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In recent years, sodium-ion batteries (SIBs) have attracted a lot of attention and are considered an ideal alternative to lithium-ion batteries (LIBs). The hard carbon (HC) anode in SIBs presents a unique challenge for studying the formation process of the solid electrolyte interphase (SEI) during initial cycling, owing to its distinctive porous structure. This study employs a combination of ultrasonic scanning techniques and differential electrochemical mass spectrometry to conduct an in-depth analysis of the two-dimensional distribution and composition of gases during the formation process. The findings reveal distinct gas evolution behaviors in SIBs compared to LIBs during formation. Notably, significant gas evolution is observed during the discharge phase of the formation cycle in SIBs, with higher discharge rates leading to increased gas evolution rates. This phenomenon is likely attributed to the adsorption of CO2 gas by the abundant pores in HC, followed by desorption during discharge. Furthermore, the study demonstrates that the addition of 5A molecular sieves, which competitively adsorb gases, effectively reduces gas adsorption on the anode during formation, thereby significantly enhancing battery performance. This research elucidates the gas adsorption and desorption behavior at the battery interface, providing new insights into the SEI formation process in SIBs.
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Ischemic stroke is a secondary cause of mortality worldwide, imposing considerable medical and economic burdens on society. Extracellular vesicles, serving as natural nano-carriers for drug delivery, exhibit excellent biocompatibility in vivo and have significant advantages in the management of ischemic stroke. However, the uncertain distribution and rapid clearance of extracellular vesicles impede their delivery efficiency. By utilizing membrane decoration or by encapsulating therapeutic cargo within extracellular vesicles, their delivery efficacy may be greatly improved. Furthermore, previous studies have indicated that microvesicles, a subset of large-sized extracellular vesicles, can transport mitochondria to neighboring cells, thereby aiding in the restoration of mitochondrial function post-ischemic stroke. Small extracellular vesicles have also demonstrated the capability to transfer mitochondrial components, such as proteins or deoxyribonucleic acid, or their sub-components, for extracellular vesicle-based ischemic stroke therapy. In this review, we undertake a comparative analysis of the isolation techniques employed for extracellular vesicles and present an overview of the current dominant extracellular vesicle modification methodologies. Given the complex facets of treating ischemic stroke, we also delineate various extracellular vesicle modification approaches which are suited to different facets of the treatment process. Moreover, given the burgeoning interest in mitochondrial delivery, we delved into the feasibility and existing research findings on the transportation of mitochondrial fractions or intact mitochondria through small extracellular vesicles and microvesicles to offer a fresh perspective on ischemic stroke therapy.
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PURPOSE: To establish molar root canal model with micro-computed tomography (Micro-CT) and evaluate the removal efficiency of calcium hydroxide by different methods. METHODS: Eight molar teeth (24 root canals) extracted from the Department of General Dentistry, Shanghai Ninth People's Hospital from October 2023 to February 2024 were collected. Root canal preparation was instrumented by M3 according to standard root canal treatment procedures, then calcium hydroxide was injected into the root canal. One week later, the samples were randomly divided into 3 groups according to different irrigation methods(n=8): lateral opening syringe group, ultrasonic group and sonic vibration group. Micro-CT was used to reconstruct the root canal system before and after irrigation, and independent root canals were marked with different colors. The root canals were divided into upper root segment, middle root segment and apex segment. The volume of calcium hydroxide in each canal was calculated, and the clearance rate of calcium hydroxide was compared among the groups. SPSS 19.0 software package was used for statistical analysis. RESULTS: None of the three methods could completely remove calcium hydroxide from the root canal. When sodium hypochlorite was used as the flushing solution, the removal effect of ultrasonic group and sonic vibration group was significantly better than that of lateral opening syringe group(Pï¼0.05). The removal efficiency of calcium hydroxide by ultrasonic group and sonic vibration group was similar, and the difference was not statistically significant(Pï¼0.05). The removal rate of calcium hydroxide in apical segment was low. CONCLUSIONS: Micro-CT can reconstruct the molar root canal model efficiently for evaluating the removal effect of calcium hydroxide. The removal efficiency of calcium hydroxide in ultrasonic group and sonic vibration group is similar, and both are better than that in lateral syringe group.
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Hidróxido de Cálcio , Cavidade Pulpar , Microtomografia por Raio-X , Hidróxido de Cálcio/química , Microtomografia por Raio-X/métodos , Humanos , Cavidade Pulpar/diagnóstico por imagem , Cavidade Pulpar/efeitos dos fármacos , Dente Molar , Irrigantes do Canal Radicular , Preparo de Canal Radicular/métodos , Hipoclorito de Sódio , VibraçãoRESUMO
The otopetrin (OTOP) proteins were recently characterized as extracellular proton-activated proton channels. Several recent OTOP channel structures demonstrated that the channels form a dimer with each subunit adopting a double-barrel architecture. However, the structural mechanisms underlying some basic functional properties of the OTOP channels remain unresolved, including extracellular pH activation, proton conducting pathway, and rapid desensitization. In this study, we performed structural and functional characterization of the Caenorhabditis elegans OTOP8 (CeOTOP8) and mouse OTOP2 (mOTOP2) and illuminated a set of conformational changes related to the proton-conducting process in OTOP. The structures of CeOTOP8 reveal the conformational change at the N-terminal part of TM12 that renders the channel in a transiently proton-transferring state, elucidating an inter-barrel, Glu/His-bridged proton passage within each subunit. The structures of mOTOP2 reveal the conformational change at the N-terminal part of TM6 that exposes the central glutamate to the extracellular solution for protonation. In addition, the structural comparison between CeOTOP8 and mOTOP2, along with the structure-based mutagenesis, demonstrates that an inter-subunit movement at the OTOP channel dimer interface plays a central role in regulating channel activity. Combining the structural information from both channels, we propose a working model describing the multi-step conformational changes during the proton conducting process.
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Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Canais Iônicos , Prótons , Animais , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/química , Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/genética , Camundongos , Canais Iônicos/metabolismo , Canais Iônicos/química , Canais Iônicos/genética , Modelos Moleculares , Conformação Proteica , Concentração de Íons de Hidrogênio , Cristalografia por Raios X , Multimerização ProteicaRESUMO
Acute lung injury (ALI) is a significant health condition with notable rates of morbidity and mortality globally. Long non-coding ribose nucleic acids (lncRNAs) play vital roles in mitigating various inflammation-related diseases, including ALI. The study aimed to investigate the functional role and molecular mechanisms of lncRNA SNHG1 on ALI in lipopolysaccharide (LPS)-treated A549 cells and in LPS-induced ALI mice. The expression of SNHG1 was initially examined in LPS-treated A549 cells. We further demonstrated the critical function of SNHG1 through various cellular assessments following SNHG1 knockdown, including cell counting kit (CCK)-8 assay, flow cytometry analysis, as well as enzyme-linked immunosorbent assay (ELISA). Reducing SNHG1 levels hindered the negative effects of LPS on cell viability, apoptosis, and inflammation. Moreover, SNHG1 acted as a negative regulator for miR-199a-3p, which targeted downstream ROCK2. Depletion of miR-199a-3p or enhanced expression of ROCK2 abolished the protective effects of SNHG1 knockdown on LPS-induced apoptosis and inflammation. Consistently, silencing SNHG1 alleviated LPS-induced lung injury in mice, demonstrating its potential therapeutic benefits in managing ALI. Overall, this study sheds light on the role of SNHG1 in modulating inflammation and apoptosis in ALI through the miR-199a-3p/ROCK2 pathway, offering new insights for the treatment of this condition.
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Lesão Pulmonar Aguda , Técnicas de Silenciamento de Genes , Lipopolissacarídeos , MicroRNAs , RNA Longo não Codificante , Quinases Associadas a rho , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/genética , MicroRNAs/metabolismo , MicroRNAs/genética , Animais , Camundongos , Humanos , Quinases Associadas a rho/metabolismo , Quinases Associadas a rho/genética , Masculino , Células A549 , Transdução de Sinais , Camundongos Endogâmicos C57BL , Apoptose/genéticaRESUMO
OBJECTIVE: To investigate the clinical features and prognostic factors of patients with primary extranodal diffuse large B-cell lymphoma (DLBCL) in the rituximab era. METHODS: The continuous data of newly diagnosed DLBCL patients with complete case data and first-line treated with rituximab, cyclophosphamide, epirubicin, vincristine, prednisone (R-CHOP) or R-CHOP treatment admitted to the Affiliated Hospital of Inner Mongolia Medical University from January 2013 to November 2023 were retrospectively analyzed. The clinical and molecular immunological features and prognosis of extranodal DLBCL were analyzed, Logistics regression model was used to analyzed the influencing factors of patients prognosis. RESULTS: A total of 237 patients were enrolled, of which 54.4% (129 cases) were primary extranodal sources of DLBCL, and the most common extranodal sites were as follows: stomach (19.4%), colon (14.7%), tonsils (12.4%), skin/muscle (9.3%), central (7.7%), nasal/nasopharynx (6.2%), bone marrow (5.4%), testes (4.7%). The 3-year PFS and OS of DLBCL patients with extranodal involvement of bone marrow, central, liver, gastrointestinal or pulmonary origin were significantly lower than those of other patients with extranodal DLBCL of non-special site origin, and the difference was statistically significant (PFS: 65.2% vs 76.7%, P =0.008; OS: 82.6% vs 88.3%, P =0.04). Multivariate analysis showed that the prognostic factors affecting OS included NCCN-IPI score >3 (OR : 0.142, 95%CI : 0.041-0.495, P =0.002), non-germinal center source (OR : 2.675ï¼95%CI :1.069-6.694ï¼P =0.036), and DEL patients (OR : 0.327, 95%CI : 0.129-0.830, P =0.019). An NCCN-IPI score >3 was the only independent adverse prognostic factor for PFS (OR : 0.235, 95%CI : 0.116-0.474, P < 0.001). CONCLUSION: Patients with primary extranodal source DLBCL are more common in gastrointestinal involvement, and the overall prognosis is worse than that of patients with lymph node origin. NCCN-IPI score is an important independent adverse prognostic factor for predicting overall survival and progression-free survival in patients with primary extranodal diffuse large B-cell lymphoma.
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Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma Difuso de Grandes Células B , Rituximab , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Estudos Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Masculino , Prognóstico , Feminino , Ciclofosfamida/uso terapêutico , Pessoa de Meia-Idade , Vincristina/uso terapêutico , Prednisona , Doxorrubicina , Adulto , IdosoRESUMO
OBJECTIVE: To explore the association between maternal thyroid peroxidase antibody (TPOAb) exposure and 5- to 6-year-old children's cardiometabolic risk (CMR). METHODS: A total of 2129 mother-child pairs were recruited from the Ma'anshan Birth Cohort (MABC) study. Serum TPOAb was retrospectively measured in pregnant women using an electrochemiluminescence immunoassay. CMR score was evaluated by the serum glycolipids, blood pressure and waist circumference for children aged 5-6 years. Growth mixture modeling (GMM) was used to fit trajectories of TPOAb levels throughout pregnancy. Multiple linear regression models and logistic regression models were used for statistical analyses. RESULTS: 2129 mother-child pairs (mean [SD] age, 26.6 [3.6] years) were enrolled for the final study. Maternal TPOAb exposure in the 1st trimester increased children's overall CMR, glucose level, HOMA-IR, triglyceride level, boys' overall CMR, boys' glucose level and girls' glucose level. TPOAb exposure in the 1st trimester was also associated with lower boys' high-density lipoprotein cholesterol (HDL-C) level. In the 2nd trimester, maternal TPOAb exposure was positively associated with children's triglyceride level. Compared with low TPOAb trajectory, children with high maternal TPOAb trajectory had an increased risk of developing high CMR (OR = 3.40; 95% CI, 1.30-8.90), hyperglycemia (OR = 5.20; 95% CI, 2.20-12.28), insulin-resistance (adjusted OR = 2.12; 95% CI, 1.10-4.07), hypertriglyceridemia (OR = 2.55; 95% CI, 1.06-6.14). CONCLUSIONS: The 1st trimester of pregnancy is a critical period for maternal TPOAb exposure to affect cardiometabolic risk in children, with some sex specificity, mainly to the detriment of boys.
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Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome with cardiac dysfunction, fluid retention and reduced exercise tolerance as the main manifestations. Current treatment of HFpEF is using combined medications of related comorbidities, there is an urgent need for a modest drug to treat HFpEF. Geniposide (GE), an iridoid glycoside extracted from Gardenia Jasminoides, has shown significant efficacy in the treatment of cardiovascular, digestive and central nervous system disorders. In this study we investigated the therapeutic effects of GE on HFpEF experimental models in vivo and in vitro. HFpEF was induced in mice by feeding with HFD and L-NAME (0.5 g/L) in drinking water for 8 weeks, meanwhile the mice were treated with GE (25, 50 mg/kg) every other day. Cardiac echocardiography and exhaustive exercise were performed, blood pressure was measured at the end of treatment, and heart tissue specimens were collected after the mice were euthanized. We showed that GE administration significantly ameliorated cardiac oxidative stress, inflammation, apoptosis, fibrosis and metabolic disturbances in the hearts of HFpEF mice. We demonstrated that GE promoted the transcriptional activation of Nrf2 by targeting MMP2 to affect upstream SIRT1 and downstream GSK3ß, which in turn alleviated the oxidative stress in the hearts of HFpEF mice. In H9c2 cells and HL-1 cells, we showed that treatment with GE (1 µM) significantly alleviated H2O2-induced oxidative stress through the MMP2/SIRT1/GSK3ß pathway. In summary, GE regulates cardiac oxidative stress via MMP2/SIRT1/GSK3ß pathway and reduces cardiac inflammation, apoptosis, fibrosis and metabolic disorders as well as cardiac dysfunction in HFpEF. GE exerts anti-oxidative stress properties by binding to MMP2, inhibiting ROS generation in HFpEF through the SIRT1/Nrf2 signaling pathway. In addition, GE can also affect the inhibition of the downstream MMP2 target GSK3ß, thereby suppressing the inflammatory and apoptotic responses in HFpEF. Taken together, GE alleviates oxidative stress/apoptosis/fibrosis and metabolic disorders as well as HFpEF through the MMP2/SIRT1/GSK3ß signaling pathway.
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CDK5RAP3 is a recognized tumor suppressor that inhibits Chk1 and Chk2 and activates p53, all of which are involved with mediating toxin-induced apoptosis of cancer cells. CDK5RAP3 also inhibits p38MAPK phosphorylation and activity via mediating a p38 interaction with wild-type p53-induced phosphatase 1. This study aimed to investigate the antiangiogenic activity of CDK5RAP3 and its molecular mechanisms in human umbilical vein endothelial cells (HUVECs) under conditions of hypoxic conditions. Angiogenesis was induced in HUVECs mainly by vascular endothelial growth factor (VEGF). The CDK5RAP3 levels of HUVECs were reduced in a time-dependent manner in response to hypoxic treatment at 2% O2. The reduction of CDK5RAP3 was accompanied with increased p38MAPK phosphorylation and activation. Moderate hypoxia was found to significantly increase secreted VEGF concentrations, and the hypoxic conditioned medium (HCM) markedly enhanced proliferation, migration, and tube formation. Our findings indicate that moderate hypoxia facilitates angiogenesis by inhibiting CDK5RAP3. CDK5RAP3 exhibits a clear regulatory role in vascular regeneration, as downregulating its expression in endothelial cells enhances VEGF synthesis and subsequently improves cell migration and lumen formation capability. This study presents evidence indicating that moderate hypoxia facilitates angiogenesis by inhibiting CDK5RAP3, demonstrating the potential for CKD5RAP3 to be a potent antiangiogenic agent in angiogenesis regulation of cancer, ischemic diseases, and wound healing.
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Proteínas de Ciclo Celular , Células Endoteliais da Veia Umbilical Humana , Neovascularização Fisiológica , Proteínas Quinases p38 Ativadas por Mitógeno , Humanos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Proteínas de Ciclo Celular/metabolismo , Neovascularização Fisiológica/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Movimento Celular , Proliferação de Células , Células Cultivadas , Hipóxia Celular/fisiologia , Fosforilação , Angiogênese , Proteínas Supressoras de TumorRESUMO
This study investigates how dynamic fluctuations in matrix stiffness affect the behavior of cardiac fibroblasts (CFs) within a three-dimensional (3D) hydrogel environment. Using hybrid hydrogels with tunable stiffness, we created an in vitro model to mimic the varying stiffness of the cardiac microenvironment. By manipulating hydrogel stiffness, we examined CF responses, particularly the expression of α-smooth muscle actin (α-SMA), a marker of myofibroblast differentiation. Our findings reveal that increased matrix stiffness promotes the differentiation of CFs into myofibroblasts, while matrix softening reverses this process. Additionally, we identified the role of focal adhesions and integrin ß1 in mediating stiffness-induced phenotypic switching. This study provides significant insights into the mechanobiology of cardiac fibrosis and suggests that modulating matrix stiffness could be a potential therapeutic strategy for treating cardiovascular diseases.
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Diferenciação Celular , Matriz Extracelular , Fibroblastos , Hidrogéis , Miofibroblastos , Fenótipo , Hidrogéis/química , Matriz Extracelular/metabolismo , Animais , Fibroblastos/metabolismo , Fibroblastos/citologia , Miofibroblastos/metabolismo , Miofibroblastos/citologia , Integrina beta1/metabolismo , Adesões Focais/metabolismo , Miocárdio/citologia , Miocárdio/metabolismo , Células Cultivadas , Ratos , Actinas/metabolismoRESUMO
A rapidly growing interest in organic bioelectronic applications has spurred the development of a wide variety of organic mixed ionic-electronic conductors. While these new mixed conductors have enabled the community to interface organic electronics with biological systems and efficiently transduce biological signals (ions) into electronic signals, the current materials selection does not offer sufficient selectivity towards specific ions of biological relevance without the use of auxiliary components such as ion-selective membranes. Here, we present the molecular design of an n-type (electron-transporting) perylene diimide semiconductor material decorated with pendant oligoether groups to facilitate interactions with cations such as Na+ and K+. Using the cyclic 15-crown-5 oligoether motif, we find that the resulting mixed conductor PDI-crown displays a strong dependence on the size of the electrolyte cation when tested in an organic electrochemical transistor configuration. In stark contrast to the low current response on the order of 1 µA observed with aqueous sodium chloride, a nearly 200-fold increase in current is observed with aqueous potassium chloride. We ascribe the high selectivity to extended molecular aggregation and therefore efficient charge transport in the presence of K+ due to a favourable sandwich-like structure between two adjacent 15-crown-5 motifs and the potassium ion.
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BACKGROUND: TBK1 positively regulates the growth factor-mediated mTOR signaling pathway by phosphorylating mTOR. However, it remains unclear how the TBK1-mTOR signaling pathway is regulated. Considering that STING not only interacts with TBK1 but also with MARCH1, we speculated that MARCH1 might regulate the mTOR signaling pathway by targeting TBK1. The aim of this study was to determine whether MARCH1 regulates the mTOR signaling pathway by targeting TBK1. METHODS: The co-immunoprecipitation (Co-IP) assay was used to verify the interaction between MARCH1 with STING or TBK1. The ubiquitination of STING or TBK1 was analyzed using denatured co-immunoprecipitation. The level of proteins detected in the co-immunoprecipitation or denatured co-immunoprecipitation samples were determined by Western blotting. Stable knocked-down cells were constructed by infecting lentivirus bearing the related shRNA sequences. Scratch wound healing and clonogenic cell survival assays were used to detect the migration and proliferation of breast cancer cells. RESULTS: We showed that MARCH1 played an important role in growth factor-induced the TBK1- mTOR signaling pathway. MARCH1 overexpression attenuated the growth factor-induced activation of mTOR signaling pathway, whereas its deficiency resulted in the opposite effect. Mechanistically, MARCH1 interacted with and promoted the K63-linked ubiquitination of TBK1. This ubiquitination of TBK1 then attenuated its interaction with mTOR, thereby inhibiting the growth factor-induced mTOR signaling pathway. Importantly, faster proliferation induced by MARCH1 deficiency was weakened by mTOR, STING, or TBK1 inhibition. CONCLUSION: MARCH1 suppressed growth factors mediated the mTOR signaling pathway by targeting the STING-TBK1-mTOR axis.
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Proliferação de Células , Proteínas Serina-Treonina Quinases , Transdução de Sinais , Serina-Treonina Quinases TOR , Ubiquitina-Proteína Ligases , Ubiquitinação , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Humanos , Serina-Treonina Quinases TOR/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Linhagem Celular Tumoral , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Feminino , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Movimento CelularRESUMO
BACKGROUND: Silicosis is an irreversible fibrotic disease of the lung caused by chronic exposure to silica dust, which manifests as infiltration of inflammatory cells, excessive secretion of pro-inflammatory cytokines, and pulmonary diffuse fibrosis. As the disease progresses, lung function further deteriorates, leading to poorer quality of life of patients. Currently, few effective drugs are available for the treatment of silicosis. Bicyclol (BIC) is a compound widely employed to treat chronic viral hepatitis and drug-induced liver injury. While recent studies have demonstrated anti-fibrosis effects of BIC on multiple organs, including liver, lung, and kidney, its therapeutic benefit against silicosis remains unclear. In this study, we established a rat model of silicosis, with the aim of evaluating the potential therapeutic effects of BIC. METHODS: We constructed a silicotic rat model and administered BIC after injury. The FlexiVent instrument with a forced oscillation system was used to detect the pulmonary function of rats. HE and Masson staining were used to assess the effect of BIC on silica-induced rats. Macrophages-inflammatory model of RAW264.7 cells, fibroblast-myofibroblast transition (FMT) model of NIH-3T3 cells, and epithelial-mesenchymal transition (EMT) model of TC-1 cells were established in vitro. And the levels of inflammatory mediators and fibrosis-related proteins were evaluated in vivo and in vitro after BIC treatment by Western Blot analysis, RT-PCR, ELISA, and flow cytometry experiments. RESULTS: BIC significantly improved static compliance of lung and expiratory and inspiratory capacity of silica-induced rats. Moreover, BIC reduced number of inflammatory cells and cytokines as well as collagen deposition in lungs, leading to delayed fibrosis progression in the silicosis rat model. Further exploration of the underlying molecular mechanisms revealed that BIC suppressed the activation, polarization, and apoptosis of RAW264.7 macrophages induced by SiO2. Additionally, BIC inhibited SiO2-mediated secretion of the inflammatory cytokines IL-1ß, IL-6, TNF-α, and TGF-ß1 in macrophages. BIC inhibited FMT of NIH-3T3 as well as EMT of TC-1 in the in vitro silicosis model, resulting in reduced proliferation and migration capability of NIH-3T3 cells. Further investigation of the cytokines secreted by macrophages revealed suppression of both FMT and EMT by BIC through targeting of TGF-ß1. Notably, BIC blocked the activation of JAK2/STAT3 in NIH-3T3 cells required for FMT while preventing both phosphorylation and nuclear translocation of SMAD2/3 in TC-1 cells necessary for the EMT process. CONCLUSION: The collective data suggest that BIC prevents both FMT and EMT processes, in turn, reducing aberrant collagen deposition. Our findings demonstrate for the first time that BIC ameliorates inflammatory cytokine secretion, in particular, TGF-ß1, and consequently inhibits FMT and EMT via TGF-ß1 canonical and non-canonical pathways, ultimately resulting in reduction of aberrant collagen deposition and slower progression of silicosis, supporting its potential as a novel therapeutic agent.
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Fibrose Pulmonar , Transdução de Sinais , Silicose , Fator de Crescimento Transformador beta1 , Animais , Silicose/tratamento farmacológico , Silicose/patologia , Silicose/metabolismo , Silicose/complicações , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/patologia , Fibrose Pulmonar/complicações , Camundongos , Transdução de Sinais/efeitos dos fármacos , Células RAW 264.7 , Masculino , Fator de Crescimento Transformador beta1/metabolismo , Células NIH 3T3 , Ratos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Pulmão/patologia , Pulmão/efeitos dos fármacos , Citocinas/metabolismo , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Inflamação/patologia , Ratos Sprague-Dawley , Modelos Animais de Doenças , Fibroblastos/metabolismo , Fibroblastos/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Compostos de BifeniloRESUMO
Pregabalin is a medication primarily used in the treatment of neuropathic pain and anxiety disorders, owing to its gabapentinoid properties. Pregabalin monotherapy faces limitations due to its variable efficacy and dose-dependent adverse reactions. In this study, we conducted a comprehensive investigation into the potentiation of pregabalin's analgesic effects by dexborneol, a neuroprotective bicyclic monoterpenoid compound. We performed animal experiments where pain models were induced using two methods: peripheral nerve injury, involving axotomy and ligation of the tibial and common peroneal nerves, and incisional pain through a longitudinal incision in the hind paw, while employing a multifaceted methodology that integrates behavioral pharmacology, molecular biology, neuromorphology, and lipidomics to delve into the mechanisms behind this potentiation. Dexborneol was found to enhance pregabalin's efficacy by promoting its transportation to the central nervous system, disrupting self-amplifying vicious cycles via the reduction of HMGB1 and ATP release, and exerting significant anti-oxidative effects through modulation of central lipid metabolism. This combination therapy not only boosted pregabalin's analgesic property but also notably decreased its side effects. Moreover, this therapeutic cocktail exceeded basic pain relief, effectively reducing neuroinflammation and glial cell activation-key factors contributing to persistent and chronic pain. This study paves the way for more tolerable and effective analgesic options, highlighting the potential of dexborneol as an adjuvant to pregabalin therapy.
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Bacillus cereus causes food poisoning by producing toxins that cause diarrhea and vomiting and, in severe cases, endocarditis, meningitis, and other diseases. It also tends to form biofilms and spores that lead to contamination of the food production environment. Citral is a potent natural antibacterial agent, but its antibacterial activity against B. cereus has not been extensively studied. In this study, we first determined the minimum inhibitory concentrations and minimum bactericidal concentrations, growth curves, killing effect in different media, membrane potential, intracellular adenosine triphosphate (ATP), reactive oxygen species levels, and morphology of vegetative cells, followed by germination rate, morphology, germination state of spores, and finally biofilm clearance effect. The results showed that the minimum inhibitory concentrations and minimum bactericidal concentrations of citral against bacteria ranged from 100 to 800 µg/mL. The lag phase of bacteria was effectively prolonged by citral, and the growth rate of bacteria was slowed down. Bacteria in Luria-Bertani broth were reduced to below the detection limit by citral at 800 µg/mL within 0.5 h. Bacteria in rice were reduced to 3 log CFU/g by citral at 4000 µg/mL within 0.5 h. After treatment with citral, intracellular ATP concentration was reduced, membrane potential was altered, intracellular reactive oxygen species concentration was increased, and normal cell morphology was altered. After treatment with citral at 400 µg/mL, spore germination rate was reduced to 16.71%, spore morphology was affected, and spore germination state was altered. It also had a good effect on biofilm removal. The present study showed that citral had good bacteriostatic activity against B. cereus vegetative cells and its spores and also had a good clearance effect on its biofilm. Citral has the potential to be used as a bacteriostatic substance for the control of B. cereus in food industry production.
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Monoterpenos Acíclicos , Bacillus cereus , Biofilmes , Monoterpenos Acíclicos/farmacologia , Anti-Infecciosos/farmacologia , Bacillus cereus/efeitos dos fármacos , Bacillus cereus/crescimento & desenvolvimento , Bacillus cereus/ultraestrutura , Esporos Bacterianos/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Oryza/microbiologia , Potenciais da Membrana/efeitos dos fármacos , Espaço Intracelular/enzimologia , Trifosfato de Adenosina/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Microscopia Eletrônica de Varredura , Microbiologia de AlimentosRESUMO
Transient Receptor Potential Mucolipin 1 (TRPML1) is a lysosomal cation channel whose loss-of-function mutations directly cause the lysosomal storage disorder mucolipidosis type IV (MLIV). TRPML1 can be allosterically regulated by various ligands including natural lipids and small synthetic molecules and the channel undergoes a global movement propagated from ligand-induced local conformational changes upon activation. In this study, we identified a functionally critical residue, Tyr404, at the C-terminus of the S4 helix, whose mutations to tryptophan and alanine yield gain- and loss-of-function channels, respectively. These allosteric mutations mimic the ligand activation or inhibition of the TRPML1 channel without interfering with ligand binding and both mutant channels are susceptible to agonist or antagonist modulation, making them better targets for screening potent TRPML1 activators and inhibitors. We also determined the high-resolution structure of TRPML1 in complex with the PI(4,5)P2 inhibitor, revealing the structural basis underlying this lipid inhibition. In addition, an endogenous phospholipid likely from sphingomyelin is identified in the PI(4,5)P2-bound TRPML1 structure at the same hotspot for agonists and antagonists, providing a plausible structural explanation for the inhibitory effect of sphingomyelin on agonist activation.
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ABSTRACT: We describe contrast-enhanced CT and FDG PET/CT findings in a case of thoracic SMARCA4-deficient undifferentiated tumor with extensive pleural involvement and mediastinal lymph node metastases. Contrast-enhanced CT showed multiple enhancing right-sided pleural masses and soft tissue plaques and enlarged mediastinal lymph nodes. The pleural lesions and mediastinal lymph nodes showed intense FDG uptake mimicking malignant pleural mesothelioma with mediastinal lymph node metastases.
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The objective of the study was to evaluate the effects of trace mineral supplementation in sows during gestation and lactation on the performance and health status of sows and their offspring. Sows (n = 30; Landrace × Yorkshire; avg parity = 3.9) were randomly allocated into two dietary treatments. Sows received a basal diet supplemented with 12 mg/kg Cu, 30 mg/kg Fe, 90 mg/kg Zn, 70 mg/kg Mn, 0.30 mg/kg Se, and 1.5 mg/kg I from an inorganic trace mineral source (ITM) or a blend of hydroxychloride and organic trace mineral source (HOTM) from day 1 of gestation until the end of the lactation period at day 21. Compared to the ITM, the HOTM supplementation increased (P < 0.05) both litter birth weight and individual piglet birth weight. Although not statistically significant, HOTM tended to increase (P = 0.069) the level of lactose in colostrum. HOTM increased (P < 0.05) the concentration of Mn and Se in the colostrum, milk, and serum of sows and/or piglets. Notably, the Zn concentration in the serum of sows was higher in sows supplemented with ITM compared to HOTM. Moreover, HOTM increased (P < 0.05) the activities of GPX and SOD in gestating sows and piglets, as well as increased (P < 0.05) cytokines (IL-1ß, TNF-α, and IL-10) in the serum of sows. The immunoglobulins (IgA, IgG, and IgM) also increased in sows and/or piglets at certain experimental time points. In conclusion, HOTM supplementation positively affected piglet development and improved the health status of sows and piglets potentially by regulating redox homeostasis and immunity.