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Meningiomas are the most common primary intracranial tumors and account for nearly 30% of all nervous system tumors. Approximately half of meningioma patients exhibit neurofibromin 2 (NF2) gene inactivation. Here, NF2 was shown to interact with the endoplasmic reticulum (ER) calcium (Ca2+) channel inositol 1,4,5-trisphosphate receptor 1 (IP3R1) in IOMM-Lee, a high-grade malignant meningioma cell line, and the F1 subdomain of NF2 plays a critical role in this interaction. Functional assays indicated that NF2 promotes the phosphorylation of IP3R (Ser 1756) and IP3R-mediated endoplasmic reticulum (ER) Ca2+ release by binding to IP3R1, which results in Ca2+-dependent apoptosis. Knockout of NF2 decreased Ca2+ release and promoted resistance to apoptosis, which was rescued by wild-type NF2 overexpression but not by F1 subdomain deletion truncation overexpression. The effects of NF2 defects on the development of tumors were further studied in mouse models. The decreased expression level of NF2 caused by NF2 gene knockout or mutation affects the activity of the IP3R channel, which reduces Ca2+-dependent apoptosis, thereby promoting the development of tumors. We elucidated the interaction patterns of NF2 and IP3R1, revealed the molecular mechanism through which NF2 regulates IP3R1-mediated Ca2+ release, and elucidated the new pathogenic mechanism of meningioma-related NF2 variants. Our study broadens the current understanding of the biological function of NF2 and provides ideas for drug screening of NF2-associated meningioma.
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Apoptosis , Señalización del Calcio , Calcio , Receptores de Inositol 1,4,5-Trifosfato , Neoplasias Meníngeas , Meningioma , Animales , Humanos , Ratones , Calcio/metabolismo , Línea Celular Tumoral , Retículo Endoplásmico/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/genética , Neoplasias Meníngeas/metabolismo , Neoplasias Meníngeas/patología , Neoplasias Meníngeas/genética , Meningioma/metabolismo , Meningioma/patología , Meningioma/genética , Neurofibromina 2RESUMEN
Brain damage is a common tissue damage caused by trauma or diseases, which can be life-threatening. Stem cell implantation is an emerging strategy treating brain damage. The stem cell is commonly embedded in a matrix material for implantation, which protects stem cell and induces cell differentiation. Cell differentiation induction by this material is decisive in the effectiveness of this treatment strategy. In this work, we present an injectable fibroin/MXene conductive hydrogel as stem cell carrier, which further enables in-vivo electrical stimulation upon stem cells implanted into damaged brain tissue. Cell differentiation characterization of stem cell showed high effectiveness of electrical stimulation in this system, which is comparable to pure conductive membrane. Axon growth density of the newly differentiated neurons increased by 290% and axon length by 320%. In addition, unfavored astrocyte differentiation is minimized. The therapeutic effect of this system is proved through traumatic brain injury model on rats. Combined with in vivo electrical stimulation, cavities formation is reduced after traumatic brain injury, and rat motor function recovery is significantly promoted.
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Bombyx , Lesiones Traumáticas del Encéfalo , Fibroínas , Células Madre Mesenquimatosas , Células-Madre Neurales , Nitritos , Elementos de Transición , Ratas , Animales , Fibroínas/metabolismo , Fibroínas/farmacología , Bombyx/metabolismo , Hidrogeles/farmacología , Neuronas/metabolismo , Encéfalo/metabolismo , Lesiones Traumáticas del Encéfalo/metabolismoRESUMEN
Glioma is the most malignant tumor in the central nervous system with a poor prognosis. The tumor immune microenvironment plays a crucial role in glioma formation and progress. TREM1, as a vital immune regulator, has not been investigated in glioma. This study aims to explore the role of TREM1 in prognosis and tumor immune microenvironment of glioma. The mRNA expression level of TREM1 was collected from TCGA and GEO databases. The correlations between the clinic-pathological features and TREM1 expression were analyzed using Cox regression analysis. Kaplan-Meier was used to evaluate the effect of TREM1 on OS. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes were performed to analyze the functional annotations and signaling pathways of the TREM1 coexpression genes. ESTIMATE and TIMER explored the correlations between TREM1 and immune cell infiltration. Spearman correlation analysis was conducted to examine the association between the TREM1 and immune checkpoint expression. The expression level of TREM1 was significantly increased in glioma. TREM1 overexpression was positively related to poor prognosis, higher World Health Organization grade, isocitrate dehydrogenase wildtype, and 1p/19q non-codeletion. TREM1 coexpression genes were mainly related to immunoregulation and inflammatory response. TREM1 participated in the initiation and progression of glioma by regulating immune cell infiltration and expression of immune checkpoints. TREM1 is an effective prognostic and diagnostic biomarker in glioma. It can be adopted as a novel predictor for clinical prognosis, pathological characteristics, and immune microenvironment in glioma patients.
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Glioma , Humanos , Pronóstico , Receptor Activador Expresado en Células Mieloides 1/genética , Glioma/genética , Sistema Nervioso Central , Aberraciones Cromosómicas , Biomarcadores , Microambiente Tumoral/genéticaRESUMEN
Biophysical factors are essential in cell survival and behaviors, but constructing a suitable 3D microenvironment for the recruitment of stem cells and exerting their physiological functions remain a daunting challenge. Here, we present a novel silk fibroin (SF)-based fabrication strategy to develop hierarchical microchannel scaffolds for biomimetic nerve microenvironments in vitro. We first modulated the formation of SF nanofibers (SFNFs) that mimic the nanostructures of the native extracellular matrix (ECM) by using graphene oxide (GO) nanosheets as templates. Then, SFNF-GO systems were shaped into 3D porous scaffolds with aligned micro-lamellar structures by freeze-casting. The interconnected microchannels successfully induced cell infiltration and migration to the SFNF-GO scaffolds' interior. Meanwhile, the nano-fibrillar structures and the GO component significantly induced neural stem cells (NSCs) to differentiate into neurons within a short timeframe of 14 d. Importantly, these 3D hierarchical scaffolds induced a mild inflammatory response, extensive cell recruitment, and effective stimulation of NSC neuronal differentiation when implanted in vivo. Therefore, these SFNF-GO lamellar scaffolds with distinctive nano-/micro-topographies hold promise in the fields of nerve injury repair and regenerative medicine.
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Fibroínas , Células-Madre Neurales , Andamios del Tejido/química , Células-Madre Neurales/metabolismo , Fibroínas/química , Neuronas , Diferenciación Celular , Ingeniería de TejidosRESUMEN
Multimodal therapy requires effective drug carriers that can deliver multiple drugs to specific locations in a controlled manner. Here, the study presents a novel nanoplatform constructed using zeolitic imidazolate framework-8 (ZIF-8), a nanoscale metal-organic framework nucleated under the mediation of silk fibroin (SF). The nanoplatform is modified with the newly discovered MCF-7 breast tumor-targeting peptide, AREYGTRFSLIGGYR (AR peptide). Indocyanine green (ICG) and doxorubicin (DOX) are loaded onto the nanoplatform with high drug encapsulation efficiency (>95%). ICG enables the resultant nanoparticles (NPs), called AR-ZS/ID-P, to release reactive oxygen species for photodynamic therapy (PDT) and heat for photothermal therapy (PTT) under near-infrared (NIR) irradiation, promoting NIR fluorescence and thermal imaging to guide DOX-induced chemotherapy. Additionally, the controlled release of both ICG and DOX at acidic tumor conditions due to the dissolution of ZIF-8 provides a drug-targeting mechanism in addition to the AR peptide. When intravenously injected, AR-ZS/ID-P NPs specifically target breast tumors and exhibit higher anticancer efficacy than other groups through ICG-enabled PDT and PTT and DOX-derived chemotherapy, without inducing side effects. The results demonstrate that AR-ZS/ID-P NPs are a promising multimodal theranostic nanoplatform with maximal therapeutic efficacy and minimal side effects for targeted and controllable drug delivery.
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BACKGROUND: Intracerebral hemorrhage (ICH) is a high mortality and disability stroke subtype. Destruction of the blood-brain barrier (BBB) is a crucial contributor to brain edema and neurological deficit after ICH. Triggering receptor expressed on myeloid cells 1 (TREM-1) has been reported to be expressed in endothelial cells, but its role in ICH remains unclear. This study aims to evaluate the role of TREM-1 on BBB permeability after ICH in mice. METHODS: Two hundred and forty-two CD1 mice were used in this study. The ICH model was established by collagenase injection. LP17 was administered intranasally at 2 or 8 h after ICH to inhibit TREM-1. To explore the underlying mechanism, SYK activation CRISPR was administered intracerebroventricularly with LP17, and Anti-mouse TREM-1 rat IgG2a (a specific TREM-1 agonist) was injected intracerebroventricularly with R406 (a specific SYK inhibitor) intraperitoneally. Neurobehavioral outcome, brain water content, BBB permeability, and protein expression were evaluated. RESULTS: The expression level of the TREM-1 receptor increased rapidly as early as 6 h after ICH, and it was mainly expressed on the endotheliocytes in the neurovascular unit. Early and delayed administration of LP17 significantly decreased brain edema and improved neurobehavioral outcomes at 24 h after ICH. LP17 reduced the BBB permeability by increasing ß-catenin, claudin-5 and ZO-1 expression. Furthermore, SYK activation CRISPR abolished the beneficial effect of LP17 on the expression of the above junction molecules. Meanwhile, R406 reversed the impact of the TREM-1 activator on the downregulation of ß-catenin, claudin-5 and ZO-1 expression. CONCLUSIONS: This study demonstrated that TREM-1 deteriorated BBB permeability via modulating the expression of interendothelial junction molecules after ICH, and this regulation is partly mediated by the SYK/ß-catenin signaling pathway.
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Barrera Hematoencefálica , Edema Encefálico , Hemorragia Cerebral , Animales , Ratones , beta Catenina/metabolismo , beta Catenina/farmacología , Barrera Hematoencefálica/metabolismo , Edema Encefálico/tratamiento farmacológico , Edema Encefálico/etiología , Edema Encefálico/metabolismo , Hemorragia Cerebral/tratamiento farmacológico , Hemorragia Cerebral/metabolismo , Claudina-5/metabolismo , Células Endoteliales/metabolismo , Transducción de Señal , Receptor Activador Expresado en Células Mieloides 1/metabolismoRESUMEN
Chronic skin inflammatory diseases including atopic dermatitis (AD) and psoriasis have been considered uncontrolled inflammatory responses, which have usually troubled patients around the world. Moreover, the recent method to treat AD and psoriasis has been based on the inhibition, not regulation, of the abnormal inflammatory response, which can induce a number of side effects and drug resistance in long-term treatment. Mesenchymal stem/stromal cells (MSCs) and their derivatives have been widely used in immune diseases based on their regeneration, differentiation, and immunomodulation with few adverse effects, which makes MSCs a promising treatment for chronic skin inflammatory diseases. As a result, in this review, we aim to systematically discuss the therapeutic effects of various resources of MSCs, the application of preconditioning MSCs and engineering extracellular vesicles (EVs) in AD and psoriasis, and the clinical evaluation of the administration of MSCs and their derivatives, which can provide a comprehensive vision for the application of MSCs and their derivatives in future research and clinical treatment.
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Dermatitis Atópica , Células Madre Mesenquimatosas , Psoriasis , Enfermedades de la Piel , Humanos , Dermatitis Atópica/terapia , Piel , Psoriasis/terapiaRESUMEN
Blood-brain barrier (BBB) is the most important component of central nervous system (CNS) to keep toxins and pathogens from CNS. Although our studies demonstrated that using interleukin-6 antibodies (IL-6-AB) reversed the increased permeability of BBB, IL-6-AB is limited in their application that only could be used a few hours before surgery and seemed delayed the surgical wounds healing process, which urges us to find another more effective method. In this study, we employed the C57BL/6J female mice to investigate the potential effects of umbilical cord-derived mesenchymal stem cells (UC-MSCs) transplantation on BBB dysfunction induced by surgical wound. Compared to IL-6-AB, the transplantation of UC-MSCs more effectively decreased the BBB permeability after surgical wound evaluated by dextran tracer (immunofluorescence imaging and luorescence quantification). In addition, UC-MSCs can largely decrease the ratio of proinflammatory cytokine IL-6 to the anti-inflammatory cytokine IL-10 in both serum and brain tissue after surgical wound. Moreover, UC-MSCs successfully increased the levels of tight junction proteins (TJs) in BBB such as ZO-1, Occludin, and Claudin-5 and extremely decreased the level of matrix metalloproteinase-9 (MMP-9). Interestingly, UC-MSCs treatment also had positive effects on wound healing while protecting the BBB dysfunction induced by surgical wound compared to IL-6-AB treatment. These findings suggest that UC-MSCs transplantation is a highly efficient and promising approach on protecting the integrity of BBB which caused by peripheral traumatic injuries.
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Background: Tubridge flow diverter is a widely used device aimed at reconstructing parent arteries and occluding complex aneurysms in China. The experience of Tubridge in treating small and medium aneurysms is still limited. In this study, we aimed to evaluate the safety and efficacy of the Tubridge flow diverter for the treatment of the two types of aneurysms. Methods: We reviewed the clinical records of aneurysms treated with a Tubridge flow diverter between 2018 and 2021 in a national cerebrovascular disease center. Cases were divided into small and medium aneurysms according to aneurysm size. The therapeutic process, occlusion rate, and clinical outcome were compared. Results: In total, 57 patients and 77 aneurysms were identified. The patients were divided into two groups: small aneurysms (39 patients, 54 aneurysms) and medium aneurysms (18 patients, 23 aneurysms). There were 19 patients with tandem aneurysms (a total of 39 aneurysms) in the two groups, among which 15 patients (30 aneurysms) were in the small aneurysm group and four patients (nine aneurysms) were in the medium aneurysm group. The results show that the mean maximal diameter/neck in the small and medium aneurysms was 3.68/3.25 and 7.61/6.24 mm, respectively. In total, 57 Tubridge flow diverters were successfully implanted without unfolding failure, and there were six patients with new mild cerebral infarction in the small aneurysm group. The complete occlusion rate on the last angiographic follow-up was achieved in 88.46% of the small aneurysms group and 81.82% of the medium aneurysms group. The complete occlusion rate of patients with tandem aneurysms in the last angiographic follow-up was 86.67% (13/15) of the small aneurysms group and 50% (2/4) of the medium aneurysm group. Intracranial hemorrhage was nonencountered in the two groups. Conclusion: Our preliminary experience suggests that the Tubridge flow diverter might be a safe and effective treatment for small and medium aneurysms along the internal carotid artery. Long stents may increase the risk of cerebral infarction. Adequate evidence is required to clarify the definite indications and complications in a multicenter randomized controlled trial with a long-term follow-up.
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BACKGROUND: The Tubridge flow diverter is a device widely used in China aimed at reconstructing parent artery and occluding complex aneurysm. The experience of the Tubridge in treating unruptured vertebrobasilar artery dissecting aneurysms is still limited. In this study, we aimed to evaluate the safety and efficacy of the Tubridge flow diverter for the treatment of vertebrobasilar artery dissecting aneurysms. METHODS: We reviewed the clinical records of aneurysms treated with the Tubridge flow diverter between 2019 and 2021 in a national cerebrovascular disease center. Therapeutic process, occlusion rate, and clinical outcome were compared. RESULTS: Twenty-three patients with 23 vertebrobasilar artery aneurysms were identified. The results showed that the mean length and mean maximal width were 15.14 and 9.14 mm, respectively, in the vertebrobasilar artery. Twenty-four Tubridge flow diverters were successfully implanted without unfold failure. A complete occlusion rate at the last angiographic follow-up was achieved in 78.26% of vertebrobasilar artery aneurysms. Fifteen branch arteries were covered, and only 1 branch artery disappeared at follow-up. Mild asymptomatic cerebral infarction occurred in 3 patients (13.04%); intracranial hemorrhage was not found in the patients. CONCLUSIONS: Our preliminary experience suggests that the Tubridge flow diverter might be a safe and effective tool for dissecting cerebral aneurysms. Branch arteries were well protected and mild asymptomatic cerebral infarction occurred in some patients. Adequate evidence is required to clear the definite indications and complications in a multicenter randomized controlled trial with a long-term follow-up.
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Disección Aórtica , Embolización Terapéutica , Procedimientos Endovasculares , Aneurisma Intracraneal , Humanos , Aneurisma Intracraneal/diagnóstico por imagen , Aneurisma Intracraneal/cirugía , Resultado del Tratamiento , Embolización Terapéutica/métodos , Stents , Disección Aórtica/diagnóstico por imagen , Disección Aórtica/cirugía , Infarto Cerebral/terapia , Procedimientos Endovasculares/métodos , Angiografía Cerebral , Estudios Retrospectivos , Estudios Multicéntricos como AsuntoRESUMEN
Neurofibromatosis type 2 is an autosomal dominant multiple neoplasia syndrome and is usually caused by mutations in the neurofibromin 2 (NF2) gene, which encodes a tumor suppressor and initiates the Hippo pathway. However, the mechanism by which NF2 functions in the Hippo pathway isn't fully understood. Here we identified a NF2 c.770-784del mutation from a neurofibromatosis type 2 family. MD simulations showed that this mutation significantly changed the structure of the F3 module of the NF2-FERM domain. Functional assays indicated that the NF2 c.770-784del variant formed LLPS in the cytoplasm with LATS to restrain LATS plasma membrane localization and inactivated the Hippo pathway. Besides, this deletion partly caused a skipping of exon 8 and reduced the protein level of NF2, collectively promoting proliferation and tumorigenesis of meningeal cells. We identified an unrecognized mechanism of LLPS and splicing skipping for the NF2-induced Hippo pathway, which provided new insight into the pathogenesis of neurofibromatosis type 2.
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Background: Burn injuries place a heavy burden on the global healthcare system. However, there is still a lack of nationwide studies on the epidemiological characteristics of burn patients in mainland China. The present study aims to accurately analyze the clinical characteristics of burn patients by collecting data in mainland China from 2009 to 2018, which will provide effective strategies for healthcare systems and the government in mainland China. Methods: Patients admitted for burn injuries to 196 hospitals in 31 provinces, autonomous regions and municipalities in mainland China from 2009 to 2018 were included. The data collected included sex, age, month distribution, etiology, region, clinical outcome, injury anatomical location, total burn surface area and mortality. SPSS 19.0 software was used to analyze the data. Results: From 2009 to 2018, the burn patients were 333,995 (0.76%), which included 222,480 (66.61%) males and 111,515 (33.39%) females. From 2009 to 2018, the number of individuals admitted to hospitals for burns showed a downward trend year by year. The burn patients accounted for the highest proportion of inpatients in 0-10 years (38.10%), followed by 40-50 years (13.14%). The highest cure ratio of burn inpatients was in the 20-30 age group (31 394, 71.53%). Among 31 provinces, autonomous regions and municipalities, the province with the highest proportion of total inpatients caused by burns was Inner Mongolia (4.61%), followed by Zhejiang (3.17%), Hainan (2.88%) and Xinjiang (2.64%). Summer (29.16%) was the season with the highest incidence of burn patients admitted to hospitals, followed by spring (25.6%). Scalding (60.19%) was the most frequent kind of burn treated, followed by fire (20.45%). The patients had multiple burn sites (68.89%) most often, followed by burns on the lower limbs (10.91%). From 0% to 10% total body surface area (TBSA) accounted for the highest ratio (37.19%), followed by 90-100% TBSA (21.74%). Conclusions: The present study is the first to describe the associated situation and trends of burn patients in mainland China from 2009 to 2018. Our findings will serve as the latest clinical evidence for healthcare planning and prevention efforts in China and other countries.
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Background: Chronic subdural haematoma (CSDH) has various causes, including trauma, coagulopathies, and intracranial hypotension. However, CSDH associated with extracranial malignancy is rare. Here, we report an extremely rare case of CSDH due to prostate cancer metastasis to a haematoma capsule. Case Description: A 79-year-old man with a history of prostate cancer had a progressive decline in consciousness during hospitalization for cancer treatment. CSDH was diagnosed from computed tomography (CT) imaging. We urgently performed burr hole drainage, and the patient's symptoms improved rapidly after surgery. After removing the drainage tube, the patient's symptoms worsened again, and the repeat head CT suggested recurrence of CSDH. In a second operation, most of the haematoma capsule was excised under craniotomy, and the thickened haematoma capsule was sent for routine pathologic examination. Pathological findings confirmed the metastasis of prostate cancer to the haematoma capsule, which we believed to be related to a rapid recurrence of CSDH. After the second operation, the disease course progressed without CSDH recurrence. Conclusions: For patients with malignant tumours diagnosed with CSDH, the possibility of metastasis to a haematoma capsule needs to be considered. Burr holes and drainage can easily lead to a rapid relapse. Excision of the haematoma capsule is the key to successful treatment.
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Background: Therapy for large or deep cystic brain metastases is a troublesome procedure in clinical departments. Stereotactic cyst aspiration, combined with Gamma Knife radiosurgery, can be an effective treatment for cystic brain metastases. However, there is still a possibility that a reaccumulation of cystic fluid may lead to poor efficacy or even reoperation. Case presentation: We present a case of a 67-year-old man who was diagnosed with lung cancer brain metastasis. The intracranial lesion seen on imaging appeared to be cystic and located deep inside the brain with associated limb dysfunction. The patient did not respond well to chemotherapy and underwent cyst aspiration with Ommaya reservoir implantation under neuronavigation. Repeated cystic fluid reaccumulation and exacerbation of symptoms occurred during treatment. We performed repeated aspiration via the Ommaya reservoir to control the symptoms and combined it with radiotherapy. During the follow-up period of 14 months, the intracranial tumor was effectively and satisfactorily controlled. Conclusions: We highlight that Ommaya reservoir implantation during stereotactic cyst aspiration is necessary to prevent fluid reaccumulation, thereby avoiding the need for a second surgical procedure.
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Cancer has been a serious threat to human health. Among drug delivery carriers, protein nanoparticles are unique because of their mild and environmentally friendly preparation methods. They also inherit desired characteristics from natural proteins, such as biocompatibility and biodegradability. Therefore, they have solved some problems inherent to inorganic nanocarriers such as poor biocompatibility. Also, the surface groups and cavity of protein nanoparticles allow for easy surface modification and drug loading. Besides, protein nanoparticles can be combined with inorganic nanoparticles or contrast agents to form multifunctional theranostic platforms. This review introduces representative protein nanoparticles applicable in cancer theranostics, including virus-like particles, albumin nanoparticles, silk protein nanoparticles, and ferritin nanoparticles. It also describes the common methods for preparing them. It then critically analyzes the use of a variety of protein nanoparticles in improved cancer imaging and therapy.
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BACKGROUND: Mesenchymal stem cells (MSCs) hold promising potential to treat systemic inflammatory diseases including severe acute pancreatitis (SAP). In our previous study, placental chorionic plate-derived MSCs (CP-MSCs) were found to possess superior immunoregulatory capability. However, the therapeutic efficacy of CP-MSCs on SAP and their underlying mechanism remain unclear. METHODS: The survival and colonization of exogenous CP-MSCs were observed by bioluminescence imaging and CM-Dil labeling in rodent animal models of SAP. The therapeutic efficacy of CP-MSCs on SAP rats was evaluated by pathology scores, the levels of pancreatitis biomarkers as well as the levels of inflammatory factors in the pancreas and serum. The potential protective mechanism of CP-MSCs in SAP rats was explored by selectively depleting M1 or M2 phenotype macrophages and knocking down the expression of TSG-6. RESULTS: Exogenous CP-MSCs could survive and colonize in the injured tissue of SAP such as the lung, pancreas, intestine, and liver. Meanwhile, we found that CP-MSCs alleviated pancreatic injury and systemic inflammation by inducing macrophages to polarize from M1 to M2 in SAP rats. Furthermore, our data suggested that CP-MSCs induced M2 polarization of macrophages by secreting TSG-6, and TSG-6 played a vital role in alleviating pancreatic injury and systemic inflammation in SAP rats. Notably, we found that a high inflammation environment could stimulate CP-MSCs to secrete TSG-6. CONCLUSION: Exogenous CP-MSCs tended to colonize in the injured tissue and reduced pancreatic injury and systemic inflammation in SAP rats through inducing M2 polarization of macrophages by secreting TSG-6. Our study provides a new treatment strategy for SAP and initially explains the potential protective mechanism of CP-MSCs on SAP rats.
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Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Pancreatitis , Enfermedad Aguda , Animales , Modelos Animales de Enfermedad , Femenino , Macrófagos , Pancreatitis/terapia , Placenta , Embarazo , RatasRESUMEN
Background and Purpose: Intracerebral hemorrhage (ICH) is a devastating subtype of stroke with high mortality and disability. Inflammatory response promotes secondary brain injury after ICH. TREM (triggering receptor expressed on myeloid cells)-1 is a key regulator of inflammation. The aim of this study was to evaluate the role of TREM-1 in neuroinflammatory response after ICH in mice. Methods: CD1 mice (n=275) were used in this study. Mice were subjected to ICH by autologous blood injection. TREM-1 knockout CRISPR was administered intracerebroventricularly to evaluate the role of TREM-1 after ICH. A selective TREM-1 inhibitor, LP17, was administered intranasally 2 hours after ICH. To elucidate TREM-1 signaling pathway, CARD9 (caspase recruitment domain family member 9) activation CRISPR was administered with LP17 and TREM-1 activating anti-mouse TREM-1 monoclonal antibody (mAb) was administered with Rottlerin, a specific PKC (protein kinase C) δ inhibitor. Lastly, to evaluate the role of HMGB1 (high-mobility group box 1) in TREM-1 mediated microglia activation, glycyrrhizin, an inhibitor of HMBG1 was administered with TREM-1 activating mAb. Neurobehavioral test, brain water content, Western blot, immunofluorescence staining, and coimmunoprecipitation was performed. Results: TREM-1 knockout reduced ICH-induced neurobehavioral deficits and neuroinflammatory response. The temporal expression of HMGB1, TREM-1, PKC δ, and CARD9 increased after ICH. TREM-1 was expressed on microglia. Intranasal administration of LP17 significantly decreased brain edema and improved neurobehavioral outcomes at 24 and 72 hours after ICH. LP17 promoted M2 microglia polarization and reduced proinflammatory cytokines after ICH, which was reversed with CARD9 activation CRISPR. TREM-1 mAb increased neurobehavior deficits, proinflammatory cytokines, and reduced M2 microglia after ICH, which was reversed with Rottlerin. HMBG1 interaction with TREM-1 increased after ICH, and glycyrrhizin reduced neuroinflammation and promoted M2 microglia which was reversed with TREM-1 mAb. Conclusions: This study demonstrated that TREM-1 enhanced neuroinflammation by modulating microglia polarization after ICH, and this regulation was partly mediated via PKC δ/CARD9 signaling pathway and increased HMGB1 activation of TREM-1.
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Proteínas Adaptadoras de Señalización CARD/metabolismo , Hemorragia Cerebral/metabolismo , Proteína Quinasa C-delta/metabolismo , Transducción de Señal , Receptor Activador Expresado en Células Mieloides 1/metabolismo , Animales , Proteínas Adaptadoras de Señalización CARD/genética , Sistemas CRISPR-Cas , Hemorragia Cerebral/genética , Técnicas de Silenciamiento del Gen , Inflamación/genética , Inflamación/metabolismo , Masculino , Ratones , Proteína Quinasa C-delta/genética , Receptor Activador Expresado en Células Mieloides 1/genéticaRESUMEN
OBJECTIVES: This study aimed to summarize the surgical strategies for subdural effusion secondary to decompressive craniectomy (SESDC) and discuss the applicable scenarios of effusion-peritoneal shunt (EP shunt). METHODS: A total of 53 consecutive patients with SESDC were screened out of 7569 cases. The SESDC was divided into five types, and the treatment methods of each type were analyzed and compared. According to the implementation strategy of cranioplasty (CP), patients were divided into CP-first and delayed-CP groups. The differences in surgical methods were compared between the two groups. RESULTS: All patients with SESDC in this cohort had undergone cranioplasty. Subcutaneous puncture and aspiration (SPAA) proved ineffective. Only 2/30 patients in the CP-first group used EP shunt, while 6/19 patients in the delayed-CP group used EP shunt; the difference was statistically significant (P = 0.03). A significant difference was found in the use of EP shunt among type 1, type 2, and type 5 SESDC (χ2 = 6.778, P = 0.034). CONCLUSIONS: CP combined with other treatments could cure most SESDC. EP shunt should be used preferentially in some specific scenarios in which CP cannot be performed first, rather than as a backup measure that can only be used when other preceding treatments fail.
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Craniectomía Descompresiva/efectos adversos , Efusión Subdural/etiología , Efusión Subdural/cirugía , Derivación Ventriculoperitoneal , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Selección de Paciente , Estudios Retrospectivos , Efusión Subdural/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Organized chronic subdural hematoma (CSDH) is a special type of CSDH. However, the optimal surgical procedure has not been established. We present our experience here to discuss the surgical procedure in treatment of organized CSDH. METHODS: Thirty-three patients with organized CSDH were admitted between January 1, 2008 and January 1, 2018. Age, gender, clinical symptoms, imaging data, type of surgical procedure, Barthel index (BI), and postoperative complications were collected and retrospectively analyzed. The BI was assessed both pre and postoperatively (1 week and 1 month after surgery). RESULTS: Overall, 14 patients underwent large craniotomy and 19 patients underwent small craniotomy. No significant differences in gender, age, initial clinical symptoms, and preoperative BI were found between the groups (p > 0.05). Among the 14 patients who underwent large craniotomy, 2 patients developed epilepsy after the operation, while 1 patient had postoperative aphasia. None of the patients had recurrence in 6 months postoperatively. Among the 19 patients who underwent small craniotomy, 1 patient developed an acute subdural hematoma and 1 patient developed aphasia. No obvious complications were found in the remaining 18 patients and none of the 19 patients had recurrence in 6 months postoperatively. BI scores of the small craniotomy group were significantly better than those of the large craniotomy group at 1 week postoperatively (p < 0.05). However, there was no significant difference in the 1-month results (p > 0.05). CONCLUSION: According to our single-center experience, a small craniotomy for treating organized CSDH can be considered as an alternative to a larger craniotomy.
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Craneotomía/métodos , Hematoma Subdural Crónico/cirugía , Anciano , Anciano de 80 o más Años , Afasia/etiología , Craneotomía/efectos adversos , Drenaje/métodos , Epilepsia/etiología , Femenino , Hematoma Subdural Crónico/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/etiología , Recurrencia , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Glioblastomas are malignant brain tumors associated with high mortality and poor prognosis. Evidence from preclinical studies suggests that statins have an antitumor role, but their effects on the survival of patients with glioblastoma remain controversial. This meta-analysis attempts to assess the association between statins and glioblastoma. METHODS: We searched 4 databases (PubMed, Web of Science, Embase, and Cochrane Library) for articles that evaluate the effect of statins on the survival of patients with glioblastoma. Two reviewers were asked to assess the quality of the studies and extract the data regarding progression-free survival (PFS) and overall survival (OS). RESULT: A total of 5 studies met the inclusion criteria with 430 statin users and 2089 nonstatin users. All 5 studies were retrospectively analyzed. The pooled hazard ratio (HR) and 95% confidence intervals (CIs) were calculated. There was no benefit of statins found pertaining to the survival of glioblastoma patients in both PFS (HR, 0.97; CI, 0.84-1.13) and OS (HR, 0.98; CI, 0.87-1.11). In a subgroup defined by the patterns of statin use, it was determined that usage before glioblastoma diagnosis favored the OS of patients (HR, 0.85). The result, however, failed to demonstrate a statistically significant difference. CONCLUSION: Use of statins was not associated with prolonged survival of patients with glioblastoma. Further well-designed randomized controlled trials are needed to confirm.