) increased. Histopathology showed that steatosis and inflammation scores were reduced within the liver and adipocyte sizes were reduced within epididymal adipocyte. In addition, a significant decrease in blood insulin and hepatic TG and a significant increase in blood adiponectin were also confirmed. The results of western blot and qPCR in week 12, showed a significant decrease in the mRNA and protein levels of C/EBPα, and the mRNA levels of PPARγ in the liver. CONCLUSION: Dark tea extracts are thought to have an anti-obesity effect by reducing the levels of the main transcription factors that promote adipocyte differentiation, such as C/EBPα, and PPARγ. Therefore, diet products using dark tea extracts could be developed.

Recent Stem Cell Research on Hemorrhagic Stroke : An Update.

Although technological advances and clinical studies on stem cells have been increasingly reported in stroke, research targeting hemorrhagic stroke is still lacking compared to that targeting ischemic stroke. Studies on hemorrhagic stroke are also being conducted, mainly in the USA and China. However, little research has been conducted in Korea. In reality, stem cell research or treatment is unfamiliar to many domestic neurosurgeons. Nevertheless, given the increased interest in regenerative medicine and the increase of life expectancy, attention should be paid to this topic. In this paper, we summarized pre-clinical rodent studies and clinical trials using stem cells for hemorrhagic stroke. In addition, we discussed results of domestic investigations and future perspectives on stem cell research for a better understanding.

Anti-Obesity Effect of Hot Water Extract of Barley Sprout through the Inhibition of Adipocyte Differentiation and Growth.

Barley sprouts are known to have several effective physiological activities. In this study, the anti-obesity effect of a barley sprout hot water extract (BSE) was confirmed. Saponarin was quantitatively analyzed in BSE using HPLC, and the inhibitory effect on 3T3-L1 pre-adipocyte differentiation into adipocytes was confirmed by Oil Red O staining, TG assay, and Western blotting. In addition, the inhibitory effect of BSE on adipocyte growth was confirmed through glucose uptake and lipolysis of adipocytes. C57/BL/6N mice were induced to obesity with a high-fat diet, and BSE was administered to confirm the effect on an animal model. Weight gain, morphological changes in adipose tissue, changes in the food efficiency ratio, and blood biochemical changes were observed, and an improvement effect on fatty liver was confirmed. As a result, the anti-obesity effect of BSE was confirmed in vitro, and it was confirmed that this effect was also effective in vivo and that it could be helpful in the treatment of obesity-related diseases.

Peripheral Nerve-Derived Stem Cell Spheroids Induce Functional Recovery and Repair after Spinal Cord Injury in Rodents.

Stem cell therapy is one of the most promising candidate treatments for spinal cord injury. Research has shown optimistic results for this therapy, but clinical limitations remain, including poor viability, engraftment, and differentiation. Here, we isolated novel peripheral nerve-derived stem cells (PNSCs) from adult peripheral nerves with similar characteristics to neural-crest stem cells. These PNSCs expressed neural-crest specific markers and showed multilineage differentiation potential into Schwann cells, neuroglia, neurons, and mesodermal cells. In addition, PNSCs showed therapeutic potential by releasing the neurotrophic factors, including glial cell-line-derived neurotrophic factor, insulin-like growth factor, nerve growth factor, and neurotrophin-3. PNSC abilities were also enhanced by their development into spheroids which secreted neurotrophic factors several times more than non-spheroid PNSCs and expressed several types of extra cellular matrix. These features suggest that the potential for these PNSC spheroids can overcome their limitations. In an animal spinal cord injury (SCI) model, these PNSC spheroids induced functional recovery and neuronal regeneration. These PNSC spheroids also reduced the neuropathic pain which accompanies SCI after remyelination. These PNSC spheroids may represent a new therapeutic approach for patients suffering from SCI.

Collapsin response mediator protein 4 enhances the radiosensitivity of colon cancer cells through calcium­mediated cell signaling.

Radiation therapy is an effective treatment against various types of cancer, but some radiation­resistant cancer cells remain a major therapeutic obstacle; thus, understanding radiation resistance mechanisms is essential for cancer treatment. In this study, we established radiation­resistant colon cancer cell lines and examined the radiation­induced genetic changes associated with radiation resistance. Using RNA­sequencing analysis, collapsin response mediator protein 4 (CRMP4) was identified as the candidate gene associated with radiation sensitivity. When cells were exposed to radiation, intracellular Ca2+ influx, collapse of mitochondrial membrane potential, and cytochrome c release into the cytosol were increased, followed by apoptosis induction. Radiation treatment­ or Ca2+ ionophore A23187­induced apoptosis was significantly inhibited in CRMP4­deficient cells, including radiation­resistant or CRMP4­shRNA cell lines. Furthermore, treatment of CRMP4­deficient cells with low levels (<5 µM) of BAPTA­AM, a Ca2+ chelator, resulted in radiation resistance. Conversely, Ca2+ deficiency induced by a high BAPTA­AM concentration (>10 µM) resulted in higher cell death in the CRMP4­depleted cells compared to CRMP4­expressing control cells. Our results suggest that CRMP4 plays an important role in Ca2+­mediated cell death pathways under radiation exposure and that CRMP4 may be a therapeutical target for colon cancer treatment.

Relationship between vertical components of maxillary molar and craniofacial frame in normal occlusion: cephalometric calibration on the vertical axis of coordinates.

OBJECTIVE: The aim of this study was to evaluate the correlation between the vertical position of maxillary first molar and vertical skeletal measurements in lateral cephalograms by using new linear measurements on the vertical axis of coordinates with calibration. METHODS: The vertical position of maxillary first molar (U6-SN), and the conventionally used variables (ConV) and the newly derived linear variables (NwLin) for vertical skeletal patterns were measured in the lateral cephalograms of 103 Korean adults with normal occlusions. Pearson correlation analyses and multiple linear regression analyses were performed with and without calibration using the anterior and posterior cranial base (ACB and PCB, respectively) lengths to identify variables related to U6-SN. RESULTS: The PCB-calibrated statistics showed the best power of explanation. ConV indicating skeletal hyperdivergency was significantly correlated with U6-SN. Six NwLin regarding the position of palatal plane were positively correlated with U6-SN. Each multiple linear regression analysis generated a two-variable model: sella and nasion to palatal plane. Among the three models, the PCBcalibrated model yielded highest adjusted R2 value, 0.880. CONCLUSIONS: U6-SN could be determined by the vertical position of the maxilla, which could then be used to plan the amount of molar intrusion and estimate its clinical stability. Cephalometric calibration on the vertical axis of coordinates by using PCB for vertical linear measurements could strengthen the analysis itself.

Association Between Copeptin and Six-Month Neurologic Outcomes in Patients With Moderate Traumatic Brain Injury.

Background: Copeptin has been reported as a predictive biomarker for the prognosis after traumatic brain injury (TBI). However, most of them were in patients with severe TBI and limited value in predicting outcomes in patients with moderate TBI defined as Glasgow Coma Scale (GCS) score from 9 to 12. We aimed to investigate the predictive value of copeptin in assessing the neurologic outcome following moderate TBI. Methods: Patients were prospectively enrolled between May 2017 and November 2020. We consecutively measured plasma copeptin within 24 h after trauma, days 3, 5, and 7 using ELISA. The primary outcome was to correlate plasma copeptin levels with poor neurologic outcome at 6 months after moderate TBI. The secondary outcome was to compare the prognostic accuracy of copeptin and C-reactive protein (CRP) in assessing the outcome of patient. Results: A total of 70 patients were included for the final analysis. The results showed that 29 patients (41.4%) experienced a poor neurologic outcome at 6 months. Multivariable logistic regression analysis revealed that increased copeptin (odds ration [OR] = 1.020, 95% CI: 1.005-1.036), GCS score of 9 or 10 (OR = 4.507, 95% CI: 1.266-16.047), and significant abnormal findings on CT (OR = 4.770; 95% CI: 1.133-20.076) were independent risk factors for poor outcomes. Consecutive plasma copeptin levels were significantly different according to outcomes (p < 0.001). Copeptin on day 7 exhibited better prognostic performance than CRP with an area under receiver operating characteristic curve (AUROC) difference of 0.179 (95% CI: 0.032-0.325) in predicting 6-month poor outcomes. Conclusion: Plasma copeptin level can be a useful marker in predicting 6-month outcomes in patients with moderate TBI.