RESUMEN
INTRODUCTION: Los Angeles grade C/D esophagitis is a severe manifestation of gastroesophageal reflux disease that require active treatment and close follow-up. Potassium competitive acid blockers (P-CAB) are promising alternatives to proton pump inhibitors (PPI). We aimed to compare the efficacy and safety of P-CAB and PPI in healing grade C/D esophagitis to aid clinical decision-making. METHODS: A systematic literature search was performed using PubMed, MEDLINE, and Cochrane Central Register of Controlled Trials. Randomized controlled trials were eligible for inclusion if efficacy of P-CAB and PPI in healing grade C/D esophagitis was reported. Pooled risk ratios and risk difference with 95% credible intervals were used to summarize estimated effect of each comparison. The benefit of treatments was ranked using the surface under the cumulative probability ranking score. RESULTS: Of 5,876 articles identified in the database, 24 studies were eligible. Studies included incorporated 3 P-CAB (vonoprazan, tegoprazan, and keverprazan) and 6 PPI (lansoprazole, esomeprazole, omeprazole, rabeprazole extended-release (ER), pantoprazole, and dexlansoprazole). Based on the failure to achieve mucosal healing, 20 mg of vonoprazan q.d. ranked the first among PPI in initial and maintained healing of grade C/D esophagitis (surface under the cumulative probability ranking score = 0.89 and 0.87, respectively). Vonoprazan had similar risk of incurring adverse events, severe adverse events, and withdrawal to drug when compared with PPI. For those who attempted lower maintenance treatment dose, 10 mg of vonoprazan q.d. was a reasonable choice, considering its moderate efficacy and safety. DISCUSSION: Vonoprazan has considerable efficacy in initial and maintained healing of grade C/D esophagitis compared with PPI, with moderate short-term and long-term safety.
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Inhibidores de la Bomba de Protones , Pirroles , Sulfonamidas , Humanos , Esofagitis/tratamiento farmacológico , Esofagitis Péptica/tratamiento farmacológico , Reflujo Gastroesofágico/tratamiento farmacológico , Metaanálisis en Red , Inhibidores de la Bomba de Protones/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del TratamientoRESUMEN
Intervertebral disc (IVD) degeneration (IVDD) is usually accompanied by nucleus pulposus (NP) fibrosis and pathologic angiogenesis, which are possibly associated with macrophage infiltration. Previous research indicates a destructive role of macrophages and the protective effect of inhibiting heat shock protein 90 (HSP90) in IVDD. Herein, the effects of inhibiting HSP90 on NP fibrosis and pathologic angiogenesis induced by macrophages were investigated further. Single-cell RNA-sequencing analysis was used to classify fibrotic NP cell (NPC) clusters and healthy NPC clusters in human NP tissues. The fibrotic NPC clusters were possibly associated with angiogenesis-related biological processes. Immunostaining showed the spatial association between blood vessel ingrowth and macrophage infiltration, as well as elevated levels of cell migration-inducing protein (CEMIP) and vascular endothelial growth factor A in severely degenerated human IVD tissues. Particularly, HSP90 inhibitor tanespimycin (17-AAG) ameliorated macrophage-induced fibrotic phenotype of NPCs via inhibiting CEMIP. M2, but not M1, macrophages promoted the pro-angiogenic ability of endothelial cells, which was attenuated by 17-AAG or HSP90 siRNA. Reversing the fibrotic phenotype of NPCs by Cemip siRNA also mitigated the pro-angiogenic effects of M2-conditioned medium-treated NPCs. Moreover, the murine IVDD model supported the 17-AAG-induced amelioration of NP fibrosis and endothelial cell invasion in IVD tissues. In conclusion, inhibiting HSP90 attenuated two interrelated pathologic processes, NP fibrosis and pathologic angiogenesis, induced by macrophages via down-regulating CEMIP.
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Degeneración del Disco Intervertebral , Disco Intervertebral , Núcleo Pulposo , Humanos , Ratones , Animales , Núcleo Pulposo/metabolismo , Disco Intervertebral/patología , Degeneración del Disco Intervertebral/metabolismo , Degeneración del Disco Intervertebral/patología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Células Endoteliales/metabolismo , Movimiento Celular , Proteínas de Choque Térmico , Neovascularización Patológica/patología , Macrófagos/metabolismo , Fibrosis , ARN Interferente Pequeño/metabolismoRESUMEN
We aimed to explore the causal effect of daytime napping on the risk of osteoporosis and the mediation role of testosterone in explaining this relationship. Summary data for Mendelian randomization (MR) analysis were obtained from the IEU OpenGWAS database. Univariable MR(UVMR) analysis and multiple sensitivity analyses were applied to explore the casual relationship between daytime napping and bone mineral density (BMD)/osteoporosis. We also conducted multivariable Mendelian randomization (MVMR) analysis to evaluate the correlation between testosterone-associated single-nucleotide variations and BMD/osteoporosis. Then, mediation analysis was performed to explore whether the association between daytime napping and BMD/osteoporosis was mediated via testosterone. Genetically predicted daytime napping was significantly associated with femoral neck BMD (ß [95% CI]: 0.2573 [0.0487, 0.4660]; P = 0.0156), lumbar spine BMD (ß [95% CI]: 0.2526 [0.0211, 0.4840]; P = 0.0324), and osteoporosis (OR [95% CI]: 0.5063 [0.2578, 0.9942]; P = 0.0481). ß and 95%CIs indicate the standard deviation (SD) unit of BMD increase per category increase in daytime napping. OR and 95%CIs represent the change in the odds ratio of osteoporosis per category increase in daytime napping. We observed a potentially causal effect of more frequent daytime napping on higher BMD and a lower risk of osteoporosis. Daytime napping was causally associated with a higher level of bioavailable testosterone (ß [95% CI]: 0.1397 [0.0619, 0.2175]; P = 0.0004). ß and 95%CIs represent the change in the SD of testosterone per category increase in daytime napping. Furthermore, the causal effects of daytime napping on BMD/osteoporosis were partly mediated by bioavailable testosterone. Daytime napping can efficiently increase BMD and reduce the risk of osteoporosis, and testosterone plays a key mediating role in this process.
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Densidad Ósea , Análisis de la Aleatorización Mendeliana , Osteoporosis , Sueño , Testosterona , Humanos , Osteoporosis/epidemiología , Osteoporosis/genética , Testosterona/sangre , Sueño/fisiología , Polimorfismo de Nucleótido Simple , Masculino , Población Blanca , Femenino , Factores de Riesgo , Europa (Continente)/epidemiologíaRESUMEN
Isoleucine is a branched chain amino acid. The role of isoleucine in cerebral ischemia-reperfusion injury remains unclear. Here, we show that the concentration of isoleucine is decreased in cerebrospinal fluid in a rat model of cerebral ischemia-reperfusion injury, the rat middle cerebral artery occlusion (MCAO). To our surprise, the level of intraneuronal isoleucine is increased in an in vitro model of cerebral ischemia injury, the oxygen-glucose deprivation (OGD). We found that the increased activity of LAT1, an L-type amino acid transporter 1, leads to the elevation of intraneuronal isoleucine after OGD insult. Reducing the level of intraneuronal isoleucine promotes cell survival after cerebral ischemia-reperfusion injury, but supplementing isoleucine aggravates the neuronal damage. To understand how isoleucine promotes ischemia-induced neuronal death, we reveal that isoleucine acts upstream to reduce the expression of CBFB (core binding factor ß, a transcript factor involved in cell development and growth) and that the phosphatase PTEN acts downstream of CBFB to mediate isoleucine-induced neuronal damage after OGD insult. Interestingly, we demonstrate that direct-current stimulation reduces the level of intraneuronal isoleucine in cortical cultures subjected to OGD and that transcranial direct-current stimulation (tDCS) decreases the cerebral infarct volume of MCAO rat through reducing LAT1-depencent increase of intraneuronal isoleucine. Together, these results lead us to conclude that LAT1 over activation-dependent isoleucine-CBFB-PTEN signal transduction pathway may mediate ischemic neuronal injury and that tDCS exerts its neuroprotective effect by suppressing LAT1 over activation-dependent signalling after cerebral ischemia-reperfusion injury.
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Isquemia Encefálica , Fármacos Neuroprotectores , Daño por Reperfusión , Estimulación Transcraneal de Corriente Directa , Ratas , Animales , Isoleucina/farmacología , Neuroprotección , Isquemia Encefálica/metabolismo , Transducción de Señal , Infarto de la Arteria Cerebral Media/metabolismo , Daño por Reperfusión/metabolismo , Fármacos Neuroprotectores/farmacología , OxígenoRESUMEN
BACKGROUND: This study aimed to analyze the clinical efficacy of one-stage anterior debridement of lower cervical tuberculosis using iliac crest bone graft fusion and internal fixation. MATERIALS AND METHODS: A retrospective analysis was performed on 48 patients with lower cervical tuberculosis admitted to multiple medical centers from June 2018 to June 2021. Among them, 36 patients had lesions involving two vertebrae and 12 patients had lesions involving more than three vertebrae. All patients were treated with quadruple antituberculosis drugs for more than 2 weeks before the operation, and then treated with one-stage anterior debridement and autogenous iliac bone graft fusion combined with titanium plate internal fixation. After the operation, antituberculosis drugs were continued for 12-18 months. The patients were followed-up to observe the improvement in clinical symptoms, bone graft fusion, Cobb angle, visual analog score (VAS), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), wound healing, and neurological function. RESULTS: The patients were followed-up for 13-43 months, with an average of 21.46 ± 1.52 months. The clinical symptoms significantly improved after the operation. The bone graft was completely fused in all patients, and the bone fusion time was 3-6 months, with an average of 4.16 ± 0.47 months. At the last follow-up, the Cobb angle, VAS, ESR, and CRP level were significantly lower than those before surgery (P < 0.05). None of the patients had loosening, detachment, or rupture of the internal fixation, and no recurrence occurred. All surgical incisions healed in one stage without infection or sinus formation. The preoperative Frankel neurological function classification was grade B in 7 cases, grade C in 13, grade D in 18, and grade E in 10. At the last follow-up, 8 cases recovered to grade D and 40 recovered to grade E. CONCLUSIONS: For patients with lower cervical tuberculosis, based on oral treatment with quadruple antituberculosis drugs, direct decompression through anterior debridement, followed by autologous iliac bone graft fusion combined with internal fixation can completely remove tuberculosis foci, rebuild the stability of the cervical spine, and obtain good clinical efficacy. Level of evidence Level 3.
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Ilion , Tuberculosis , Humanos , Estudios Retrospectivos , Desbridamiento , Antituberculosos/uso terapéutico , Vértebras Cervicales/cirugíaRESUMEN
Precise timing of macrophage polarization plays a pivotal role in immunomodulation of tissue regeneration, yet most studies mainly focus on M2 macrophages for their anti-inflammatory and regenerative effects while the essential proinflammatory role of the M1 phenotype on the early inflammation stage is largely underestimated. Herein, a superparamagnetic hydrogel capable of timely controlling macrophage polarization is constructed by grafting superparamagnetic nanoparticles on collagen nanofibers. The magnetic responsive hydrogel network enables efficient polarization of encapsulated macrophage to the M2 phenotype through the podosome/Rho/ROCK mechanical pathway in response to static magnetic field (MF) as needed. Taking advantage of remote accessibility of magnetic field together with the superparamagnetic hydrogels, a temporal engineered M1 to M2 transition course preserving the essential role of M1 at the early stage of tissue healing, as well as enhancing the prohealing effect of M2 at the middle/late stages is established via delayed MF switch. Such precise timing of macrophage polarization matching the regenerative process of injured tissue eventually leads to optimized immunomodulatory bone healing in vivo. Overall, this study offers a remotely time-scheduled approach for macrophage polarization, which enables precise manipulation of inflammation progression during tissue healing.
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Regeneración Ósea , Macrófagos , Colágeno/metabolismo , Humanos , Hidrogeles/farmacología , Inmunomodulación , Inflamación/metabolismo , Macrófagos/metabolismo , FenotipoRESUMEN
Intervertebral disc (IVD) degeneration (IVDD) is the most common spinal disorder, which can lead to the symptoms of neck pain or low back pain. In healthy mature IVD tissues, extracellular matrix (ECM) complex possesses favorable biochemical and biomechanical properties, withstanding compression and torsion forces. IVD cells and ECM associate with each other to form a coordinated functional system. IVD cells are the main producers of ECM components, while ECM could modulate the viability and phenotype of IVD cells via direct interactions or indirect regulations. However, with the process of IVDD and ageing, ECM of IVD undergoes content loss and structure degeneration. Moreover, the accumulation of catabolic products may further deteriorate the IVD microenvironment. A better understanding of the physiology and the pathology of ECM within the IVD provides new insight into potential IVD regeneration strategies. Natural ECM components, functional motifs, or mimetic peptides are widely used in IVD repair by not only restoring structural support but also regulating cell fate and tissue microenvironment. Herein, we reviewed recent advances in the involvement of ECM in IVD health and disease, with an emphasis on ECM composition and organization, cell-matrix interactions, pathological ECM degradation, and promising matrix-based biomaterials for IVD regeneration.
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Degeneración del Disco Intervertebral , Disco Intervertebral , Dolor de la Región Lumbar , Materiales Biocompatibles , Matriz Extracelular/metabolismo , Humanos , Disco Intervertebral/patología , Degeneración del Disco Intervertebral/patología , Dolor de la Región Lumbar/patologíaRESUMEN
Low back pain (LBP) is a major clinical problem that lacks effective treatments. The sensory innervation in porous vertebral endplates and anxiety contributes to spinal hyperalgesia. We hypothesized that SIRT1 activator resveratrol alleviates LBP and anxiety via promotion of osteogenesis in the porous endplates. The hyperalgesia and anxiety-related behaviors; sensory innervation, inflammation and porosity of endplates; and osteogenic/osteoclastic factors expression were measured following resveratrol treatment after lumbar spine instability (LSI) surgery. To explore whether resveratrol promotes endplates osteogenesis and thus alleviates LBP through activation of SIRT1 in the osteoprogenitor cells of endplates, SIRT1OSX-/- mice were employed. Additionally, the levels of inflammation markers, phosphorylation of cAMP response element-binding protein (pCREB), and brain-derived neurotrophic factor (BDNF) in hippocampus were evaluated. After 4 or 8 weeks LSI surgery, the mice suffered from hyperalgesia and anxiety, which were efficiently attenuated by resveratrol at 8 weeks. Resveratrol treatment-enhanced osteogenesis and decreased endplates porosities accompanied with the reduction of TNFα, IL-1ß, and COX2 levels and CGRP+ nerve fibers innervation in porous endplates. Resveratrol-mediated endplates osteogenesis, decreased endplates porosities, and analgesic and antianxiety effects were abrogated in SIRT1OSX-/- mice. Furthermore, resveratrol relieved inflammation and increased pCREB and BDNF expression in the hippocampus after 8 weeks, which alleviate anxiety-related behaviors. This study provides that resveratrol-mediated porous endplates osteogenesis via the activation of SIRT1 markedly blocked sensory innervation and inflammation in endplates, therefore, alleviating LSI surgery-induced LBP and hippocampus-related anxiety.
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Ansiedad/tratamiento farmacológico , Conducta Animal/efectos de los fármacos , Dolor de la Región Lumbar/tratamiento farmacológico , Osteogénesis/efectos de los fármacos , Resveratrol/farmacología , Sirtuina 1/efectos de los fármacos , Animales , Ansiolíticos/farmacología , Ansiedad/metabolismo , Conducta Animal/fisiología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Dolor de la Región Lumbar/metabolismo , Masculino , Ratones Endogámicos C57BL , Osteoclastos/efectos de los fármacos , Osteoclastos/metabolismoRESUMEN
BACKGROUND: Mitophagy protects against cerebral ischemia/reperfusion (CI/R)-induced neuronal apoptosis via mitochondrial clearance. Although taurine-upregulated gene 1 (lncRNA TUG1) has been proposed to be involved in the neuronal apoptosis evoked by CI/R, its specific role in mitophagy during the progression of CI/R injury remains unknown. METHODS: The CI/R rat model was established using middle cerebral artery occlusion/reperfusion (MCAO/R). Human neuroblastoma cell line SH-SY5Y was subjected to oxygen-glucose deprivation and reoxygenation (OGD/R). Ubiquitination assay, co-immunoprecipitation assay, RNA pull-down, and RNA immunoprecipitation were used to determine the interplay among TUG1, sirtuin 1 (SIRT1), and F-box and WD repeat domain-containing 7 (FBXW7). RESULTS: The upregulation of the TUG1 level and downregulation of the mitophagy were observed in both MCAO/R-treated rats and OGD/R-treated cells. The administration of si-TUG1 (a siRNA directed against TUG1) potentiated mitophagy and suppressed neuronal apoptosis in OGD/R-treated cells. However, the neuroprotective effect of si-TUG1 was reversed by mitophagy inhibitor or SIRT1 knockdown in vitro. Functionally, TUG1 enhanced FBXW7-mediated SIRT1 ubiquitination by upregulating FBXW7 expression. The overexpression of FBXW7 abrogated the si-TUG1-reinforced mitophagy by decreasing SIRT1 expression, thus aggravating neuronal apoptosis in the OGD/R+si-TUG1-treated cells. In rats with MCAO/R, the interference of TUG1 clearly decreased neuronal apoptosis, lessened the infarct volume, and relieved the neurological deficits. CONCLUSION: TUG1 knockdown promotes SIRT1-induced mitophagy by suppressing FBXW7-mediated SIRT1 degradation, thus relieving the neuronal apoptosis induced by CI/R injury. LncRNA TUG1 promotes neuronal apoptosis through inhibition of mitophagy. TUG1 decreased SIRT1 expression by promoting FBXW7-mediated SIRT1 ubiquitination. FBXW7/SIRT1 axis mediated the effect of TUG1 on OGD/R-induced neuronal apoptosis by regulating mitophagy.
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Isquemia Encefálica , MicroARNs , Neuroblastoma , ARN Largo no Codificante , Daño por Reperfusión , Humanos , Ratas , Animales , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Sirtuina 1/genética , Sirtuina 1/metabolismo , Mitofagia , Proteína 7 que Contiene Repeticiones F-Box-WD/metabolismo , Daño por Reperfusión/genética , Daño por Reperfusión/metabolismo , Isquemia Encefálica/genética , Apoptosis/genética , Glucosa/metabolismo , MicroARNs/genéticaRESUMEN
BACKGROUND Fundamental and clinical interest in mesenchymal stem cells (MSCs) has risen dramatically over the past 3 decades. The immunomodulatory and differentiation abilities are the main mechanisms in vitro and in vivo. However, increasing evidence casts doubt on the stemness and immunogenicity of MSCs. MATERIAL AND METHODS We conducted a high-throughput 10x RNA sequencing and Smart-seq2 scRNA-seq analysis to reveal gene expression of Wharton jelly MSCs (WJ-MSCs) at a single-cell level. Multipotent differentiation, subpopulations, marker genes, human leucocyte antigen (HLA) gene expression, and cell cluster trajectory analysis were evaluated. RESULTS The WJ-MSCs had considerable heterogeneity between cells in terms of gene expression. They highly, partially, and hardly expressed genes related to mesodermal differentiation, endodermal differentiation, and ectodermal differentiation, respectively. Some cells seem to be bipotent or unipotent stem cells. Further, Monocle and cell cluster trajectory analysis demonstrated that 1 of the 3 divided clusters performed as stem cells, accounting for 12.6% of the population. The marker genes for a stem cell cluster were CRIM1, GLS, PLOD2, NEXN, ACTR2, FN1, MBNL1, LMOD1, COL3A1, NCL, SEC62, EPRS, COL5A2, COL8A1, and VCAN. In addition, the MSCs also highly, partially, and hardly expressed HLA-I antigen genes, HLA-II genes, and the HLA-G gene, respectively, indicating that MSCs probably have immunogenicity. A Kyoto Encyclopedia of Genes and Genomes pathway analysis of the 3 clusters demonstrated that they were mainly connected with viral infectious diseases, cancer, and endocrine and metabolic disorders. The most expressed transcription factors were zf-C2H2, HMG/HMGY, and Homeobox. CONCLUSIONS We found that only a subpopulation of WJ-MSCs are real stem cells and WJ-MSCs probably do not have immune privilege.
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Privilegio Inmunológico , Células Madre Mesenquimatosas/citología , ARN/genética , Cordón Umbilical/citología , Gelatina de Wharton/citología , Diferenciación Celular , Proliferación Celular , Células Cultivadas , Humanos , Células Madre Mesenquimatosas/inmunología , Análisis de Secuencia de ARN , Factores de Transcripción , Cordón Umbilical/inmunología , Gelatina de Wharton/inmunología , Gelatina de Wharton/metabolismoRESUMEN
BACKGROUND: The updated Chicago Classification version 4.0 (CCv4.0) establishes a more stringent criteria to diagnose ineffective esophageal motility (IEM). This study aims to investigate the clinical significance of IEM in CCv4.0 in the context of gastroesophageal reflux disease (GERD). METHODS: A retrospective study was conducted among suspected GERD patients who had heartburn and/or regurgitation as their chief complaints and completed esophageal function tests in our center from 2017 to 2019. Patients were further grouped as "CCv3.0 IEM" and normal motility according to Chicago Classification version 3.0 (CCv3.0), and as "CCv4.0 IEM" and normal motility according to CCv4.0. The clinical characteristics, high-resolution manometry, esophageal reflux monitoring, and proton pump inhibitor (PPI) efficacy were compared between different groups. Multivariate analyses were performed to identify esophageal motility parameters associated with reflux burden and symptom outcome. RESULTS: Of 172 subjects included, 93 patients were identified as CCv3.0 IEM, 69 as CCv4.0 IEM. IEM in either version was concomitant with elevated acid burden and impaired esophageal clearance as compared to normal motility in corresponding diagnostic criteria, while the only presence of IEM in CCv4.0 was predictive to abnormal acid exposure (AET > 6%: OR = 2.66, 95% CI [1.27-5.56], p < 0.01). The presence of "CCv3.0 IEM" and low EGJ-CI (EGJ-CI < 39.1 mmHg·cm) had no added value in predicting increased reflux burden. No interaction effect was found between the presence of IEM and a weakened EGJ. None of the manometric variables was capable of predicting PPI response. CONCLUSIONS: Stringent criteria of IEM in CCv4.0 can better predict abnormal acid exposure as compared to CCv3.0.
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Trastornos de la Motilidad Esofágica , Reflujo Gastroesofágico , Reflujo Gastroesofágico/complicaciones , Reflujo Gastroesofágico/diagnóstico , Pirosis/complicaciones , Humanos , Manometría , Estudios RetrospectivosRESUMEN
The endogenous repair failure of degenerated intervertebral disk (IVD) is highly related to the exhaustion of nucleus pulposus stem cells (NPSCs). Excessive oxidative stress could induce apoptosis and senescence of NPSCs, thus, declining the quantity and quality of NPSCs. Heat shock protein 70 (HSP70) is a family of cytoprotective and antioxidative proteins. However, there is no report on the protective effects of HSP70 on oxidative stress-induced NPSC impairments and underlying mechanisms. In the present study, we treated NPSCs with tert-butyl hydroperoxide (t-BHP) in vitro to simulate an oxidative stress condition. HSP70 inducer TRC051384 was used to evaluate the cytoprotective effects of HSP70. The results suggested that HSP70 impeded t-BHP-mediated cell viability loss and protected the ultrastructure of NPSCs. Moreover, t-BHP could induce mitochondrial apoptosis and p53/p21-mediated senescence of NPSCs, both of which were significantly inhibited in HSP70 activation groups. Excessive oxidative stress and mitochondrial dysfunction reinforced each other and contributed to the cellular damage processes. HSP70 decreased reactive oxygen species (ROS) production, rescued mitochondrial membrane potential (MMP) collapse, and blocked ATP depletion. Finally, our data showed that HSP70 downregulated the JNK/c-Jun pathway. Taken together, activation of HSP70 could protect against t-BHP-induced NPSC apoptosis and senescence, thus, improving the quantity and quality of NPSCs. Therefore, HSP70 may be a promising therapeutic target for IVD degeneration.
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Apoptosis/efectos de los fármacos , Senescencia Celular/efectos de los fármacos , Proteínas HSP70 de Choque Térmico/metabolismo , MAP Quinasa Quinasa 4/metabolismo , Núcleo Pulposo/metabolismo , Proteínas Proto-Oncogénicas c-jun/metabolismo , Transducción de Señal/efectos de los fármacos , Células Madre/metabolismo , terc-Butilhidroperóxido/farmacología , Células Cultivadas , HumanosRESUMEN
Glycine is a simple nonessential amino acid known to have neuroprotective properties. Treatment with glycine results in reduced infarct volume of the brain, neurologic function scores, and neuronal and microglial death in ischemic stroke injury. Neuroinflammation has been considered a major contributor to cerebral ischemia-induced brain damage. However, the role of glycine in neuroinflammation following ischemic stroke is unclear. The present study aimed to determine whether neuroinflammation is involved in the neuroprotective effects of glycine in cerebral ischemia injury. Ischemic stroke promotes M1 microglial polarization. Interestingly, we found that the injection of glycine in rats after injury can inhibit ischemia-induced inflammation and promote M2 microglial polarization in vivo (Sprague-Dawley rats) and in vitro (cortical microglia and BV-2 cells). We show that glycine suppresses Hif-1α by inhibiting the upregulation of NF-κB p65 after ischemia-reperfusion injury, resulting in the inhibition of proinflammatory activity. The activation of AKT mediates the inhibition of NF-κB p65/Hif-1α signaling by glycine. Moreover, we confirm that glycine-regulated AKT activation is mediated by the inhibition of PTEN in a PTEN depletion cell line, U251 cells. Glycine modulates microglial polarization after ischemic stroke, which indirectly inhibits ischemia-induced neuronal death and functional recovery. Taken together, our findings provide a new understanding of glycine in neuroprotection by inhibiting M1 microglial polarization and promoting anti-inflammation by suppressing NF-κB p65/Hif-1α signaling.
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Encéfalo/efectos de los fármacos , Glicina/farmacología , Microglía/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Accidente Cerebrovascular/inmunología , Animales , Encéfalo/inmunología , Encéfalo/patología , Isquemia Encefálica/inmunología , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Femenino , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/patología , Factor de Transcripción ReIA/metabolismoRESUMEN
BACKGROUND AND AIM: Most of patients with erosive esophagitis (EE) are of LA grade A&B with low reflux burden, therefore require further esophageal function tests (EFTs). One-third of them respond poorly to pump proton inhibitor (PPI) treatment. The aim was to establish and validate a physiologic nomogram to discriminate symptom outcome to PPI treatment in patients with EE. METHODS: A total of 79 EE patients with heartburn who underwent EFTs and received PPI therapy were randomly assigned into a training set (n = 55) and a validation set (n = 24). Clinical data including physiologic parameters from EFTs were collected. Significant factors for the positive symptomatic outcome were identified using logistic regression analysis. Physiologic signature was developed using the least absolute shrinkage and selection operator algorithm. The nomogram was established by combining significant factors and physiologic signature, and its performance was evaluated and validated in the training and validation set. The clinical value of the nomogram was measured by decision curve analysis. RESULTS: Significant factors for positive symptomatic response to PPI treatment were identified as follows: acid exposure time, total number of reflux episodes, and two novel metrics including mean nocturnal baseline impedance and post-reflux swallow-induced peristaltic wave index. The nomogram which incorporated both significant factors and physiologic signature demonstrated good performance in the training and validation sets [C-index: 0.938 (95% CI 0.882-0.995); 0.839 (95% CI 0.678-0.995), respectively]. Decision curves showed significant clinical usefulness. CONCLUSION: The first physiologic nomogram was developed to discriminate the individualized response to PPI therapy among EE patients.
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Esofagitis Péptica , Nomogramas , Monitorización del pH Esofágico , Esofagitis Péptica/diagnóstico , Esofagitis Péptica/tratamiento farmacológico , Pirosis/diagnóstico , Pirosis/etiología , Humanos , Inhibidores de la Bomba de Protones/uso terapéuticoRESUMEN
To investigate whether TP53-induced glycolysis and apoptosis regulator (TIGAR) participates in compression-induced intervertebral disc (IVD) degeneration, and to determine the regulatory effect of TIGAR on nucleus pulposus (NP) cell autophagy and apoptosis following compression-induced injuries. IVD tissues were collected from human patients undergoing surgery (n = 20) and skeletally mature Sprague-Dawley rats (n = 15). Initially, the effect of compression on the expression of TIGAR was evaluated with in vivo and in vitro models. In addition, TIGAR was silenced to investigate the regulatory effect of TIGAR on compression-induced intracellular reactive oxygen species (ROS) levels, autophagy, and apoptosis in rat NP cells. Furthermore, the P53 inhibitor pifithrin-α (PFTα) and SP1 inhibitor mithramycin A were employed to detect expression level changes of TIGAR and autophagy-associated target molecules. TIGAR expression of NP cells increased gradually in human degenerative IVDs and in rat NP cells under compression both in vivo and in vitro. TIGAR knockdown enhanced compression-induced intracellular ROS generation and the NADPH/NADP+ and GSH/GSSG ratios. Moreover, TIGAR knockdown amplified the compression-induced caspase-3 activation and the apoptosis rate of rat NP cells. Likewise, knockdown of TIGAR significantly accelerated LC3B expression and autophagosome formation in rat NP cells during compression-induced injuries. The results also established that mithramycin A could inhibit TIGAR expression and autophagy levels in NP cells under compression conditions, while PFTα had no similar effect. Our data demonstrated that TIGAR acted as an important endogenous negative regulator of ROS levels, which might inhibit compression-induced apoptosis and autophagy through SP1-dependent mechanisms.
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Proteínas Reguladoras de la Apoptosis/metabolismo , Núcleo Pulposo/citología , Monoéster Fosfórico Hidrolasas/metabolismo , Anciano , Animales , Apoptosis , Proteínas Reguladoras de la Apoptosis/genética , Autofagia , Supervivencia Celular , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Degeneración del Disco Intervertebral , Masculino , Persona de Mediana Edad , Monoéster Fosfórico Hidrolasas/genética , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno , Estrés MecánicoRESUMEN
Glucocorticoids have been widely used in multiple inflammatory and autoimmune diseases. However, long-term glucocorticoid therapy may result in osteoporosis. The present study aimed to evaluate the potential therapeutic effects and investigate the underlying mechanisms of Daphnetin (Daph) on glucocorticoid-induced osteoporosis (GIOP). In vivo, male Sprague Dawley rats were intramuscularly injected with dexamethasone (DEX) to induce GIOP and Daph was given intraperitoneally. Bone histological changes, mineral content, microstructure parameters and bone turnover markers were detected. Gut microbiota composition and intestinal barrier function were further assessed. In vitro, MC3T3-E1 pre-osteoblasts were treated with DEX and the abilities of Daph on osteoblast proliferation, differentiation and mineralization were assessed. A Wnt signaling inhibitor, XAV939, was added additionally to evaluate the effect of Daph on Wnt signaling. The results showed that in vivo, Daph increased the DEX-induced reduction in body weight gain, bone mineral content and microstructure parameters and restored the levels of bone turnover markers in GIOP rats. In vitro, Daph promoted osteoblast proliferation, differentiation and mineralization in DEX-treated MC3T3-E1 pre-osteoblasts. Moreover, Daph activated the Wnt/GSK-3ß/ß-catenin signaling pathway. XAV939 successfully abolished the beneficial effects of Daph on GIOP in vitro. Besides, Daph showed improvement on gut microbiota disorder and intestinal barrier dysfunction post GIOP. Collectively, these data demonstrated that Daph effectively ameliorates GIOP and the possible mechanism may be that Daph activated Wnt/GSK-3ß/ß-catenin signaling.
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Glucocorticoides/farmacología , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Osteoporosis/tratamiento farmacológico , Umbeliferonas/farmacología , Vía de Señalización Wnt/efectos de los fármacos , beta Catenina/metabolismo , Animales , Huesos/efectos de los fármacos , Huesos/metabolismo , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Dexametasona/farmacología , Masculino , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismo , Osteogénesis/efectos de los fármacos , Osteoporosis/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND AND AIM: Laryngopharyngeal reflux (LPR) is caused by the reflux of gastric contents beyond the esophagus into the larynx and pharynx. However, upper esophageal sphincter (UES) motility and proximal esophagus reflux parameters are poorly studied. This study aims to explore the characteristics of UES motility and reflux parameter among LPR patients. METHODS: Patients with laryngopharyngeal symptoms only (L), patients with laryngopharyngeal symptoms and typical esophageal symptoms (L + E), patients with typical esophageal symptoms only (E), and healthy controls (H) were retrospectively included. Physiological profiles were studied and compared among groups using both high-resolution manometry and pH-impedance monitoring, including UES basal pressure, residual pressure, relaxation duration time, recovery time, the time to nadir pressure, UES length, proximal contractile integral, and proximal mean nocturnal baseline impedance (MNBI). Patients' symptom outcomes were also analyzed. RESULTS: A total of 242 patients were included. Proximal MNBI was significantly lower in patients with both laryngopharyngeal and esophageal symptoms (17 cm above low esophageal sphincter [LES]: L vs L + E vs E vs H = 3689.7 vs 2500.0 vs 3073.0 vs 3996.0; 15 cm above LES: L vs L + E vs E vs H = 3155.9 vs 2553.4 vs 3198.9 vs 2985.2; P < 0.001). Patients responded to proton pump inhibitor treatment also had lower proximal MNBI than those who did not (17 cm above LES: 1834.0 vs 3500.0; 15 cm above LES: 1946.5 vs 3432.6; P < 0.001). CONCLUSION: Decreased proximal MNBI can not only identify LPR patients but also predict patients' symptom outcomes.
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Monitorización del pH Esofágico/métodos , Reflujo Laringofaríngeo/diagnóstico , Manometría/métodos , Resultados Negativos , Impedancia Eléctrica , Unión Esofagogástrica/fisiopatología , Motilidad Gastrointestinal , Humanos , Reflujo Laringofaríngeo/fisiopatología , Sensibilidad y EspecificidadRESUMEN
This study aimed to investigate the specific role of Wnt/ß-catenin signaling in compression-induced apoptosis, autophagy, and senescence in rat nucleus pulposus (NP) cells. Initially, the cells underwent various periods of exposure to 1.0 MPa compression. Wnt/ß-catenin signaling associated molecules were assessed in detail, and then 0, 24 and 48 hours exposure periods were selected. The cells were then divided into control, Wnt/ß-catenin inhibitor (IWP-2), Wnt/ß-catenin activator (LiCl), and ß-catenin overexpression groups. After 0, 24, and 48 hours of compression, apoptosis, autophagy, and senescence were evaluated by Western blot analysis and real-time polymerase chain reaction and were visually observed by Hoechst33258, monodansylcadaverine, and SA-ß-gal stainings, respectively. Additionally, the regulatory effect of Wnt/ß-catenin signaling on cell morphology, viability, cell cycle, death ratio, and ultrastructure was detected to thoroughly evaluate the survival capacity of NP cells. The results established that compression elicited a time-dependent activation of Wnt/ß-catenin signaling. The IWP-2 treatment decreased cell survival rate, which corresponded to downregulation of autophagy as well as increases in apoptosis and senescence. LiCl treatment enabled more efficient of cell survival accompanied by increased autophagy and downregulated apoptosis and senescence; however, in contrast to LiCl, overexpression of ß-catenin aggravated compression-induced NP cells death. In conclusion, moderate activation of Wnt/ß-catenin signaling enables more efficient of NP cells survival via downregulation of apoptosis, senescence, and upregulation of autophagy, and overactivation of Wnt/ß-catenin signaling achieved the opposite effect. Treatment strategies that aim to regulate Wnt/ß-catenin signaling might be a novel target for improving compression-induced NP cells death and potential treatment of intervertebral disc degeneration.
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Apoptosis , Autofagia , Senescencia Celular , Núcleo Pulposo/metabolismo , Vía de Señalización Wnt , Animales , Fenómenos Biomecánicos , Degeneración del Disco Intervertebral/metabolismo , Degeneración del Disco Intervertebral/fisiopatología , Núcleo Pulposo/fisiología , RatasRESUMEN
BACKGROUND: High level of reactive oxygen species (ROS) has been detected in almost all cancers, which make it become one of the best-characterized phenotypes in cancers. Though ROS plays an important role in tumors, the degree of oxidative stress can be better evaluated by assessing stable metabolites of oxidative reactions because of its high instability. 8-hydroxy-2'-deoxyguanosine (8-OHdG), a product of oxidative damage to 2'-deoxyguanosine, is known as a useful marker for assessing oxidative DNA damage and has been a feature of carcinogenesis in several researches. But the exact prognostic value of 8-OHdG expression in patients with cancer is still unclear. METHODS: A comprehensive search was performed in PubMed, Web of Science, EMBASE. Eligible studies were included based on defined exclusion and inclusion criteria to perform a meta-analysis. STATA 14.0 was used to estimate pooled hazard ratios (HRs) with 95% confidence interval (95% CI), the heterogeneity among studies and publication bias to judge the prognostic value. RESULTS: A total of 2121 patients from 21 eligible studies were included in the meta-analysis. A significant association was found between elevated 8-OHdG expression and poor OS (overall survival) in cancer patients (pooled HR 1.921, 95% CI: 1.437-2.570); In the subgroup analysis, race of sample, cancer types, detection method of 8-OHdG, sample classification, detection location of 8-OHdG and paper quality (score more or less than 7) did not alter the association between 8-OHdG expression and cancer prognosis. Furthermore, 8-OHdG expression was an independent prognostic marker for overall survival in patients with cancer (pooled HR 2.110, 95% CI: 1.482-3.005) using Cox multivariate analyses. CONCLUSIONS: This meta-analysis found that highly expressed 8-OHdG in tumor tissues may be a predictor of prognosis in most solid tumors. However, especially in breast cancer, low 8-OHdG expression is associated with poor prognosis, which is partly because of the increased antioxidant mechanisms in breast cancer tissues. This study demonstrates for the first time that 8-OHdG expression is associated with the prognosis of cancer patients. In the future, whether the expression level of 8-OHdG can be used as a biomarker for the prognosis of all human cancers requires more research.
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8-Hidroxi-2'-Desoxicoguanosina/metabolismo , Neoplasias/terapia , Biomarcadores de Tumor/metabolismo , Daño del ADN , Supervivencia sin Enfermedad , Humanos , Estrés Oxidativo/genética , Pronóstico , Modelos de Riesgos Proporcionales , Especies Reactivas de OxígenoRESUMEN
Autophagy dysfunction has been observed in intervertebral disc degeneration (IVDD) cells, a main contributing factor to cell death, but the precise role of autophagy during IVDD is still controversial. This study aimed to investigate the role of autophagy involved in the pathogenesis of human IVDD and determine the signal transduction pathways responsible for compression-induced autophagy in human nucleus pulposus (NP) cells. Autophagy, suppressing the induction of apoptosis, was activated in NP cells exposed to compression. Molecular analysis showed that compression promoted the activity of NRF1, a transcription regulator increasing Atg7 expression by binding to its promoter, through activating the Ras/MEK/ERK signaling in NP cells. Loss- and gain-of-function studies demonstrate that NRF1 induced autophagy and dampened the apoptotic response by promoting Atg7 expression in NP cells subjected to compression. This study confirmed that compression-induced autophagy could be induced by Ras via MEK/ERK/NRF1/Atg7 signaling pathways, while inhibiting Ras/MEK/ERK/NRF1/Atg7 signaling pathways attenuated this autophagic process, implicating a promising therapeutic strategy for IVDD.