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1.
J Biol Chem ; 299(7): 104856, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37230388

RESUMO

Neuroblastoma (NB) is one of the most common extracranial solid tumors in children. MYCN gene amplification is highly associated with poor prognosis in high-risk NB patients. In non-MYCN-amplified high-risk NB patients, the expression of c-MYC (MYCC) and its target genes is highly elevated. USP28 as a deubiquitinase is known to regulate the stability of MYCC. We show here USP28 also regulates the stability of MYCN. Genetic depletion or pharmacologic inhibition of the deubiquitinase strongly destabilizes MYCN and stops the growth of NB cells that overexpress MYCN. In addition, MYCC could be similarly destabilized in non-MYCN NB cells by compromising USP28 function. Our results strongly suggest USP28 as a therapeutic target for NB with or without MYCN amplification/overexpression.


Assuntos
Células-Tronco Neurais , Neuroblastoma , Criança , Humanos , Linhagem Celular Tumoral , Enzimas Desubiquitinantes/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteína Proto-Oncogênica N-Myc/genética , Proteína Proto-Oncogênica N-Myc/metabolismo , Proteína Proto-Oncogênica N-Myc/uso terapêutico , Células-Tronco Neurais/metabolismo , Neuroblastoma/patologia , Fatores de Transcrição/metabolismo , Ubiquitina Tiolesterase/metabolismo
2.
J Biol Chem ; 298(1): 101443, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34822842

RESUMO

Triple-negative breast cancer (TNBC) lacks significant expression of the estrogen receptor, the progesterone receptor, and of human epidermal growth factor receptor. It is the most aggressive and malignant of all breast cancers, and for which, there are currently no effective targeted therapies. We have shown previously that the RecQ helicase family member RECQL5 is essential for the proliferation and survival of TNBC cells; however, the mechanism of its involvement in cell viability has not been shown. Here, we report that the expression of RecQ family helicases, including RECQL5, is regulated by the deubiquitinase USP28. We found using genetic depletion or a small molecule inhibitor that like RECQL5, USP28 is also essential for TNBC cells to proliferate in vitro and in vivo. Compromising the function of USP28 by shRNA knockdown or the inhibitor caused TNBC cells to arrest in S/G2 phases, concurrent with DNA-damage checkpoint activation. We further showed that the small molecule inhibitor of USP28 displayed anti-tumor activity against xenografts derived from TNBC cells. Our results suggest that USP28 could be a potential therapeutic target for triple negative breast cancer.


Assuntos
RecQ Helicases , Neoplasias de Mama Triplo Negativas , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Enzimas Desubiquitinantes/metabolismo , Humanos , RecQ Helicases/biossíntese , RecQ Helicases/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Ubiquitina Tiolesterase/genética
3.
Cell Biol Toxicol ; 39(4): 1561-1575, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-35953652

RESUMO

Anaesthetics may modify colorectal cancer cell biology which potentially affects long-term survival. This study aims to compare propofol and sevoflurane regarding with the direct anaesthetic effects on cancer malignancy and the indirect effects on host immunity in a cancer xenograft mode of mice. Cultured colon cancer cell (Caco-2) was injected subcutaneously to nude mice (day 1). Mice were exposed to either 1.5% sevoflurane for 1.5 h or propofol (20 µg g-1; ip injection) with or without 4 µg g-1 lipopolysaccharide (LPS; ip) from days 15 to 17, compared with those without anaesthetic exposure as controls. The clinical endpoints including tumour volumes over 70 mm3 were closely monitored up to day 28. Tumour samples from the other cohorts were collected on day 18 for PCR array, qRT-PCR, western blotting and immunofluorescent assessment. Propofol treatment reduced tumour size (mean ± SD; 23.0 ± 6.2mm3) when compared to sevoflurane (36.0 ± 0.3mm3) (p = 0.008) or control (23.6 ± 4.7mm3). Propofol decreased hypoxia inducible factor 1α (HIF1α), interleukin 1ß (IL1ß), and hepatocyte growth factor (HGF) gene expressions and increased tissue inhibitor of metalloproteinases 2 (TIMP-2) gene and protein expression in comparison to sevoflurane in the tumour tissue. LPS suppressed tumour growth in any conditions whilst increased TIMP-2 and anti-cancer neutrophil marker expressions and decreased macrophage marker expressions compared to those in the LPS-untreated groups. Our data indicated that sevoflurane increased cancer development when compared with propofol in vivo under non-surgical condition. Anaesthetics tested in this study did not alter the effects of LPS as an immune modulator in changing immunocyte phenotype and suppressing cancer development.


Assuntos
Anestésicos Inalatórios , Éteres Metílicos , Neoplasias , Propofol , Humanos , Camundongos , Animais , Propofol/farmacologia , Propofol/uso terapêutico , Sevoflurano/farmacologia , Anestésicos Intravenosos/farmacologia , Inibidor Tecidual de Metaloproteinase-2 , Anestésicos Inalatórios/farmacologia , Éteres Metílicos/farmacologia , Xenoenxertos , Lipopolissacarídeos/farmacologia , Células CACO-2 , Camundongos Nus , Neoplasias/tratamento farmacológico
4.
J Invertebr Pathol ; 201: 108003, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37838064

RESUMO

In this study, silkworms were treated by injection of the bioactive depsipeptide beauvericin (BEA) to explore its effect on the cellular immunity of larvae of the silkworm Bombyx mori. The results showed that: The LC50 of BEA for silkworms on the 3rd day of the 4th instar was 362.36 µM. The total count of circulating hemocytes in the silkworms decreased at 12 h after injection with 350 µM BEA, and reached the minimum value at 72 h post-treatment; at 48 h post-treatment, a large number of nodules formed by the aggregation of blood cells of the silkworms were observed under the light microscope. The survival rate of hemocytes in the larvae treated with BEA was significantly reduced in a dose-dependent manner in vivo and in vitro. The encapsulation of Q-Sepharose Fast Flow (QFF) gel particles by hemocytes in the treatment group was significantly higher than that in the control group at 1.5 h and 3 h post-treatment (P < 0.05). Moreover, the melanization ratio of QFF gel particles kept increasing with treatment time. The melanization rate at 24 h after treatment was significantly higher than that at other times (P < 0.05), reaching 55.33 %. Under the scanning electron microscope, BEA-treated larvae showed protrusions on the surface of their blood cells in vivo. Under the transmission electron microscope, it was observed that silkworm hemocytes were vacuolated. This study demonstrated that BEA had an effect on the blood cells of silkworms, and has thrown some light on the inhibitory effect and mechanism of BEA on insect cellular immunity.


Assuntos
Bombyx , Depsipeptídeos , Animais , Hemócitos , Depsipeptídeos/farmacologia , Larva , Proteínas de Insetos
5.
Cancer Sci ; 113(10): 3463-3475, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35880246

RESUMO

Overexpression of ubiquitin-specific protease 28 (USP28) is found in hepatic carcinoma. It is unclear whether the deubiquitinase plays a role in hepatocarcinogenesis. Deregulation of the Wnt signaling pathway is frequently associated with liver cancer. Transcription factor 7-like 2 (TCF7L2) is an important downstream transcription factor of the Wnt/ß-catenin signaling pathway, but the mechanisms by which TCF7L2 itself is regulated have not yet been revealed. Here, we report that USP28 promotes the activity of the Wnt signaling pathway through maintaining the stability of TCF7L2. We further show that FBXW7 is the E3 ubiquitin ligase for TCF7L2. By regulating the levels of TCF7L2, USP28 modulates the Wnt/ß-catenin signaling in liver cancer and USP28 depletion or inhibition by a small molecule inhibitor leads to a halt of growth in liver cancer cells. These results suggest that USP28 could be a potential therapeutic target for liver cancer.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Linhagem Celular Tumoral , Enzimas Desubiquitinantes , Proteína 7 com Repetições F-Box-WD/metabolismo , Humanos , Fator 1 de Transcrição de Linfócitos T/metabolismo , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Proteína 2 Semelhante ao Fator 7 de Transcrição/metabolismo , Ubiquitina Tiolesterase/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Proteases Específicas de Ubiquitina/metabolismo , Via de Sinalização Wnt/fisiologia , beta Catenina/metabolismo
6.
BMC Nephrol ; 22(1): 43, 2021 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-33514328

RESUMO

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is identified as mesangial IgA deposition and is usually accompanied by other immunofluorescence deposits. The impact of immunofluorescent features in IgAN patients, however, remains unclear. METHODS: Baseline clinicopathologic parameters and renal outcomes of 337 patients diagnosed with IgAN between January 2009 and December 2015 were analyzed. We then categorized these patients into four groups: without immunofluorescence deposits, mesangial-only, mesangial and glomerular capillary loops (GCLs), and GCLs-only. The study endpoint was end-stage kidney disease (ESKD) or a ≥ 50% decline in the estimated glomerular filtration rate (eGFR). Kaplan-Meier and Cox regression analyses were performed to calculate renal survival. RESULTS: Of the 337 IgAN patients, women comprised 57.0%. Compared to patients with IgA deposition in the mesangial-only group, patients with IgA deposition in the mesangial +GCLs group were much heavier, and exhibited higher systolic blood pressure, lower serum IgG levels, and heavier proteinuria (all P < 0.05). Patients with IgG deposition in the mesangial +GCLs group presented with higher levels of cholesterol, heavier proteinuria than IgG deposition in the mesangial-only group (both P < 0.05). Compared with the mesangial-only group exhibiting C3 deposits, patients in the mesangial +GCLs group with C3 deposition had a higher systolic blood pressure (P = 0.028). A total of 38 patients (11.3%) continued to the study endpoint after a median follow-up time of 63.5 months (range,49.8-81.4). Kaplan-Meier analysis and Cox regression analysis showed that C1q deposition in the mesangial +GCLs group predicted a poor renal prognosis. CONCLUSIONS: IgA and IgG deposits in the mesangial region and GCLs were associated with more unfavorable clinical and histopathologic findings in IgAN patients. C1q deposition in the mesangial region and GCLs predicted a poor renal prognosis. However, the impact of the pattern of immunofluorescence deposits on renal outcomes remains to be proven by further investigation.


Assuntos
Complemento C1q/fisiologia , Mesângio Glomerular/irrigação sanguínea , Glomerulonefrite por IGA/patologia , Imunoglobulina A/análise , Glomérulos Renais/metabolismo , Adulto , Capilares , Feminino , Imunofluorescência , Glomerulonefrite por IGA/imunologia , Glomerulonefrite por IGA/metabolismo , Humanos , Masculino , Prognóstico , Estudos Retrospectivos , Adulto Jovem
7.
Int J Neurosci ; 131(9): 843-853, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32345086

RESUMO

AIM OF THE STUDY: Hypoxic-ischemic encephalopathy (HIE) is a major cause of newborn brain injury. Apoptosis and necroptosis are two forms of cell death which may occur in HIE but reported data are yet limited. This study investigates the expression of receptor interacting protein kinase (RIPK) 1 and 3, and caspase3, the key modulators of necroptosis and apoptosis, respectively, in a model of HIE to determine whether both forms of cell death occur in the corresponding brain regions. MATERIALS AND METHODS: Postneonatal day 7 Sprague-Dawley rats were subjected to right carotid artery ligation followed by hypoxia or subjected to skin incision under surgical anesthesia without ligation and hypoxia. Neuroglioma (H4) cell was cultured and subjected to 24 h hypoxic insults. Necrostatin-1, a RIPK1 inhibitor, was administered in both in vivo and in vitro settings before insult. RESULTS: After hypoxic-ischemic insults, both RIPK1 and RIPK3 expression were significantly increased in the region of hippocampal dentate gyrus in the injurious hemisphere. However, cleaved caspase3 was significantly increased in the hippocampal cornu ammonis 1 region in the injurious hemisphere. After hypoxic insults, RIPK1 and RIPK3 expression was also found in H4 cells. In addition, it was identified that the increased RIPK1 and RIPK3 can be inhibited by necrostatin-1 in both in vivo and in vitro. CONCLUSIONS: These data indicated that apoptosis and necroptosis occur in different brain regions of hippocampus in a model of HIE which may suggest that strategies to prevent each form of neuronal death is valuable to be developed.


Assuntos
Apoptose , Asfixia/metabolismo , Hipocampo/metabolismo , Hipóxia-Isquemia Encefálica/metabolismo , Necroptose , Animais , Asfixia/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Hipocampo/patologia , Humanos , Hipóxia-Isquemia Encefálica/patologia , Ratos Sprague-Dawley , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo
8.
Anesthesiology ; 132(6): 1469-1481, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32412720

RESUMO

BACKGROUND: Sevoflurane is commonly used for cervical cancer surgery, but its effect on cervical cancer cell biology remains unclear. This mechanistic study explores how sevoflurane affects the proliferation and metastatic potential of immortalized cervical cancer cell lines. METHODS: Cultured cervical cancer Caski and HeLa lines were exposed to 1, 2, or 3% sevoflurane for 2 or 4 h. Cell proliferation was determined through the Kit-8 assay and Ki-67 immunofluorescent staining. Cell migration and invasion were evaluated with the Transwell assay. Immunofluorescent staining and Western blot analysis were used to identify sevoflurane-induced morphological and biochemical changes. RESULTS: Sevoflurane exposure for either 2 or 4 h significantly increased HeLa cell proliferation in a time- and concentration-dependent manner to be 106 ± 2.7% and 107 ± 1.4% relative to the controls (n = 10; P = 0.036; P = 0.022) at 24 h after exposure and to be 106 ± 2.2% and 106 ± 1.7% relative to the controls (n = 10; P = 0.031; P = 0.023) at the highest concentration of 3% sevoflurane studied, respectively, but not Caski cells. Sevoflurane promoted invasion ability (1.63 ± 0.14 and 1.92 ± 0.12 relative to the controls) and increased cell size (1.69 ± 0.21 and 1.76 ± 0.13 relative to the controls) of Caski and HeLa cells (n = 6; all P < 0.001), respectively. Sevoflurane increased histone deacetylase 6 expression in both cells, and histone deacetylase 6 knockdown abolished the prometastatic effects of sevoflurane. Sevoflurane also induced deacetylation of α-tubulin in a histone deacetylase 6-dependent manner. The protein kinase B (AKT) or extracellular regulated protein kinase (ERK1/2) phosphorylation inhibition attenuated sevoflurane-induced histone deacetylase 6 expression. CONCLUSIONS: Sevoflurane enhanced proliferation, migration, and invasion of immortalized cervical cancer cells, which was likely associated with increasing histone deacetylase 6 expression caused by phosphatidylinositide 3-kinase/AKT- and ERK1/2-signaling pathway activation.


Assuntos
Anestésicos Inalatórios/farmacologia , Proliferação de Células/efeitos dos fármacos , Desacetilase 6 de Histona/metabolismo , Sevoflurano/farmacologia , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia , Linhagem Celular Tumoral , Movimento Celular , Feminino , Humanos , Técnicas In Vitro , Metástase Neoplásica , Transdução de Sinais
9.
BMC Nephrol ; 21(1): 447, 2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-33109129

RESUMO

BACKGROUND: Interstitial fibrosis/tubular atrophy (T) score is a known determinant of the progression of immunoglobulin A nephropathy (IgAN). Strong evidence indicates that the components of the coagulation system closely linked with fibrotic events have been highlighted in the kidney. However, whether the coagulation system can affect the renal outcome of IgAN remains unclear. Herein, we investigated the association of coagulation parameters and pathological phenotype of IgAN and their combined effects on the deterioration of renal function. METHODS: This retrospective study included N = 291 patients with biopsy-proven IgAN from May 2009 to April 2013 in the Second Xiangya Hospital. Clinical data, pathological features were collected, and the associations of coagulation parameters at biopsy, T score, and renal outcome were evaluated. T score indicated the degree of tubular atrophy or interstitial fibrosis. The renal outcome was defined as an end-stage renal disease (ESRD) or an irreversible 50% estimated glomerular filtration rate (eGFR) reduction. RESULTS: Shorter prothrombin time (PT) and the activated partial thromboplastin time (APTT) were significantly associated with T (both p < 0.001). PT (< 11.15 s) or APTT (< 29.65 s) had worse cumulative survival rate (p = 0.008, p = 0.027 respectively) and were significantly but not independently associated with a higher risk of renal outcome (p = 0.012, p = 0.032 respectively). In the combined analyses of PT, APTT, and T lesions, the odd ratios for the outcome were significantly higher in the presence of T with PT (< 11.15 s) or APTT (< 29.65 s). CONCLUSION: Shorter PT and APTT are associated with an increased incidence of the T lesion and are additional factors that portend a poorer prognosis in IgAN. Monitoring coagulation function might be important when assessing the risk of progression. Additional studies exploring the molecular mechanism between coagulation and IgAN pathology are needed.


Assuntos
Coagulação Sanguínea , Glomerulonefrite por IGA/patologia , Glomerulonefrite por IGA/fisiopatologia , Túbulos Renais/patologia , Adulto , Biópsia , Pressão Sanguínea , Creatinina/sangue , Progressão da Doença , Feminino , Fibrose , Taxa de Filtração Glomerular , Humanos , Masculino , Tempo de Tromboplastina Parcial , Tempo de Protrombina , Estudos Retrospectivos
10.
Lab Invest ; 99(12): 1795-1809, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31570770

RESUMO

Sepsis-related acute lung injury (ALI) remains a major cause of mortality in critically ill patients and lacks specific therapy. Mitochondrial dysfunction is involved in the progression of septic lung injury. Mitochondrial dynamics, mitophagy, and biogenesis converge to constitute the assiduous quality control of mitochondria (MQC). Heme oxygenase-1 (HO-1) protects against sepsis-induced ALI through the modulation of mitochondrial dynamics. However, the causal relationship between HO-1 and the general processes of MQC, and their associated cellular pathways in sepsis-related ALI remain ill-defined. Herein, lipopolysaccharide (LPS)-induced ALI in Sprague-Dawley rats together with LPS-induced oxidative injury in RAW264.7 macrophages were used to investigate whether the PI3K/Akt pathway-mediated induction of HO-1 preserves MQC and alleviates septic lung injury. After pretreatment with hemin, a potent inducer of HO-1, LPS-induced cell apoptosis, enhanced mitochondrial fragmentation, and mitochondrial membrane potential damage were significantly reduced in macrophages. In rats, these effects were accompanied by a higher survival rate, less damage to lung tissue, a 28.5% elevation in lung mitochondria MnSOD activity, and a 39.2% increase in respiratory control ratios. Concomitantly, HO-1 induction preserved the dynamic process of mitochondrial fusion/fission (Mfn2, OPA1, Drp1), promoted mitochondrial biogenesis (NRF1, PGC1α, Tfam), and facilitated the key mediators of mitochondrial mitophagy (Parkin, PINK1) at mRNA and protein levels. Notably, LY294002, a PI3K inhibitor, or knockdown of PI3K by small interfering RNA significantly suppressed Akt phosphorylation, attenuated HO-1 induction, and further reversed these beneficial effects evoked by hemin pretreatment in RAW264.7 cells or rats received LPS, indicating a direct involvement of PI3K/Akt pathway. Taken together, our results indicated that HO-1 activation, through PI3K/Akt pathway, plays a critical role in protecting lung from oxidative injury in the setting of sepsis by regulating MQC. HO-1 may therefore be a therapeutic target for the prevention sepsis-related lung injury.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Heme Oxigenase-1/metabolismo , Hemina/uso terapêutico , Renovação Mitocondrial/efeitos dos fármacos , Sepse/complicações , Lesão Pulmonar Aguda/etiologia , Animais , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática , Hemina/farmacologia , Lipopolissacarídeos , Pulmão/enzimologia , Masculino , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células RAW 264.7 , Ratos Sprague-Dawley , Transdução de Sinais
11.
Acta Anaesthesiol Scand ; 63(7): 905-912, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30982954

RESUMO

BACKGROUND: Tracheostomy and endotracheal intubation can result in subglottic tracheal stenosis, and predisposition to keloid scar formation can increase stenosis risk after tracheal injury. This study aims to compare the incidence and severity of subglottic tracheal stenosis in keloid and non-keloid patients following iatrogenic tracheal injury, in particular tracheostomy. METHODS: From 2012 to 2017, 218 573 patients were intubated for surgery; 2276 patients received tracheostomy in People's Hospital of Zhengzhou University, China. Among these patients, 133 patients, who developed tracheal stenosis after intubation and/or tracheostomy, were divided into keloid or non-keloid groups; their Myer and Cotton grading of tracheal stenosis, time-to-onset of airway stenosis, and treatment outcome were assessed and compared. RESULTS: The percentages of high grade (Myer and Cotton grading III/IV) tracheal stenosis were higher among keloid patients than non-keloid patients (intubation: 83.3% vs 25.7%; tracheostomy: 77.7% vs 33.3%). Time-to-onset of airway stenosis following intubation (tracheostomy) was 27 ± 5 (38 ± 13) and 41 ± 7 (82 ± 14) days for keloid and non-keloid patients, respectively (P < 0.01). The incidence of tracheal stenosis is higher in keloid than non-keloid subjects (19.4% vs 1.82%, P < 0.001). Keloid patients also required more frequent treatment (P < 0.01) of longer duration, yet cure rate was significantly lower (P < 0.01). CONCLUSIONS: Our study suggests that tracheostomized patients with keloid phenotype are more susceptibility to develop iatrogenic tracheal stenosis of greater severity and with poorer treatment outcome. Greater cautions may be required when performing tracheostomy in keloid subjects. More substantive analysis is warranted to establish keloid phenotype as a risk factor for tracheal stenosis.


Assuntos
Doença Iatrogênica/epidemiologia , Intubação Intratraqueal/efeitos adversos , Queloide/patologia , Estenose Traqueal/etiologia , Traqueostomia/efeitos adversos , Adulto , Idade de Início , Idoso , China/epidemiologia , Estudos de Coortes , Feminino , Humanos , Incidência , Queloide/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Estenose Traqueal/epidemiologia , Resultado do Tratamento
12.
J Anesth ; 33(2): 321-335, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30859366

RESUMO

General anesthetics are commonly used in major surgery. To achieve the depth of anesthesia for surgery, patients are being subjected to a variety of general anesthetics, alone or in combination. It has been long held an illusory concept that the general anesthesia is entirely reversible and that the central nervous system is returned to its pristine state once the anesthetic agent is eliminated from the active site. However, studies indicate that perturbation of the normal functioning of these targets may result in long-lasting desirable or undesirable effects. This review focuses on the impact of general anesthetic exposure to the brain and summarizes the molecular and cellular mechanisms by which general anesthetics may induce long-lasting undesirable effects when exposed at the developing stage of the brain. The vulnerability of aging brain to general anesthetics, specifically in the context of cognitive disorders and Alzheimer's disease pathogeneses are also discussed. Moreover, we will review emerging evidence regarding the neuroprotective property of xenon and anesthetic adjuvant dexmedetomidine in the immature and mature brains. In conclusion, "mixed picture" effects of general anesthetics should be well acknowledged and should be implemented into daily clinical practice for better patient outcome.


Assuntos
Anestesia Geral/métodos , Anestésicos Gerais/farmacologia , Encéfalo/efeitos dos fármacos , Fatores Etários , Idoso , Envelhecimento , Anestesia Geral/efeitos adversos , Anestésicos/farmacologia , Animais , Sistema Nervoso Central/efeitos dos fármacos , Disfunção Cognitiva/induzido quimicamente , Humanos , Síndromes Neurotóxicas/prevenção & controle
13.
J Anesth ; 33(1): 17-25, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30426213

RESUMO

BACKGROUND: Retrospective studies indicate that the use of regional anaesthesia causes a reduction in cancer recurrence after oncological surgery, which could be due to anaesthetic's negating effect on immunosuppression related to the surgical stress response. Local anaesthetics may also exert direct suppressive effects on malignant cells, an area where further investigation is urgently needed. METHODS: Human colon cancer cells and human melanoma cells were cultured and then treated with 1 mM bupivacaine or levobupivacaine for up to 24 or 48 h. Their migratory ability was measured by scratch assay, proliferation determined with Ki67 immunofluorescence staining, and apoptosis accessed with annexin V and PI staining on flow cytometry. The effects of bupivacaine and levobupivacaine on cellular signaling and molecular response, specifically, on endoplasmic reticulum stress (ERS), were studied with immunostaining and western blot. RESULTS: In colon cancer cells, treatment with bupivacaine and levobupivacaine significantly inhibited cell migration (**p < 0.01, ***p < 0.001; n = 4) and proliferation (**p < 0.01; n = 4), while increasing the expression of CHOP (***p < 0.001; n = 4) and decreased the expression of Grp78 (*p < 0.05; n = 4). These effects were not mirrored by melanoma cells, such that no significant increase in apoptosis was seen in either melanoma cell lines following treatment. CONCLUSION: These in vitro data suggested that both bupivacaine and levobupivacaine suppress colorectal adenocarcinoma cell proliferation and migration, which are concurrent with increased endoplasmic reticulum stress. Conversely, melanoma cells are more resilient to these two commonly used local anaesthetics. Further in vivo studies or clinical trials are needed.


Assuntos
Anestésicos Locais/farmacologia , Bupivacaína/farmacologia , Neoplasias do Colo/tratamento farmacológico , Levobupivacaína/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chaperona BiP do Retículo Endoplasmático , Humanos , Melanoma/tratamento farmacológico
14.
Anesthesiology ; 129(5): 1000-1014, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30157038

RESUMO

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Several factors within the perioperative period may influence postoperative metastatic spread. Dexmedetomidine and midazolam are widely used general anesthetics during surgery. The authors assessed their effects on human lung carcinoma (A549) and neuroglioma (H4) cell lines in vitro and in vivo. METHODS: Cell proliferation and migration were measured after dexmedetomidine (0.001 to 10 nM) or midazolam (0.01 to 400 µM) treatment. Expression of cell cycle and apoptosis markers were assessed by immunofluorescence. Mitochondrial membrane potential and reactive oxygen species were measured by JC-1 staining and flow cytometry. Antagonists atipamezole and flumazenil were used to study anesthetic mechanisms of action. Tumor burden after anesthetic treatment was investigated with a mouse xenograft model of lung carcinoma. RESULTS: Dexmedetomidine (1 nM) promoted cell proliferation (2.9-fold in A549 and 2-fold in H4 cells vs. vehicle, P < 0.0001; n = 6), migration (2.2-fold in A549 and 1.9-fold in H4 cells vs. vehicle, P < 0.0001; n = 6), and upregulated antiapoptotic proteins in vitro. In contrast, midazolam (400 µM) suppressed cancer cell migration (2.6-fold in A549 cells, P < 0.0001; n = 4), induced apoptosis via the intrinsic mitochondrial pathway, decreased mitochondrial membrane potential, and increased reactive oxygen species expression in vitro-effects partly attributable to peripheral benzodiazepine receptor activation. Furthermore, midazolam significantly reduced tumor burden in mice (1.7-fold vs. control; P < 0.05; n = 6 per group). CONCLUSIONS: Midazolam possesses antitumorigenic properties partly mediated by the peripheral benzodiazepine receptor, whereas dexmedetomidine promotes cancer cell survival through signaling via the α2-adrenoceptor in lung carcinoma and neuroglioma cells.


Assuntos
Neoplasias Encefálicas/metabolismo , Dexmedetomidina/farmacologia , Glioma/metabolismo , Hipnóticos e Sedativos/farmacologia , Neoplasias Pulmonares/metabolismo , Midazolam/farmacologia , Animais , Apoptose , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Modelos Animais de Doenças , Citometria de Fluxo , Imunofluorescência , Glioma/patologia , Humanos , Neoplasias Pulmonares/patologia , Camundongos
15.
Small ; 12(21): 2913-20, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27106517

RESUMO

Promoted by the localized surface plasmon resonance nanotechnology, a simple and sensitive plasmonic aptamer nanosensor (nanoaptasensor) on an individual Au@Ag core-shell nanocube (Au@Ag NC) has been proposed for real-time monitoring of the formation process of G-quadruplex structures and label-free analysis of potassium ions (K(+) ). In particular, the analysis of the thermodynamic parameters indicates that there are two types of binding states accompanied with a remarkable change of free energy (ΔG) in the sequential folding process of telomere DNA sequence. This nanoaptasensor has raised promising applications in monitoring the dynamic process of the structural switch of the G-quadruplex.


Assuntos
Técnicas Biossensoriais/métodos , Ressonância de Plasmônio de Superfície/métodos , Quadruplex G , Potássio/química , Telômero/genética , Termodinâmica
16.
Phys Chem Chem Phys ; 18(3): 2054-8, 2016 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-26687543

RESUMO

BaMnF4 microsheets have been prepared using a hydrothermal method. Strong room-temperature blue-violet photoluminescence has been observed (an absolute luminescence quantum yield of 67%) with two peaks located at 385 nm and 410 nm. More interestingly, photon self-absorption phenomenon has been observed, leading to an unusual abrupt decrease in the luminescence intensity at a wavelength of 400 nm. To understand the underlying mechanism of such emission, the electronic structure of BaMnF4 has been studied using first principles calculations. The observed two peaks are attributed to electron transitions between the upper-Hubbard bands of the Mn's t2g orbitals and the lower-Hubbard bands of the Mn's eg orbitals. The Mott gap mediated d-d orbital transitions may provide additional degrees of freedom to tune the photon generation and absorption in ferroelectrics.

17.
Zhonghua Yi Xue Za Zhi ; 95(32): 2607-11, 2015 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-26711609

RESUMO

OBJECTIVE: To investigate the expression and pathological mechanism of matrix metalloproteinase (MMP)-9 and hypoxia-inducible factor (HIF)-2α in CD133⁺ lung cancer stem cells. METHODS: Sixty-two cases of lung cancer paraffin embedding tissues were collected from the First Affiliated Hospital of Soochow University between January 2009 and December 2009. Immunohistochemistry (IHC) was used for detection of CD133 expression in lung cancer tissues and the clinical significance was analyzed. Real-time polymerase chain reaction (PCR) was used for the investigation of expression of tumor metastasis associated genes, including MMP-1, MMP-2, MMP-9, HIF-1α, HIF-1ß, HIF-2α and tissue inhibitor of metalloproteinase (TIMP)-1, TIMP-2, TIMP-3, TIMP-4. Scrambled siRNA or CD133 siRNA were used to transfect the lung cancer cell line A549, then Control-si-A549 cells and CD133-si-A549 cells were generated respectively. PCR was used to analysis CD133, MMP-9 and HIF-2α genes expression and transwell invasion assay was used to study the invasion ability of A549 cells in two groups. RESULTS: 51.6% of lung cancer tissues expressed CD133 (P<0.05); the expression level of CD133 was related to tumor metastasis and patients' survival rate (P<0.05). The gene expression of HIF-2α and MMP-9 were increased in CD133⁺ lung cancer cells compared with CD133⁻ cancer cells (1.58 ± 0.39 vs 1.10 ± 0.31, 1.67 ± 0.38 vs 1.05 ± 0.21, all P<0.05), whereas no difference was found in gene expression of MMP-1, MMP-2, HIF-1α, HIF-1ß and TIMP-1, TIMP-2, TIMP-3, TIMP-4 (all P>0.05). Compared with the Control-si-A549 cell, the expression of CD133, HIF-2α and MMP-9 (0.24 ± 0.10 vs 0.85 ± 0.23, 0.19 ± 0.09 vs 0.54 ± 0.18, 0.31 ± 0.17 vs 1.12 ± 0.31, all P<0.05) in CD133-si-A549 cell were remarkably decreased. The number of CD133-si-A549 cells migrated to below room was significantly smaller than that of Control-si-A549 cells (207 ± 25 vs 82 ± 10, P<0.05). CONCLUSIONS: The CD133⁺ lung cancer stem cell is correlated to the tumor metastasis and patients' survival. CD133⁺ tumor stem cell can promote the tumor invasion and metastasis via the up-regulation of HIF-2α and MMP-9 expression.


Assuntos
Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares , Células-Tronco Neoplásicas , Antígeno AC133 , Antígenos CD , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Expressão Gênica , Glicoproteínas , Humanos , Imuno-Histoquímica , Metaloproteinase 2 da Matriz , Metaloproteinase 9 da Matriz , Inibidores de Metaloproteinases de Matriz , Peptídeos , RNA Interferente Pequeno , Reação em Cadeia da Polimerase em Tempo Real , Regulação para Cima
18.
J Anesth ; 28(5): 740-58, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24610035

RESUMO

Inhalational anesthetics-induced organoprotection has received much research interest and has been consistently demonstrated in different models of organ damage, in particular, ischemia-reperfusion injury, which features prominently in the perioperative period and in cardiovascular events. The cellular mechanisms accountable for effective organoprotection over heart, brain, kidneys, and other vital organs have been elucidated in turn in the past two decades, including receptor stimulations, second-messenger signal relay and amplification, end-effector activation, and transcriptional modification. This review summarizes the signaling pathways and the molecular participants in inhalational anesthetics-mediated organ protection published in the current literature, comparing and contrasting the 'preconditioning' and 'postconditioning' phenomena, and the similarities and differences in mechanisms between organs. The salubrious effects of inhalational anesthetics on vital organs, if reproducible in human subjects in clinical settings, would be of exceptional clinical importance, but clinical studies with better design and execution are prerequisites for valid conclusions to be made. Xenon as the emerging inhalational anesthetic, and its organoprotective efficacy, mechanism, and relative advantages over other anesthetics, are also discussed.


Assuntos
Anestésicos Inalatórios/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Encéfalo/efeitos dos fármacos , Coração/efeitos dos fármacos , Humanos , Período Perioperatório
19.
Cell Death Discov ; 10(1): 277, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38862503

RESUMO

Hypoxic-ischaemic encephalopathy (HIE) in termed infants remains a significant cause of morbidity and mortality worldwide despite the introduction of therapeutic hypothermia. Depending on the cell type, cellular context, metabolic predisposition and insult severity, cell death in the injured immature brain can be highly heterogenous. A continuum of cell death exists in the H/I-injured immature brain. Aside from apoptosis, emerging evidence supports the pathological activation of necroptosis, pyroptosis and ferroptosis as alternative regulated cell death (RCD) in HIE to trigger neuroinflammation and metabolic disturbances in addition to cell loss. Upregulation of autophagy and mitophagy in HIE represents an intrinsic neuroprotective strategy. Molecular crosstalk between RCD pathways implies one RCD mechanism may compensate for the loss of function of another. Moreover, mitochondrion was identified as the signalling "hub" where different RCD pathways converge. The highly-orchestrated nature of RCD makes them promising therapeutic targets. Better understanding of RCD mechanisms and crosstalk between RCD subtypes likely shed light on novel therapy development for HIE. The identification of a potential RCD converging node may open up the opportunity for simultaneous and synergistic inhibition of cell death in the immature brain.

20.
PLoS One ; 19(4): e0300440, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38598505

RESUMO

The automatic detection of the degree of surface corrosion on metal structures is of significant importance for assessing structural damage and safety. To effectively identify the corrosion status on the surface of coastal metal facilities, this study proposed a CBG-YOLOv5s model for metal surface corrosion detection, based on the YOLOv5s model. Firstly, we integrated the Convolutional Block Attention Module (CBAM) into the C3 module and developed the C3CBAM module. This module effectively enhanced the channel and spatial attention capabilities of the feature map, thereby improving the feature representation. Second, we introduced a multi-scale feature fusion concept in the feature fusion part of the model and added a small target detection layer to improve small target detection. Finally, we designed a lighter C3Ghost module, which reduced the number of parameters and the computational load of the model, thereby improving the running speed of the model. In addition, to verify the effectiveness of our method, we constructed a dataset containing 6000 typical images of metal surface corrosion and conducted extensive experiments on this dataset. The results showed that compared to the YOLOv5s model and several other commonly used object detection models, our method achieved superior performance in terms of detection accuracy and speed.


Assuntos
Utensílios Domésticos , Reconhecimento Psicológico , Corrosão , Metais
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