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1.
FASEB J ; 38(2): e23444, 2024 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-38252081

RESUMO

Metabolic reprogramming is a hallmark of cancer. The nicotinamide phosphoribosyltransferase (NAMPT)-mediated salvage pathway maintains sufficient cellular NAD levels and is required for tumorigenesis and development. However, the molecular mechanism by which NAMPT contributes to HBV-associated hepatocellular carcinoma (HCC) remains not fully understood. In the present study, our results showed that NAMPT protein was obviously upregulated in HBV-positive HCC tissues compared with HBV-negative HCC tissues. NAMPT was positively associated with aggressive HCC phenotypes and poor prognosis in HBV-positive HCC patients. NAMPT overexpression strengthened the proliferative, migratory, and invasive capacities of HBV-associated HCC cells, while NAMPT-insufficient HCC cells exhibited decreased growth and mobility. Mechanistically, we demonstrated that NAMPT activated SREBP1 (sterol regulatory element-binding protein 1) by increasing the expression and nuclear translocation of SREBP1, leading to the transcription of SREBP1 downstream lipogenesis-related genes and the production of intracellular lipids and cholesterol. Altogether, our data uncovered an important molecular mechanism by which NAMPT promoted HBV-induced HCC progression through the activation of SREBP1-triggered lipid metabolism reprogramming and suggested NAMPT as a promising prognostic biomarker and therapeutic target for HBV-associated HCC patients.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Nicotinamida Fosforribosiltransferase , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/virologia , Vírus da Hepatite B , Lipogênese , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virologia , Nicotinamida Fosforribosiltransferase/genética
2.
Arterioscler Thromb Vasc Biol ; 44(1): 156-176, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37942612

RESUMO

BACKGROUND: Senescence is a series of degenerative changes in the structure and physiological function of an organism. Whether JPX (just proximal to XIST)-a newly identified age-related noncoding RNA by us-is associated with atherosclerosis is still unknown. Our study was to investigate the role of JPX and provide insights into potential therapies targeting atherosclerosis. METHODS: We analyzed clinical data from multiple tissues including meniscus tissue, leukemia cells, and peripheral blood monocytes to identify age-related noncoding RNAs in senescent vascular smooth muscle cells (VSMCs). The molecular mechanism of JPX was investigated by capture hybridization analysis of RNA targets and chromatin immunoprecipitation. IGVTools and real-time quantitative polymerase chain reaction were used to evaluate the JPX expression during phenotype regulation in age-related disease models. The therapeutic potential of JPX was evaluated after establishing an atherosclerosis model in smooth muscle-specific Jpx knockout mice. RESULTS: JPX expression was upregulated in activated ras allele (H-rasV12)-induced senescent VSMCs and atherosclerotic arteries. JPX knockdown substantially reduced the elevation of senescence-associated secretory phenotype (SASP) genes in senescent VSMCs. Cytoplasmic DNA leaked from mitochondria via mitochondrial permeability transition pore formed by VDAC1 (voltage-dependent anion channel 1) oligomer activates the STING (stimulator of interferon gene) pathway. JPX could act as an enhancer for the SASP genes and functions as a scaffold molecule through interacting with phosphorylated p65/RelA and BRD4 (bromodomain-containing protein 4) in chromatin remodeling complex, promoting the transcription of SASP genes via epigenetic regulation. Smooth muscle knockout of Jpx in ApoeKO mice resulted in a decrease in plaque area, a reduction in SASP gene expression, and a decrease in senescence compared with controls. CONCLUSIONS: As an enhancer RNA, JPX can integrate p65 and BRD4 to form a chromatin remodeling complex, activating SASP gene transcription and promoting cellular senescence. These findings suggest that JPX is a potential therapeutic target for the treatment of age-related atherosclerosis.


Assuntos
Aterosclerose , RNA Longo não Codificante , Camundongos , Animais , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Músculo Liso Vascular/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Cromatina , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Epigênese Genética , Aterosclerose/genética , Aterosclerose/metabolismo , Senescência Celular/genética , Camundongos Knockout , Miócitos de Músculo Liso/metabolismo
3.
Eur Heart J ; 45(39): 4219-4235, 2024 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-39088352

RESUMO

BACKGROUND AND AIMS: Vascular smooth muscle cell (VSMC) senescence is crucial for the development of atherosclerosis, characterized by metabolic abnormalities. Tumour necrosis factor receptor-associated protein 1 (TRAP1), a metabolic regulator associated with ageing, might be implicated in atherosclerosis. As the role of TRAP1 in atherosclerosis remains elusive, this study aimed to examine the function of TRAP1 in VSMC senescence and atherosclerosis. METHODS: TRAP1 expression was measured in the aortic tissues of patients and mice with atherosclerosis using western blot and RT-qPCR. Senescent VSMC models were established by oncogenic Ras, and cellular senescence was evaluated by measuring senescence-associated ß-galactosidase expression and other senescence markers. Chromatin immunoprecipitation (ChIP) analysis was performed to explore the potential role of TRAP1 in atherosclerosis. RESULTS: VSMC-specific TRAP1 deficiency mitigated VSMC senescence and atherosclerosis via metabolic reprogramming. Mechanistically, TRAP1 significantly increased aerobic glycolysis, leading to elevated lactate production. Accumulated lactate promoted histone H4 lysine 12 lactylation (H4K12la) by down-regulating the unique histone lysine delactylase HDAC3. H4K12la was enriched in the senescence-associated secretory phenotype (SASP) promoter, activating SASP transcription and exacerbating VSMC senescence. In VSMC-specific Trap1 knockout ApoeKO mice (ApoeKOTrap1SMCKO), the plaque area, senescence markers, H4K12la, and SASP were reduced. Additionally, pharmacological inhibition and proteolysis-targeting chimera (PROTAC)-mediated TRAP1 degradation effectively attenuated atherosclerosis in vivo. CONCLUSIONS: This study reveals a novel mechanism by which mitonuclear communication orchestrates gene expression in VSMC senescence and atherosclerosis. TRAP1-mediated metabolic reprogramming increases lactate-dependent H4K12la via HDAC3, promoting SASP expression and offering a new therapeutic direction for VSMC senescence and atherosclerosis.


Assuntos
Aterosclerose , Senescência Celular , Proteínas de Choque Térmico HSP90 , Histona Desacetilases , Histonas , Músculo Liso Vascular , Animais , Humanos , Masculino , Camundongos , Aterosclerose/metabolismo , Aterosclerose/patologia , Senescência Celular/fisiologia , Histona Desacetilases/metabolismo , Histonas/metabolismo , Lisina/metabolismo , Camundongos Knockout , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Proteínas de Choque Térmico HSP90/genética , Proteínas de Choque Térmico HSP90/metabolismo
4.
Biochem Biophys Res Commun ; 715: 149979, 2024 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-38678779

RESUMO

Endothelial dysfunction is an initiating factor in atherosclerosis. Endothelial cells (ECs) are constantly subject to blood flow shear stress, and atherosclerotic plaques tend to occur in aortic bends or bifurcations impaired by low oscillatory shear stress (OSS). However, the mechanism that how OSS affects the initiation and progression of atherosclerosis remains to be explored. Here, we first reported that OSS can promote endothelial dysfunction and atherogenesis in vivo and in vitro by activating STING pathway. Mechanistically, at atherosclerosis-prone areas, OSS caused mitochondria damage in ECs, leading to the leakage of mitochondrial DNA (mtDNA) into the cytoplasm. The cytoplasmic mtDNA was recognized by cGAS to produce cGAMP, activating the STING pathway and leading to endothelial senescence, which resulted in endothelial dysfunction and atherosclerosis. We found that STING was activated in plaques of atherosclerotic patients and in aortic arch ECs of high-fat diet (HFD)-fed ApoeKO mice, as well as in ECs exposed to OSS. STING-specific deficiency in ECs attenuates endothelial senescence and resulted in a significant reduction in aortic arch plaque area in HFD-fed ApoeKO mice. Consistently, specific deficiency or pharmacological inhibition of STING attenuated OSS-induced senescence and endothelial dysfunction. Pharmacological depletion of mtDNA ameliorated OSS-induced senescence and endothelial dysfunction. Taken together, our study linked hemodynamics and endothelial senescence, and revealed a novel mechanism by which OSS leads to endothelial dysfunction. Our study provided new insights into the development of therapeutic strategies for endothelial senescence and atherosclerosis.


Assuntos
Aterosclerose , Senescência Celular , Células Endoteliais , Proteínas de Membrana , Estresse Mecânico , Animais , Humanos , Camundongos , Aterosclerose/metabolismo , Aterosclerose/patologia , Aterosclerose/genética , Células Cultivadas , Senescência Celular/genética , Dieta Hiperlipídica , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Mitocôndrias/patologia
5.
Inflamm Res ; 73(4): 597-617, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38353723

RESUMO

OBJECTIVE: PANoptosis, a new form of regulated cell death, concomitantly manifests hallmarks for pyroptosis, apoptosis, and necroptosis. It has been usually observed in macrophages, a class of widely distributed innate immune cells in various tissues, upon pathogenic infections. The second-generation curaxin, CBL0137, can trigger necroptosis and apoptosis in cancer-associated fibroblasts. This study aimed to explore whether CBL0137 induces PANoptosis in macrophages in vitro and in mouse tissues in vivo. METHODS: Bone marrow-derived macrophages and J774A.1 cells were treated with CBL0137 or its combination with LPS for indicated time periods. Cell death was assayed by propidium iodide staining and immunoblotting. Immunofluorescence microscopy was used to detect cellular protein distribution. Mice were administered with CBL0137 plus LPS and their serum and tissues were collected for biochemical and histopathological analyses, respectively. RESULTS: The results showed that CBL0137 alone or in combination with LPS induced time- and dose-dependent cell death in macrophages, which was inhibited by a combination of multiple forms of cell death inhibitors but not each alone. This cell death was independent of NLRP3 expression. CBL0137 or CBL0137 + LPS-induced cell death was characterized by simultaneously increased hallmarks for pyroptosis, apoptosis and necroptosis, indicating that this is PANoptosis. Induction of PANoptosis was associated with Z-DNA formation in the nucleus and likely assembly of PANoptosome. ZBP1 was critical in mediating CBL0137 + LPS-induced cell death likely by sensing Z-DNA. Moreover, intraperitoneal administration of CBL0137 plus LPS induced systemic inflammatory responses and caused multi-organ (including the liver, kidney and lung) injury in mice due to induction of PANoptosis in these organs. CONCLUSIONS: CBL0137 alone or plus inflammatory stimulation induces PANoptosis both in vitro and in vivo, which is associated with systemic inflammatory responses in mice.


Assuntos
Carbazóis , DNA Forma Z , Neoplasias , Camundongos , Animais , Lipopolissacarídeos/farmacologia , Apoptose , Piroptose
6.
J Org Chem ; 89(15): 10987-10997, 2024 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-39037887

RESUMO

Herein, visible light-induced, nickel-catalyzed direct functionalization of the Hantzsch esters (HEs) with readily accessible alkyl bromides has been successfully achieved by taking advantage of HE as the reductant and substrate through an aromatization-dearomatization process. In this strategy, the single electron reduction of alkyl bromides by reactive Ni(I) species is essential for the success of this late-stage transformation. A wide range of 4-alkyl-1,4-dihydropyridines were rapidly assembled in moderate to good yields under mild conditions, rendering this photoinduced approach attractive for synthetic and medicinal chemistry.

7.
J Org Chem ; 89(17): 12658-12667, 2024 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-39159404

RESUMO

Nickel/photoredox catalysis has emerged as a powerful platform for exploring nontraditional and challenging cross-couplings. Herein, a metallaphotoredox catalytic protocol has been developed on the basis of a tertiary amine-ligated boryl radical-induced halogen atom transfer process under blue-light irradiation. A wide variety of aryl and heteroaryl bromides featuring different functional groups and pharmaceutical moieties were facilely coupled to rapidly install C(sp3)-enriched aromatic scaffolds. The compatibility of Lewis base-ligated borane with nickel catalysis was well exemplified to extend the chemical space for Ni-catalyzed cross-electrophile coupling.

8.
Phys Chem Chem Phys ; 26(9): 7388-7397, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38351835

RESUMO

As a type of intelligent dimming film, polymer-dispersed liquid crystals (PDLCs) have been widely applied in various fields, such as smart windows, light shutters and displays. The properties of PDLCs are greatly influenced by the structure of the raw materials. In this work, the impact of crosslinking agents with different cyclic or chain groups was investigated by comparing the electro-optical performance and the morphology of the polymer matrix in the as-made PDLC films. It was found that the incorporation of large steric groups into the crosslinking agents can alter the morphology of the polymer matrix and thus affect the electro-optical properties. However, the impact is distinct when the spatial structure or rigidity is different. Besides, a combination of crosslinking agents with flexible alkyl-chain structures and steric structures can further reduce the threshold voltage while keeping the high contrast ratio. After detailed comparison, an optimized combination of BDDA/TCDDA in a weight ratio of 1/1 is selected to demonstrate the enhanced properties of the as-constructed film with a thickness of 20 µm. It exhibits low threshold voltage (8.2 V), low saturation voltage (21.2 V) and a high contrast ratio (203) simultaneously. This research offers an optimizing method from the crosslinking agent perspective and is anticipated to promote the further improvement of the PDLC's performance.

9.
J Nat Prod ; 87(9): 2327-2334, 2024 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-39258410

RESUMO

Two sulfur-containing heterodimers of a cytochalasan and a macrolide, sucurchalasins A and B (1 and 2), and four known cytochalasan monomers (3-6), as well as four known macrolide derivatives (7-10), were obtained from the endophytic fungus Aspergillus spelaeus GDGJ-286. Sucurchalasins A and B (1 and 2) are the first cytochalasan heterodimers formed via a thioether bridge between cytochalasan and curvularin macrolide units. Their structures were elucidated by detailed analysis of NMR, LC-MS/MS, and X-ray crystallography. In bioassays, 1 and 2 exhibited cytotoxic effects on A2780 cells, with IC50 values of 3.9 and 8.3 µM, respectively. They also showed antibacterial activities against E. faecalis and B. subtilis with MIC values of 3.1 and 6.3 µg/mL, respectively.


Assuntos
Aspergillus , Citocalasinas , Macrolídeos , Aspergillus/química , Citocalasinas/farmacologia , Citocalasinas/química , Citocalasinas/isolamento & purificação , Macrolídeos/farmacologia , Macrolídeos/química , Estrutura Molecular , Humanos , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Antibacterianos/química , Enxofre/química , Cristalografia por Raios X , Bacillus subtilis/efeitos dos fármacos
10.
Acta Pharmacol Sin ; 45(3): 594-608, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37964019

RESUMO

PANoptosis is a new type of cell death featured with pyroptosis, apoptosis and necroptosis, and is implicated in organ injury and mortality in various inflammatory diseases, such as sepsis and hemophagocytic lymphohistiocytosis (HLH). Reverse electron transport (RET)-mediated mitochondrial reactive oxygen species (mtROS) has been shown to contribute to pyroptosis and necroptosis. In this study we investigated the roles of mtROS and RET in PANoptosis induced by TGF-ß-activated kinase 1 (TAK1) inhibitor 5Z-7-oxozeaenol (Oxo) plus lipopolysaccharide (LPS) as well as the effects of anti-RET reagents on PANoptosis. We showed that pretreatment with anti-RET reagents 1-methoxy PMS (MPMS) or dimethyl fumarate (DMF) dose-dependently inhibited PANoptosis in macrophages BMDMs and J774A.1 cells induced by Oxo/LPS treatment assayed by propidium iodide (PI) staining. The three arms of the PANoptosis signaling pathway, namely pyroptosis, apoptosis and necroptosis signaling, as well as the formation of PANoptosomes were all inhibited by MPMS or DMF. We demonstrated that Oxo/LPS treatment induced RET and mtROS in BMDMs, which were reversed by MPMS or DMF pretreatment. Interestingly, the PANoptosome was co-located with mitochondria, in which the mitochondrial DNA was oxidized. MPMS and DMF fully blocked the mtROS production and the formation of PANoptosome induced by Oxo plus LPS treatment. An HLH mouse model was established by poly(I:C)/LPS challenge. Pretreatment with DMF (50 mg·kg-1·d-1, i.g. for 3 days) or MPMS (10 mg·kg-1·d-1, i.p. for 2 days) (DMF i.g. MPMS i.p.) effectively alleviated HLH lesions accompanied by decreased hallmarks of PANoptosis in the liver and kidney. Collectively, RET and mtDNA play crucial roles in PANoptosis induction and anti-RET reagents represent a novel class of PANoptosis inhibitors by blocking oxidation of mtDNA, highlighting their potential application in treating PANoptosis-related inflammatory diseases. PANoptotic stimulation induces reverse electron transport (RET) and reactive oxygen species (ROS) in mitochondia, while 1-methoxy PMS and dimethyl fumarate can inhibit PANoptosis by suppressing RETmediated oxidation of mitochondrial DNA.


Assuntos
DNA Mitocondrial , Fumarato de Dimetilo , Animais , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Transporte de Elétrons , Fumarato de Dimetilo/metabolismo , Fumarato de Dimetilo/farmacologia , DNA Mitocondrial/metabolismo , Lipopolissacarídeos/farmacologia , Elétrons , Mitocôndrias , Apoptose
11.
Acta Pharmacol Sin ; 2024 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-39223367

RESUMO

PANoptosis is an emerging form of regulated cell death (RCD) characterized by simultaneous activation of pyroptotic, apoptotic, and necroptotic signaling that not only participates in pathologies of inflammatory diseases but also has a critical role against pathogenic infections. Targeting PANoptosis represents a promising therapeutic strategy for related inflammatory diseases, but identification of inhibitors for PANoptosis remains an unmet demand. Baicalin () is an active flavonoid isolated from Scutellaria baicalensis Georgi (Huangqin), a traditional Chinese medicinal herb used for heat-clearing and detoxifying. Numerous studies suggest that baicalin possesses inhibitory activities on various forms of RCD including apoptosis/secondary necrosis, pyroptosis, and necroptosis, thereby mitigating inflammatory responses. In this study we investigated the effects of baicalin on PANoptosis in macrophage cellular models. Primary macrophages (BMDMs) or J774A.1 macrophage cells were treated with 5Z-7-oxozeaenol (OXO, an inhibitor for TAK1) in combination with TNF-α or LPS. We showed that OXO plus TNF-α or LPS induced robust lytic cell death, which was dose-dependently inhibited by baicalin (50-200 µM). We demonstrated that PANoptosis induction was accompanied by overt mitochondrial injury, mitochondrial DNA (mtDNA) release and Z-DNA formation. Z-DNA was formed from cytosolic oxidized mtDNA. Both oxidized mtDNA and mitochondrial Z-DNA puncta were co-localized with the PANoptosome (including ZBP1, RIPK3, ASC, and caspase-8), a platform for mediating PANoptosis. Intriguingly, baicalin not only prevented mitochondrial injury but also blocked mtDNA release, Z-DNA formation and PANoptosome assembly. Knockdown of ZBP1 markedly decreased PANoptotic cell death. In a mouse model of hemophagocytic lymphohistiocytosis (HLH), administration of baicalin (200 mg/kg, i.g., for 4 times) significantly mitigated lung and liver injury and reduced levels of serum TNF-α and IFN-γ, concomitant with decreased levels of PANoptosis hallmarks in these organs. Baicalin also abrogated the hallmarks of PANoptosis in liver-resident macrophages (Kupffer cells) in HLH mice. Collectively, our results demonstrate that baicalin inhibits PANoptosis in macrophages by blocking mitochondrial Z-DNA formation and ZBP1-PANoptosome assembly, thus conferring protection against inflammatory diseases. PANoptosis is a form of regulated cell death displaying simultaneous activation of pyroptotic, apoptotic, and necroptotic signaling. This study shows that induction of PANoptosis is linked to mitochondrial dysfunction and mitochondrial Z-DNA formation. Baicalin inhibits PANoptosis in macrophages in vitro via blocking mitochondrial dysfunction and the mitochondrial Z-DNA formation and thereby impeding the assembly of ZBP1-associated PANoptosome. In a mouse model of hemophagocytic lymphohistiocytosis (HLH), baicalin inhibits the activation of PANoptotic signaling in liver-resident macrophages (Kupffer cells) in vivo, thus mitigating systemic inflammation and multiple organ injury in mice.

12.
Surg Endosc ; 38(2): 671-678, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38012442

RESUMO

BACKGROUND: The potential impact of learning curve on long-term health-related quality of life (QoL) after esophagectomy for cancer has not been investigated. The aim of this article is to investigate the relationship between learning curve for McKeown minimally invasive esophagectomy (MIE) and health-related quality of life (QoL) in long-term, disease free survivors up to 10 years after esophageal cancer resection. METHODS: Esophageal cancer patients who underwent McKeown MIE between 2009 and 2019 were identified in which 280 who were free of disease at the time of survey and completed health-related QoL and symptom questionnaires, including EORTC QLQ-C30, EORTC QLQ-OES18, and Digestive Symptom Questionnaire. Patients were assessed in 3 cohorts according to the learning phases of expertise reported by our previous study: initial phase; plateau phase, and; experienced phase. RESULTS: Median time from operation to survey was 5.8 years (interquartile range 4.6-8.2). The QLQ-C30 mean scores of functional scales, and symptom scales of respiratory and digestive systems including dyspnea (P = 0.006), shortness of breath (P = 0.003), and dysphagia (P = 0.031) were significantly better in experienced phase group. Furthermore, in the subgroup analyses for patients without postoperative major complications, patients in the initial learning phase remained suffering from more symptoms of dyspnea (P = 0.040) and shortness of breath (P = 0.001). CONCLUSION: Esophageal cancer patients undergoing McKeown MIE in initial learning phase tend to suffer from a deterioration in long-term health-related QoL and higher symptomatic burden as compared to experienced learning phase, which did not improved over time and warranted more attention.


Assuntos
Neoplasias Esofágicas , Qualidade de Vida , Humanos , Esofagectomia/efeitos adversos , Curva de Aprendizado , Neoplasias Esofágicas/complicações , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/cirurgia , Sobreviventes , Dispneia/complicações , Dispneia/cirurgia
13.
J Public Health (Oxf) ; 46(1): 107-115, 2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38264954

RESUMO

BACKGROUND: This study examined the moderating role of outdoor time on the relationship between overweight and myopia. METHODS: The data for this study was obtained from a prospective study in Shanghai, where non-myopic children wore wristwear and were followed up for 1 year. Eye examinations were performed at each visit. The modification effect was assessed on the additive scale using multivariable logistic regression, and relative excess risk due to interaction was used to calculate the modification effect. RESULTS: A total of 4683 non-myopic children were included with 32.20% being overweight at baseline. Following a 1-year period, 17.42% of children had myopia. When compared to those who spent <90 minutes outdoors, children who spent >120 had a relative risk of myopia onset that was reduced to 0.61. As time spent outdoors decreased, more risks of myopia onset were identified among overweight children than among normal children, the modification effect on the additive scale was -0.007, with ~70% of this effect attributed to the modifying influence of outdoor time. CONCLUSIONS: Increasing outdoor time can reduce myopia more among overweight children than normal. Future interventions should focus on outdoor activities among overweight children to reduce myopia risks.


Assuntos
Miopia , Obesidade Infantil , Criança , Humanos , Pré-Escolar , Seguimentos , Estudos Prospectivos , Sobrepeso/complicações , Sobrepeso/epidemiologia , Obesidade Infantil/epidemiologia , Obesidade Infantil/etiologia , Atividades de Lazer , China/epidemiologia , Miopia/epidemiologia , Miopia/etiologia , Inquéritos e Questionários
14.
Eur J Orthod ; 46(6)2024 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-39412181

RESUMO

OBJECTIVE: This study aimed to evaluate the biomechanical effects of aligner overtreatment on molar distalization using clear aligners. METHODS: Various models were created and integrated into finite-element software. Six distinct study models were devised for analysis. The first three models examined second molar distalization with different configurations of attachments, i.e. no attachment, horizontal or vertical attachment on the second molar. For the fourth and fifth models, Class II elastic traction, either implemented via a precision cut or button on canines, was applied. Lastly, aligner overtreatment with varying degrees of root distal tipping (0°, 2°, 4°, 6°, 8°, 10°, and 12°) for the second molar was designed in the last study model. RESULTS: Distalization of the second molar produced buccal tipping, distal tipping and intrusion of the second molar, and labial proclination and intrusion of the central incisor. These displacement tendencies were enhanced by adding attachments on the second molar, especially the vertical attachment. Class II elastic tractions enhanced molar distalization and diminish anchorage loss, with the precision-cut configuration being biomechanically superior to the button design. Aligner overtreatment produced bodily molar distalization and mitigated adverse biomechanical effects on anchorage teeth. LIMITATIONS: The study's limitations include the use of finite-element models, which may not fully represent real clinical scenarios, and the lack of consideration for individual patient variability. CONCLUSIONS: We suggest that Class II elastic traction via the precision-cut configuration and the design of vertical attachment on the second molar be applied for molar distalization. Appropriate aligner overtreatment helps achieve bodily molar distalization and minimizes adverse biomechanical effects on anchorage teeth.


Assuntos
Análise de Elementos Finitos , Dente Molar , Técnicas de Movimentação Dentária , Humanos , Técnicas de Movimentação Dentária/métodos , Técnicas de Movimentação Dentária/instrumentação , Fenômenos Biomecânicos , Desenho de Aparelho Ortodôntico , Procedimentos de Ancoragem Ortodôntica/métodos , Procedimentos de Ancoragem Ortodôntica/instrumentação , Incisivo , Dente Canino , Simulação por Computador , Análise do Estresse Dentário/métodos
15.
Minim Invasive Ther Allied Technol ; 33(1): 43-50, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37946501

RESUMO

INTRODUCTION: This study aimed to compare early efficacy of UBED and PEID in the treatment of L5/S1 IDH. MATERIAL AND METHODS: Forty-two patients who underwent surgical treatment for L5/S1 IDH were divided into two groups: UBED and PEID. Operation time, complications, VAS/ODI score were recorded. MacNab evaluation was completed one and three months postoperatively. RESULTS: All patients were successfully operated without infection, nerve injury, or huge hematoma in the spinal canal. There were no significant differences in operation time and hospitalization days between the two groups (p > 0.05). All patients were followed up after the operation and low back/leg pain was significantly reduced. VAS for low back pain, VAS for leg pain, ODI scores in both groups one and three months after the operation were significantly lower than pre-operation (p < 0.05). There were no significant differences between one and three months after the operation in both groups (p > 0.05). There were no significant differences in VAS for low back pain, leg pain, ODI score, and overall efficacy between the two groups one and three months post-operation (p > 0.05). CONCLUSION: UBED and PEID have very good early efficacy in treating L5/S1 IDH. Because UBED has a wider vision field and more flexible operation, it can be used as a useful complement to PEID.


Assuntos
Discotomia Percutânea , Deslocamento do Disco Intervertebral , Dor Lombar , Humanos , Deslocamento do Disco Intervertebral/cirurgia , Dor Lombar/etiologia , Dor Lombar/cirurgia , Resultado do Tratamento , Estudos Retrospectivos , Vértebras Lombares/cirurgia , Endoscopia
16.
Apoptosis ; 28(11-12): 1646-1665, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37702860

RESUMO

Macrophages represent the first lines of innate defense against pathogenic infections and are poised to undergo multiple forms of regulated cell death (RCD) upon infections or toxic stimuli, leading to multiple organ injury. Triptolide, an active compound isolated from Tripterygium wilfordii Hook F., possesses various pharmacological activities including anti-tumor and anti-inflammatory effects, but its applications have been hampered by toxic adverse effects. It remains unknown whether and how triptolide induces different forms of RCD in macrophages. In this study, we showed that triptolide exhibited significant cytotoxicity on cultured macrophages in vitro, which was associated with multiple forms of lytic cell death that could not be fully suppressed by any one specific inhibitor for a single form of RCD. Consistently, triptolide induced the simultaneous activation of pyroptotic, apoptotic and necroptotic hallmarks, which was accompanied by the co-localization of ASC specks respectively with RIPK3 or caspase-8 as well as their interaction with each other, indicating the formation of PANoptosome and thus the induction of PANoptosis. Triptolide-induced PANoptosis was associated with mitochondrial dysfunction and ROS production. PANoptosis was also induced by triptolide in mouse peritoneal macrophages in vivo. Furthermore, triptolide caused kidney and liver injury, which was associated with systemic inflammatory responses and the activation of hallmarks for PANoptosis in vivo. Collectively, our data reveal that triptolide induces PANoptosis in macrophages in vitro and exhibits nephrotoxicity and hepatotoxicity associated with induction of PANoptosis in vivo, suggesting a new avenue to alleviate triptolide's toxicity by harnessing PANoptosis.


Assuntos
Diterpenos , Fenantrenos , Camundongos , Animais , Apoptose , Macrófagos/metabolismo , Diterpenos/efeitos adversos , Diterpenos/metabolismo , Fenantrenos/toxicidade , Fenantrenos/metabolismo , Compostos de Epóxi/toxicidade , Compostos de Epóxi/metabolismo
17.
BMC Cancer ; 23(1): 1212, 2023 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-38066484

RESUMO

BACKGROUND: Anastomotic leakage (AL) is a severe complication following esophagectomy with high mortality. Perioperative decreased serum albumin level is considered a predictive of AL, however, its impact on AL incidence in patients treated with neoadjuvant chemotherapy (NCT) followed by minimally invasive esophagectomy (MIE) is not well defined. METHODS: The data of 318 consecutive esophageal cancer patients who underwent MIE were collected retrospectively from January 2021 to December 2021. The perioperative level of albumin was detected and the baseline of altering levels for albumin was established. The incidence of postoperative complications and survival rate were analyzed between groups. RESULTS: After exclusion, 137 patients were enrolled and assigned to more decreased albumin (MA) and less decreased albumin (LA) groups. The levels of albumin descended significantly after MIE (p < 0.0001). There was no significant difference in the clinicopathologic characteristics or surgical outcomes between groups. The incidence of postoperative AL was 10.2% in MA group and 1.4% in LA group (p = 0.033). Three patients died due to AL in MA group, while no mortality was observed in LA group (p = 0.120). The rate of other postoperative complications was similar between groups. Progression-free survival (PFS) in LA group was a little higher than that in MA group, but it was no significant difference (p = 0.853). Similarly, no difference was observed in overall survival (OS) between groups (p = 0.277). CONCLUSIONS: Severely deficient serum albumin after MIE was an indicator of AL in esophageal cancer patients treated with NCT. TRIAL REGISTRATION: Chinese clinical trial registry: ChiCTR2200066694, registered December14th,2022. https://www.chictr.org.cn/edit.aspx?pid=185067&htm=4 .


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Albumina Sérica , Humanos , Fístula Anastomótica/epidemiologia , Fístula Anastomótica/etiologia , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/cirurgia , Carcinoma de Células Escamosas do Esôfago/cirurgia , Carcinoma de Células Escamosas do Esôfago/complicações , Esofagectomia/efeitos adversos , Terapia Neoadjuvante/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Albumina Sérica/análise , Resultado do Tratamento
18.
Pharmacol Res ; 189: 106697, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36796462

RESUMO

Necroptosis has been implicated in various inflammatory diseases including tumor-necrosis factor-α (TNF-α)-induced systemic inflammatory response syndrome (SIRS). Dimethyl fumarate (DMF), a first-line drug for treating relapsing-remitting multiple sclerosis (RRMS), has been shown to be effective against various inflammatory diseases. However, it is still unclear whether DMF can inhibit necroptosis and confer protection against SIRS. In this study, we found that DMF significantly inhibited necroptotic cell death in macrophages induced by different necroptotic stimulations. Both the autophosphorylation of receptor-interacting serine/threonine kinase 1 (RIPK1) and RIPK3 and the downstream phosphorylation and oligomerization of MLKL were robustly suppressed by DMF. Accompanying the suppression of necroptotic signaling, DMF blocked the mitochondrial reverse electron transport (RET) induced by necroptotic stimulation, which was associated with its electrophilic property. Several well-known anti-RET reagents also markedly inhibited the activation of the RIPK1-RIPK3-MLKL axis accompanied by decreased necrotic cell death, indicating a critical role of RET in necroptotic signaling. DMF and other anti-RET reagents suppressed the ubiquitination of RIPK1 and RIPK3, and they attenuated the formation of necrosome. Moreover, oral administration of DMF significantly alleviated the severity of TNF-α-induced SIRS in mice. Consistent with this, DMF mitigated TNF-α-induced cecal, uterine, and lung damage accompanied by diminished RIPK3-MLKL signaling. Collectively, DMF represents a new necroptosis inhibitor that suppresses the RIPK1-RIPK3-MLKL axis through blocking mitochondrial RET. Our study highlights DMF's potential therapeutic applications for treating SIRS-associated diseases.


Assuntos
Proteínas Quinases , Fator de Necrose Tumoral alfa , Camundongos , Animais , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases/metabolismo , Fumarato de Dimetilo , Necroptose , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Síndrome de Resposta Inflamatória Sistêmica , Fosforilação Oxidativa , Apoptose
19.
Inorg Chem ; 62(8): 3395-3408, 2023 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-36763897

RESUMO

Half-sandwich iridium(III) complexes show potential value in the anticancer field. However, complexes with favorable luminescence performance are rare, which limits further investigation of the anticancer mechanism. In this paper, 10 triphenylamine-modified fluorescent half-sandwich iridium(III) pyridine complexes {[(η5-Cpx)Ir(L)Cl2]} (Ir1-Ir10) were prepared and showed potential antiproliferative activity, effectively inhibiting the migration of A549 cells. Ir6, showing the best activity among these complexes, exhibited excellent fluorescence performance (absolute fluorescence quantum yield of 15.17%) in solution. Laser confocal detection showed that Ir6 followed an energy-dependent cellular uptake mechanism, specifically accumulating in mitochondria (Pearson co-localization coefficient of 0.95). A Western blot assay further confirmed the existence of a mitochondrial apoptotic channel. Additionally, Ir6 could arrest the cell cycle at the G2/M phase, catalyze NADH oxidation, reduce the mitochondrial membrane potential, induce an increase in the level of intracellular reactive oxygen species, and exhibit a mechanism of oxidation. An in vivo antitumor assay confirmed that Ir6 can effectively inhibit tumor growth and is safer than cisplatin.


Assuntos
Antineoplásicos , Complexos de Coordenação , Complexos de Coordenação/farmacologia , Antineoplásicos/farmacologia , Irídio/farmacologia , Cisplatino/farmacologia , Piridinas/farmacologia , Apoptose , Proliferação de Células , Linhagem Celular Tumoral , Espécies Reativas de Oxigênio/metabolismo
20.
BMC Gastroenterol ; 23(1): 252, 2023 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-37491210

RESUMO

BACKGROUND: Periampullary diverticulum (PAD) may make the performance of endoscopic retrograde cholangiopancreatography (ERCP) in patients with choledocholithiasis more difficult and may increase complication rates. The present study evaluated the effects of PAD on first-time ERCP in patients with choledocholithiasis. METHODS: Outcomes were compared in patients with and without PAD and in those with four types of PAD: papilla located completely inside the diverticulum (type I), papilla located in the inner (type II a) and outer (type II b) margins of the diverticulum; and papilla located outside the diverticulum (type III). Parameters compared included cannulation time and rates of difficult cannulation, post-ERCP pancreatitis (PEP) and perforation. RESULTS: The median cannulation times in patients with types I, II a, II b, III PAD and in those without PAD were 2.0 min, 5.0 min, 0.67 min, 3.5 min, and 3.5 min, respectively, with difficult cannulation rates in these groups of 7.4%, 31.4%, 8.3%, 18.9%, and 23.2%, respectively. The rates of PEP in patients with and without PAD were 5.3% and 5.1%, respectively. Four patients with and one without PAD experienced perforation. CONCLUSIONS: The division of PAD into four types may be more appropriate than the traditional division into three types. Cannulation of type I and II b PAD was easier than cannulation of patients without PAD, whereas cannulation of type II a PAD was more challenging. PAD may not increase the rates of PEP.


Assuntos
Ampola Hepatopancreática , Coledocolitíase , Divertículo , Duodenopatias , Humanos , Coledocolitíase/etiologia , Cateterismo/efeitos adversos , Colangiopancreatografia Retrógrada Endoscópica/efeitos adversos , Duodenopatias/etiologia
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