Astrocyte-Derived Extracellular Vesicular miR-143-3p Dampens Autophagic Degradation of Endothelial Adhesion Molecules and Promotes Neutrophil Transendothelial Migration after Acute Brain Injury.

Pivotal roles of extracellular vesicles (EVs) in the pathogenesis of central nervous system (CNS) disorders including acute brain injury are increasingly acknowledged. Through the analysis of EVs packaged miRNAs in plasma samples from patients with intracerebral hemorrhage (ICH), it is discovered that the level of EVs packaged miR-143-3p (EVs-miR-143-3p) correlates closely with perihematomal edema and neurological outcomes. Further study reveals that, upon ICH, EVs-miR-143-3p is robustly secreted by astrocytes and can shuttle into brain microvascular endothelial cells (BMECs). Heightened levels of miR-143-3p in BMECs induce the up-regulated expression of cell adhesion molecules (CAMs) that bind to circulating neutrophils and facilitate their transendothelial cell migration (TEM) into brain. Mechanism-wise, miR-143-3p directly targets ATP6V1A, resulting in impaired lysosomal hydrolysis ability and reduced autophagic degradation of CAMs. Importantly, a VCAM-1-targeting EVs system to selectively deliver miR-143-3p inhibitor to pathological BMECs is created, which shows satisfactory therapeutic effects in both ICH and traumatic brain injury (TBI) mouse models. In conclusion, the study highlights the causal role of EVs-miR-143-3p in BMECs' dysfunction in acute brain injury and demonstrates a proof of concept that engineered EVs can be devised as a potentially applicable nucleotide drug delivery system for the treatment of CNS disorders.

MiR-146b-5p enriched bioinspired exosomes derived from fucoidan-directed induction mesenchymal stem cells protect chondrocytes in osteoarthritis by targeting TRAF6.

Osteoarthritis (OA) is a common degenerative joint disease characterized by progressive cartilage degradation and inflammation. In recent years, mesenchymal stem cells (MSCs) derived exosomes (MSCs-Exo) have attracted widespread attention for their potential role in modulating OA pathology. However, the unpredictable therapeutic effects of exosomes have been a significant barrier to their extensive clinical application. In this study, we investigated whether fucoidan-pretreated MSC-derived exosomes (F-MSCs-Exo) could better protect chondrocytes in osteoarthritic joints and elucidate its underlying mechanisms. In order to evaluate the role of F-MSCs-Exo in osteoarthritis, both in vitro and in vivo studies were conducted. MiRNA sequencing was employed to analyze MSCs-Exo and F-MSCs-Exo, enabling the identification of differentially expressed genes and the exploration of the underlying mechanisms behind the protective effects of F-MSCs-Exo in osteoarthritis. Compared to MSCs-Exo, F-MSCs-Exo demonstrated superior effectiveness in inhibiting inflammatory responses and extracellular matrix degradation in rat chondrocytes. Moreover, F-MSCs-Exo exhibited enhanced activation of autophagy in chondrocytes. MiRNA sequencing of both MSCs-Exo and F-MSCs-Exo revealed that miR-146b-5p emerged as a promising candidate mediator for the chondroprotective function of F-MSCs-Exo, with TRAF6 identified as its downstream target. In conclusion, our research results demonstrate that miR-146b-5p encapsulated in F-MSCs-Exo effectively inhibits TRAF6 activation, thereby suppressing inflammatory responses and extracellular matrix degradation, while promoting chondrocyte autophagy for the protection of osteoarthritic cartilage cells. Consequently, the development of a therapeutic approach combining fucoidan with MSC-derived exosomes provides a promising strategy for the clinical treatment of osteoarthritis.

Swimming performance of Cyprinus carpio (Carp) in China.

Cyprinus carpio (Carp) is a fish of great economic importance in China. However, its population has declined considerably due to the construction of barrages. Thus, fishways need to be constructed at barrages to protect fish resources. It is essential for the fishway design to study the swimming performance of carp. By applying incremental flow velocities in a glass open-type flume, three indicators of swimming performance of the carp in China with the body length (BL) of 13-21 cm, including the induced flow velocity (IFV), the critical swimming speed (Ucrit) and the burst swimming speed (Uburst), are systematically assessed. The correlation between the swimming performance and the BL is also analyzed. The results indicate that the IFV of the carp is 15.56 ± 1.79 cm/s, which is not significantly influenced by the BL. The value of Ucrit varies from 60 to 82 cm/s and gradually increases with the increasing value of BL. The relative critical swimming speed (U'crit) is 4.23 ± 0.28 BL/s and gradually decreases with the increasing value of BL. The value of Uburst ranges from 77.2 to 105.1 cm/s, which is linearly positively correlated to BL. The relative burst swimming speed (U'burst) is 5.42 ± 0.39 BL/s. The value of Uburst is approximately 1.28 times of that of Ucrit for the carps with the same BL. These findings are meaningful to the further study of ecological behavior and to the fishway design and optimization of carps.

Prognostic significance of perihematomal edema in basal ganglia hemorrhage after minimally invasive endoscopic evacuation.

OBJECTIVE: Spontaneous basal ganglia hemorrhage is a common type of intracerebral hemorrhage (ICH) with no definitive treatment. Minimally invasive endoscopic evacuation is a promising therapeutic approach for ICH. In this study the authors examined prognostic factors associated with long-term functional dependence (modified Rankin Scale [mRS] score ≥ 4) in patients who had undergone endoscopic evacuation of basal ganglia hemorrhage. METHODS: In total, 222 consecutive patients who underwent endoscopic evacuation between July 2019 and April 2022 at four neurosurgical centers were enrolled prospectively. Patients were dichotomized into functionally independent (mRS score ≤ 3) and functionally dependent (mRS score ≥ 4) groups. Hematoma and perihematomal edema (PHE) volumes were calculated using 3D Slicer software. Predictors of functional dependence were assessed using logistic regression models. RESULTS: Among the enrolled patients, the functional dependence rate was 45.50%. Factors independently associated with long-term functional dependence included female sex, older age (≥ 60 years), Glasgow Coma Scale score ≤ 8, larger preoperative hematoma volume (OR 1.02), and larger postoperative PHE volume (OR 1.03, 95% CI 1.01-1.05). A subsequent analysis evaluated the effect of stratified postoperative PHE volume on functional dependence. Specifically, patients with large (≥ 50 to < 75 ml) and extra-large (≥ 75 to 100 ml) postoperative PHE volumes had 4.61 (95% CI 0.99-21.53) and 6.75 (95% CI 1.20-37.85) times greater likelihood of long-term dependence, respectively, than patients with a small postoperative PHE volume (≥ 10 to < 25 ml). CONCLUSIONS: A large postoperative PHE volume is an independent risk factor for functional dependence among basal ganglia hemorrhage patients after endoscopic evacuation, especially with postoperative PHE volume ≥ 50 ml.

SLC1A5 enhances malignant phenotypes through modulating ferroptosis status and immune microenvironment in glioma.

Glioma is the most common type of primary malignant tumor in the central nervous system with limited treatment satisfaction. Finding new therapeutic targets has remained a major challenge. Ferroptosis is a novel and distinct type of programmed cell death, playing a regulatory role in the progression of tumors. However, the role of ferroptosis or ferroptosis-related genes (FRGs) in glioma progression has not been extensively studied. In our study, a novel ferroptosis-related prognostic model, including 7 genes, was established, in which patients classified into the high-risk group had more immuno-suppressive status and worse prognosis. Among these 7 genes, we screened solute carrier family 1 member 5 (SLC1A5), an FRG, as a possible new target for glioma treatment. Our results showed that the expression of SLC1A5 was significantly upregulated in glioblastoma tissues compared with the low-grade gliomas. In addition, SLC1A5 knockdown could significantly inhibit glioma cell proliferation and invasion, and reduce the sensitivity of ferroptosis via the GPX4-dependent pathway. Furthermore, SLC1A5 was found to be related to immune response and SLC1A5 knockdown decreased the infiltration and M2 polarization of tumor-associated macrophages. Pharmacological inhibition of SLC1A5 by V9302 was confirmed to promote the efficacy of anti-PD-1 therapy. Overall, we developed a novel prognostic model for glioma based on the seven-FRGs signature, which could apply to glioma prognostic and immune status prediction. Besides, SLC1A5 in the model could regulate the proliferation, invasion, ferroptosis and immune state in glioma, and be applied as a prognostic biomarker and potential therapeutic target for glioma.

Bone-targeting delivery of platelet lysate exosomes ameliorates glucocorticoid-induced osteoporosis by enhancing bone-vessel coupling.

BACKGROUND: Glucocorticoids (GCs) overuse is associated with decreased bone mass and osseous vasculature destruction, leading to severe osteoporosis. Platelet lysates (PL) as a pool of growth factors (GFs) were widely used in local bone repair by its potent pro-regeneration and pro-angiogenesis. However, it is still seldom applied for treating systemic osteopathia due to the lack of a suitable delivery strategy. The non-targeted distribution of GFs might cause tumorigenesis in other organs. RESULTS: In this study, PL-derived exosomes (PL-exo) were isolated to enrich the platelet-derived GFs, followed by conjugating with alendronate (ALN) grafted PEGylated phospholipid (DSPE-PEG-ALN) to establish a bone-targeting PL-exo (PL-exo-ALN). The in vitro hydroxyapatite binding affinity and in vivo bone targeting aggregation of PL-exo were significantly enhanced after ALN modification. Besides directly modulating the osteogenic and angiogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and endothelial progenitor cells (EPCs), respectively, PL-exo-ALN also facilitate their coupling under GCs' stimulation. Additionally, intravenous injection of PL-exo-ALN could successfully rescue GCs induced osteoporosis (GIOP) in vivo. CONCLUSIONS: PL-exo-ALN may be utilized as a novel nanoplatform for precise infusion of GFs to bone sites and exerts promising therapeutic potential for GIOP.

Astrocytic NDRG2-PPM1A interaction exacerbates blood-brain barrier disruption after subarachnoid hemorrhage.

Blood-brain barrier (BBB) injury critically exacerbates the poor prognosis of patients with subarachnoid hemorrhage (SAH). The massively increased matrix metalloproteinases 9 (MMP-9) plays a deleterious role in BBB. However, the main source and mechanism of MMP-9 production after SAH remain unclear. We reported that the increased MMP-9 was mainly derived from reactive astrocytes after SAH. Ndrg2 knockout in astrocytes inhibited MMP-9 expression after SAH and attenuated BBB damage. Astrocytic Ndrg2 knockout decreased the phosphorylation of Smad2/3 and the transcription of MMP-9. Notably, cytoplasmic NDRG2 bound to the protein phosphatase PPM1A and restricted the dephosphorylation of Smad2/3. Accordingly, TAT-QFNP12, a novel engineered peptide that could block the NDRG2-PPM1A binding and reduce Smad2/3 dephosphorylation, decreased astrocytic MMP-9 production and BBB disruption after SAH. In conclusion, this study identified NDRG2-PPM1A signaling in reactive astrocytes as a key switch for MMP-9 production and provided a novel therapeutic avenue for BBB protection after SAH.

Can Even a Small Amount of Greenery Be Helpful in Reducing Stress? A Systematic Review.

A positive experience of nature triggers beneficial mental and physical responses. Today, we live in a rapidly urbanizing world where access to nature is often limited. Against this backdrop, this systematic review investigated studies on the effectiveness of small-scale greenery for stress reduction. We searched EMBASE, Cochrane, Web of Science, Scopus, PubMed, and Science Direct, searching databases from inception to April 2022. Studies were screened against predetermined criteria, and the risk of bias was assessed using the Cochrane Handbook for Systematic Reviews of Interventions for RCTs and The Risk of Bias in Non-Randomized Studies of Interventions (ROBINS-I) tool. Of the 2500 records identified, we screened 1817 citations for eligibility, which included 13 RCT studies and 6 non-RCT studies. The studies were conducted in eight different countries. The study populations included office workers, students, senior citizens, and patients with specific diseases. Research has mainly focused on indoor greening, with relatively little research on small-scale outdoor greening. All included studies assessed the impact of the intervention on various stress reduction-related outcomes, with the most common stress measures being blood pressure and the State Trait Anxiety Inventory (STAI). Various beneficial effects of the interventions on human health were reported in all 19 studies, 15 of which reported positive effects on stress reduction. All included studies were at high risk of bias. It is recommended that future studies in this area take appropriate measures to reduce bias and improve quality in order to build a strong evidence-based medical foundation. According to our findings, even very small-scale greening, including indoor green walls and potted plants, may provide effective help for stress relief. Understanding the physiological and psychological benefits of small-scale greenery can help better provide more opportunities for urban residents to engage with nature in the context of dense urban trends, as well as provide some reference for urban design planning.

MicroRNA-124/Death-Associated Protein Kinase 1 Signaling Regulates Neuronal Apoptosis in Traumatic Brain Injury via Phosphorylating NR2B.

Death-associated protein kinase 1 (DAPK1), a Ca2+/calmodulin-dependent serine/threonine-protein kinase, promotes neurons apoptosis in ischemic stroke and Alzheimer's disease (AD). We hypothesized that knockdown DAPK1 may play a protective role in traumatic brain injury (TBI) and explore underlying molecular mechanisms. ELISA, Western blotting, immunofluorescence, dual-luciferase assay, and Reverse Transcription and quantitative Polymerase Chain Reaction (RT-qPCR) were used to determine the mechanism for the role of DAPK1 in TBI. Open field and novel objective recognition tests examined motor and memory functions. The morphology and number of synapses were observed by transmission electron microscopy and Golgi staining. DAPK1 was mainly found in neurons and significantly increased in TBI patients and TBI mice. The dual-luciferase assay showed that DAPK1 was upregulated by miR-124 loss. The number of TUNEL+ cells, expression levels of cleaved caspase3 and p-NR2B/NR2B were significantly reduced after knocking-down DAPK1 or overexpressing miR-124 in TBI mice; and motor and memory dysfunction was recovered. After Tat-NR2B were injected in TBI mice, pathological and behavioral changes were mitigated while the morphology while the number of synapses were not affected. Overall, DAPK1 is a downstream target gene of miR-124 that regulates neuronal apoptosis in TBI mice via NR2B. What's more, DAPK1 restores motor and memory dysfunctions without affecting the number and morphology of synapses.

Activating Parkin-dependent mitophagy alleviates oxidative stress, apoptosis, and promotes random-pattern skin flaps survival.

The random-pattern skin flap is a crucial technique in reconstructive surgery and flap necrosis caused by ischemia/reperfusion injury is a major postoperative complication. Herein, we investigated the mechanism of mitophagy induced by Melatonin (ML) and its effect on the survival of skin flaps. Our results demonstrated that ML could activate mitophagy, ameliorate oxidative stress and alleviate apoptosis in Tert-Butyl hydroperoxide solution (TBHP)-stimulated human umbilical vein endothelial cells in vitro. Inhibiting ML-induced mitophagy considerably abolished its protective effects. Moreover, knockdown of Parkin by siRNA inhibited ML-induced mitophagy, and subsequently exacerbated oxidative stress and apoptosis. Further study demonstrated that inhibition of AMPK reversed these protective effects of ML and downregulated the expression of TFEB. In the vivo study, ML effectively promoted flap survival by activating mitophagy and subsequently ameliorating oxidative stress and mitigating apoptosis. These results established that ML is a potent agent capable for increasing random-pattern skin flap survival by activating Parkin-dependent mitophagy through the AMPK-TFEB signaling pathway.

A high acromion-greater tuberosity impingement index increases the risk of retear after arthroscopic rotator cuff repair.

BACKGROUND: No evaluation has been done on the relationship of the acromion-greater tuberosity impingement index (ATI) with retear after arthroscopic rotator cuff repair (ARCR). Our purpose was to evaluate whether a higher ATI is associated with retear after ARCR. METHODS: 132 patients received ARCR and underwent MRI scan at a one year follow-up to assess tendon healing, and the findings were graded no retear (NR), partial-thickness retear (PR) or full-thickness retear (FR). The ATI, the critical shoulder angle (CSA), acromion index (AI) and lateral acromial angle (LAA) were measured with postoperative radiographs. Functional scores were obtained preoperatively and at a one year follow-up. RESULTS: Postoperative Constant scores and ASES scores were significantly different between groups with inferior outcomes in the FR group (p < 0.05 for all). The UCLA score was significantly better in the NR group compared with the PR and FR groups (p < 0.05), and in the PR group compared with the FR group (p < 0.05). For ATI and CSA, the values of the PR and FR groups were larger than the NR group (p < 0.05 for all), but there were no significant differences between the PR and FR groups (p > 0.05 for all). No significant differences were observed with regard to the AI and LAA (p > 0.05, respectively). The repair integrity was positively related to the ATI (0.304, p < 0.05) and CSA (0.252, p < 0.05), but not related to the AI or LAA (p > 0.05 for both). ATI was not related to any functional scores (p > 0.05 for all). CONCLUSION: This study revealed that the ATI was positively related to rotator cuff retear. Patients with retears had significantly greater ATIs after ARCR. Level of Evidence: III, case-control study.

The Specific Role of Reactive Astrocytes in Stroke.

Astrocytes are essential in maintaining normal brain functions such as blood brain barrier (BBB) homeostasis and synapse formation as the most abundant cell type in the central nervous system (CNS). After the stroke, astrocytes are known as reactive astrocytes (RAs) because they are stimulated by various damage-associated molecular patterns (DAMPs) and cytokines, resulting in significant changes in their reactivity, gene expression, and functional characteristics. RAs perform multiple functions after stroke. The inflammatory response of RAs may aggravate neuro-inflammation and release toxic factors to exert neurological damage. However, RAs also reduce excitotoxicity and release neurotrophies to promote neuroprotection. Furthermore, RAs contribute to angiogenesis and axonal remodeling to promote neurological recovery. Therefore, RAs' biphasic roles and mechanisms make them an effective target for functional recovery after the stroke. In this review, we summarized the dynamic functional changes and internal molecular mechanisms of RAs, as well as their therapeutic potential and strategies, in order to comprehensively understand the role of RAs in the outcome of stroke disease and provide a new direction for the clinical treatment of stroke.

Single-Nucleus RNA Sequencing Reveals that Decorin Expression in the Amygdala Regulates Perineuronal Nets Expression and Fear Conditioning Response after Traumatic Brain Injury.

Traumatic brain injury (TBI) is a risk factor for posttraumatic stress disorder (PTSD). Augmented fear is a defining characteristic of PTSD, and the amygdala is considered the main brain region to process fear. The mechanism by which the amygdala is involved in fear conditioning after TBI is still unclear. Using single-nucleus RNA sequencing (snRNA-seq), transcriptional changes in cells in the amygdala after TBI are investigated. In total, 72 328 nuclei are obtained from the sham and TBI groups. 7 cell types, and analysis of differentially expressed genes (DEGs) reveals widespread transcriptional changes in each cell type after TBI are identified. In in vivo experiments, it is demonstrated that Decorin (Dcn) expression in the excitatory neurons of the amygdala significantly increased after TBI, and Dcn knockout in the amygdala mitigates TBI-associated fear conditioning. Of note, this effect is caused by a Dcn-mediated decrease in the expression of perineuronal nets (PNNs), which affect the glutamate-γ-aminobutyric acid balance in the amygdala. Finally, the results suggest that Dcn functions by interacting with collagen VI α3 (Col6a3). Consequently, the findings reveal transcriptional changes in different cell types of the amygdala after TBI and provide direct evidence that Dcn relieves fear conditioning by regulating PNNs.

Long-term outcome of stereotactic aspiration, endoscopic evacuation, and open craniotomy for the treatment of spontaneous basal ganglia hemorrhage: a propensity score study of 703 cases.

BACKGROUND: To compare the long-term therapeutic effects of stereotactic aspiration (SA), endoscopic evacuation (EE), and open craniotomy (OC) in the surgical treatment of spontaneous basal ganglia hemorrhage and explore the appropriate clinical indications for each technique. METHODS: Multiple-treatment inverse probability of treatment weighting (IPTW)-adjusted logistic regression analysis was performed to evaluate the therapeutic effects of these techniques. The primary and secondary outcomes were 6-month modified Rankin Scale (mRS) and mortality rates, respectively. RESULTS: A total of 703 patients were ultimately enrolled. For the entire cohort, the 6-month mortality rate was significantly higher (OR 2.396, 95% CI: 1.865-3.080), and the 6-month functional outcome was significantly worse (OR 1.359, 95% CI: 1.091-1.692) for SA than that of EE. The 6-month mortality rate for OC was significantly higher (OR 1.395, 95% CI: 1.059-1.837) than that of EE. Further subgroup analysis was stratified by initial hematoma volume and Glasgow Coma Scale (GCS) score. The mortality rate for SA was significantly higher for patients with hematoma volume of 20-40 mL (OR 6.226, 95% CI: 3.848-10.075), 40-80 mL (OR 2.121, 95% CI: 1.492-3.016), and ≥80 mL (OR 5.544, 95% CI: 3.315-9.269) than in the same subgroups of EE. The functional outcomes for SA were significantly worse than that of EE for hematoma volume subgroups of 40-80 mL (OR 1.424, 95% CI: 1.039-1.951) and ≥80 mL (OR 4.224, 95% CI: 1.655-10.776). The mortality rate for SA was significantly higher than that of EE for the GCS score subgroups of 6-8 (OR 2.082, 95% CI: 1.410-3.076) and 3-5 (OR 2.985, 95% CI: 1.904-4.678). The mortality rate for OC was significantly higher for the GCS score of 3-5 subgroup (OR 1.718, 95% CI: 1.115-2.648), and a tendency for a higher mortality rate of 6-8 subgroup (OR 1.442, 95% CI: 0.965-2.156) than that of EE. CONCLUSIONS: EE can decrease the 6-month mortality rate and improve the 6-month functional outcomes of spontaneous basal ganglia hemorrhage in patients with a hematoma volume ≥40 mL. EE can decrease the 6-month mortality rate of spontaneous basal ganglia hemorrhage in patients with a GCS score of 3-8.

Modified double-pulley suture-bridge techniques with or without medial knot tying show comparable clinical and radiological outcomes in arthroscopic rotator cuff repair.

PURPOSE: The optimal technique for arthroscopic rotator cuff repair is still controversial. The aim of this study was to compare modified arthroscopic double-pulley suture-bridge (DPSB) technique with medial knot tying to those without tying, considering clinical and radiological outcomes. METHODS: This study included 292 patients with large full-thickness rotator cuff tears treated with modified DPSB technique. The patients were divided into 158 cases with medial knot tying (knot-tying group) and 134 without tying (knotless group). At follow-up, clinical outcome was assessed by the Constant score, American Shoulder and Elbow Surgeons (ASES) score, and Shoulder Rating Scale of the University of California at Los Angeles (UCLA) score. The assessment of tendon healing was performed with magnetic resonance imaging (MRI) at a minimum of 12 months postoperatively. RESULTS: The Constant score, ASES score and UCLA score in the knot-tying and knotless groups all improved significantly from before surgery to 12 months postoperatively (P < 0.05, respectively). No significant differences were observed between groups for each phase evaluated (n.s.). Tendon healing was categorised according to Sugaya's classification. The retearing rate was 27/158 (17.0%) in the knot-tying group and 20/134 (14.9%) in the knotless group, with no statistically significant difference between groups (n.s.). Additionally, the retear was classified using the Cho's classification. When comparing the retear rates of different types independently, no statistically significant differences were found between groups (n.s.). CONCLUSIONS: The knotless modified DPSB technique showed comparable short-term functional outcomes to those of the knot tying method in large full-thickness rotator cuff tears. Additionally, no significant differences in repair integrity were observed between the two methods. Both techniques can be considered effective treatments for patients with large-sized full-thickness rotator cuff tears. LEVEL OF EVIDENCE: III.

Acrolein Induces Systemic Coagulopathy via Autophagy-dependent Secretion of von Willebrand Factor in Mice after Traumatic Brain Injury.

Traumatic brain injury (TBI)-induced coagulopathy has increasingly been recognized as a significant risk factor for poor outcomes, but the pathogenesis remains poorly understood. In this study, we aimed to investigate the causal role of acrolein, a typical lipid peroxidation product, in TBI-induced coagulopathy, and further explore the underlying molecular mechanisms. We found that the level of plasma acrolein in TBI patients suffering from coagulopathy was higher than that in those without coagulopathy. Using a controlled cortical impact mouse model, we demonstrated that the acrolein scavenger phenelzine prevented TBI-induced coagulopathy and recombinant ADAMTS-13 prevented acrolein-induced coagulopathy by cleaving von Willebrand factor (VWF). Our results showed that acrolein may contribute to an early hypercoagulable state after TBI by regulating VWF secretion. mRNA sequencing (mRNA-seq) and transcriptome analysis indicated that acrolein over-activated autophagy, and subsequent experiments revealed that acrolein activated autophagy partly by regulating the Akt/mTOR pathway. In addition, we demonstrated that acrolein was produced in the perilesional cortex, affected endothelial cell integrity, and disrupted the blood-brain barrier. In conclusion, in this study we uncovered a novel pro-coagulant effect of acrolein that may contribute to TBI-induced coagulopathy and vascular leakage, providing an alternative therapeutic target.

Erratum: Microporous polysaccharide multilayer coated BCP composite scaffolds with immobilised calcitriol promote osteoporotic bone regeneration both in vitro and in vivo: Erratum.

[This corrects the article DOI: 10.7150/thno.29566.].

Inhibiting TLR4 signaling by linarin for preventing inflammatory response in osteoarthritis.

Osteoarthritis (OA) is one of the most common degenerative diseases, ultimately leading to long-term joint pain and severe articular malformation. Controlling local chronic inflammation is a crucial strategy for delaying OA development. Linarin is a natural flavonoid glycoside that is widely available in Compositae, Chrysanthemum indicum and Dendrocalamus and processes protective effects in several animal models. The purpose of our work was to study the protective effect of Linarin for OA. Cellular experiments data showed that Linarin suppressed lipopolysaccharide (LPS)-caused the overproduction of nitric oxide (NO), prostaglandin E2 (PGE2), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α) in chondrocyte. In addition, LPS-stimulated expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide nitrate (iNOS) was decreased by Linarin pre-treatment. Together, Linarin prevented the catabiosis of extracellular matrix caused by LPS. For mechanism, Linarin inhibited the formation of Toll-like receptor 4 (TLR4) / myeloid differentiation protein-2 (MD-2) dipolymer complex and subsequently intervened NF-κB activation. Our mouse DMM model further clarified the protection of Linarin in vivo. In summary, our results suggested that Linarin may be a potential effective agent for OA.

Theaflavin protects chondrocytes against apoptosis and senescence via regulating Nrf2 and ameliorates murine osteoarthritis.

Oxidative stress-mediated excessive apoptosis and senescence of chondrocytes are the main pathological alterations in the osteoarthritis (OA) development. The protective effects of theaflavin (TF), a common group of polyphenols in black tea, against many degenerative diseases by attenuating oxidative stress are well reported. Nevertheless, its role in the OA treatment is still scantily understood. In the current research, by applying enzyme-linked immunosorbent assay (ELISA) kits and immunofluorescent staining, TF treatment was found to inhibit tert-Butyl hydroperoxide (TBHP)-induced imbalance of anabolism and catabolism in primary mouse chondrocytes. Then, according to western blot, live-dead staining, and SA-ß-gal staining, the dramatically increased level of apoptosis and senescence of chondrocytes in response to TBHP was also found to be reduced by TF administration. With regard to upstream signaling investigation, the in vitro molecular binding analysis indicated that the beneficial effects of TF might be related to the regulation of the Keap1/Nrf2/HO-1 axis. Furthermore, the Silencing of Nrf2 resulted in the abolishment of the anti-apoptosis and anti-senescence effects of TF. In addition, the oral administration of TF was demonstrated to ameliorate osteoarthritis development in a surgically induced mouse OA model. Taken together, these results suggest that TF might be a promising therapeutic option for the treatment of OA.