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1.
Anesth Analg ; 133(4): 1048-1059, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34524989

RESUMO

BACKGROUND: Cardiotoxicity can be induced by the commonly used amide local anesthetic, bupivacaine. Bupivacaine can inhibit protein kinase B (AKT) phosphorylation and activated adenosine monophosphate-activated protein kinase alpha (AMPKα). It can decouple mitochondrial oxidative phosphorylation and enhance reactive oxygen species (ROS) production. Apelin enhances the phosphatidylinositol 3-kinase (PI3K)/AKT and AMPK/acetyl-CoA carboxylase (ACC) pathways, promotes the complete fatty acid oxidation in the heart, and reduces the release of ROS. In this study, we examined whether exogenous (Pyr1) apelin-13 could reverse bupivacaine-induced cardiotoxicity. METHODS: We used the bupivacaine-induced inhibition model in adult male Sprague Dawley (SD) rats (n = 48) and H9c2 cardiomyocyte cell cultures to explore the role of apelin-13 in the reversal of bupivacaine cardiotoxicity, and its possible mechanism of action. AMPKα, ACC, carnitine palmitoyl transferase (CPT), PI3K, AKT, superoxide dismutase 1 (SOD1), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (p47-phox) were quantified. Changes in mitochondrial ultrastructure were examined, and mitochondrial DNA, cell viability, ROS release, oxygen consumption rate (OCR) were determined. RESULTS: Apelin-13 reduced bupivacaine-induced mitochondrial DNA lesions in SD rats (P < .001), while increasing the expression of AMPKα (P = .007) and PI3K (P = .002). Furthermore, apelin-13 blocked bupivacaine-induced depolarization of the mitochondrial membrane potential (P = .019) and the bupivacaine-induced increases in ROS (P = .001). Also, the AMPK pathway was activated by bupivacaine as well as apelin-13 (P = .002) in H9c2 cardiomyocytes. Additionally, the reduction in the PI3K expression by bupivacaine was mitigated by apelin-13 in H9c2 cardiomyocytes (P = .001). While the aforementioned changes induced by bupivacaine were not abated by apelin-13 after pretreatment with AMPK inhibitor compound C; the bupivacaine-induced changes were still mitigated by apelin-13, even when pretreated with PI3K inhibitor-LY294002. CONCLUSIONS: Apelin-13 treatment reduced bupivacaine-induced oxidative stress, attenuated mitochondrial morphological changes and mitochondrial DNA damage, enhanced mitochondrial energy metabolism, and ultimately reversed bupivacaine-induced cardiotoxicity. Our results suggest a role for the AMPK in apelin-13 reversal of bupivacaine-induced cardiotoxicity.

2.
BMJ Open ; 11(8): e043883, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376438

RESUMO

OBJECTIVE: The transmuscular quadratus lumborum (TQL) block and the oblique subcostal transversus abdominis plane (OSTAP) block both contribute to multimodal analgesia after laparoscopic surgery. The objective of this study was to compare the analgesic effects of the TQL block versus OSTAP block after laparoscopic hysterectomy. DESIGN: Prospective single-centre randomised single-blind trial. SETTING: University-affiliated hospital. PARTICIPANTS: Patients aged between 18 and 65 years scheduled for laparoscopic hysterectomy. INTERVENTIONS: Patients were randomised into two groups (1:1 ratio) and received bilateral TQL block or bilateral OSTAP block with 0.375% ropivacaine 20 mL on each side before surgery. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome measure was the cumulative morphine dose in the first 24 hours. The secondary outcome measures were the morphine consumption at each time interval after surgery, the time from the end of surgery to the first need for morphine, the Numerical Rating Scale (NRS) scores for visceral and incisional pain intensity, and the incidence of adverse events. RESULTS: The cumulative morphine dose was significantly lower in the TQL group than in the OSTAP group (17.2 (12.5) vs 26.1 (13.3) mg, p=0.010). Compared with the OSTAP group, the morphine doses from 6 to 12, 12 to 18, and 18 to 24 hours were significantly lower, the time of first need for morphine was significantly longer and the NRS scores for visceral pain intensity were significantly lower in the TQL group. CONCLUSION: Compared with the OSTAP block, the TQL block reduced morphine consumption and provided better visceral pain relief with a longer duration of effect after laparoscopic hysterectomy. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Registry (ChiCTR1800017995); pre-results.


Assuntos
Analgesia , Laparoscopia , Músculos Abdominais , Adolescente , Adulto , Idoso , Analgésicos Opioides , Anestésicos Locais , Método Duplo-Cego , Feminino , Humanos , Histerectomia , Pessoa de Meia-Idade , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/prevenção & controle , Estudos Prospectivos , Método Simples-Cego , Adulto Jovem
3.
Ann Palliat Med ; 10(6): 6104-6111, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34044563

RESUMO

BACKGROUND: A larger volume of local anesthetic provides a wider range of blocked sensory but carries a greater risk. The purpose of this trial was to compare the effect of different volumes of ropivacaine injected to deep serratus anterior plane in patients undergoing breast surgery. METHODS: In this randomized double-blind trial, 60 patients undergoing breast surgery were randomly allocated to R10, R20 and R30 groups (n=20), and received deep serratus anterior plane block with 10, 20 and 30 mL of 0.5% ropivacaine respectively. 30 minutes after block, the cutaneous sensory was tested by cold stimulus in the craniocaudal direction along the midaxillary line. We recorded the numerical rating scale pain scores over 24 h after surgery and estimated the area under curve by numerical rating scale pain scores. The cases of rescue analgesia and the prevalence of adverse events were also recorded. RESULTS: The blocked dermatomes were 3 [3, 4], 6 [5, 7] and 7 [6, 8] in the R10, R20 and R30 groups, respectively (R10 vs. R20, P<0.001; R10 vs. R30, P<0.001; R20 vs. R30, P=0.005). The area under curve of R10 group was significantly higher compared with the R20 and R30 groups (P=0.014, P=0.003, at rest; P<0.001, P<0.001, on movement). CONCLUSIONS: The blocked dermatomes increased with increasing volume when 10, 20 and 30 mL ropivacaine was used for deep serratus anterior plane block. The analgesic effects of 20 and 30 mL were similar to each other and better than 10 mL. Therefore, in breast surgery, volume of 20 mL ropivacaine is considered to be appropriate for deep serratus anterior plane block.


Assuntos
Neoplasias da Mama , Bloqueio Nervoso , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Feminino , Humanos , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/prevenção & controle , Estudos Prospectivos , Ropivacaina
4.
Zhongguo Fei Ai Za Zhi ; 24(4): 271-278, 2021 Apr 20.
Artigo em Chinês | MEDLINE | ID: mdl-33910275

RESUMO

Hyperprogressive disease (HPD) is a novel pattern of progression caused by immune checkpoint inhibitors (ICIs). It is characterized by a dramatic tumor surge and is associated with poor clinical outcomes. Up to now, the definition of HPD is still controversial across various studies. Although it has been indicated that HPD has related to multiple clinicopathological features and genetic alterations, it is lack of biomarker to predict its occurrence, and the potential mechanism remains unknown. This review is to summarize current data on HPD specialized in the field of non-small cell lung cancer. And we expect to provide helpful clinical strategies for oncologists using ICIs.
.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Imunoterapia , Neoplasias Pulmonares/tratamento farmacológico , Animais , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Progressão da Doença , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia
5.
Arch Pharm Res ; 43(7): 744-754, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32715385

RESUMO

Ganoderic Acid A (GA) has many pharmacological effects such as anti-tumor, antibacterial, anti-inflammatory, and immunosuppressive effects. However, the protective effect of GA on liver injury has not been reported. This study aimed to investigate the action of GA on insufficient methionine and choline combined with high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) in rats. NAFLD model was established by insufficient methionine and choline combined with high fat feeding to rats. The levels of Acetyl-CoA carboxylase, fatty acid synthase, sterol regulatory element binding protein, liver X receptors, AMP-activated protein kinase, peroxisome proliferator-activated receptor α, PPARg coactivator 1α and NF-κB pathway in the liver were detected by western blot. The results of this study demonstrated that the expression of GA can not only significantly decrease the live weight and liver weight per body weight of HFD mice, but also restore the alanine aminotransferase, aspartate aminotransferase, total bilirubin levels, triglyceride and cholesterol in serum. In addition, the expression of GA increased the levels of high-density lipoprotein cholesterol in serum, ameliorated pathological changes and decreased NAS score of mice's liver. In conclusion, the treatment with GA could improve NAFLD in rats by regulating the levels of signaling events involved in free fatty acid production, lipid oxidation and liver inflammation.


Assuntos
Ácidos Heptanoicos/farmacologia , Inflamação/tratamento farmacológico , Lanosterol/análogos & derivados , Metabolismo dos Lipídeos/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Substâncias Protetoras/farmacologia , Administração Oral , Animais , Citocinas/antagonistas & inibidores , Citocinas/sangue , Citocinas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Ácidos Heptanoicos/administração & dosagem , Inflamação/induzido quimicamente , Inflamação/metabolismo , Lanosterol/administração & dosagem , Lanosterol/farmacologia , Masculino , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/metabolismo , Substâncias Protetoras/administração & dosagem , Ratos , Ratos Sprague-Dawley
6.
J Pain Res ; 13: 997-1005, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32494188

RESUMO

Purpose: Continuous femoral nerve block (cFNB) is effective for analgesia after total knee arthroplasty (TKA). However, it is not clear which low-dose regimen of ropivacaine infusion for cFNB provides adequate analgesia and enables rapid recovery. The aim of this study was to compare the effects of different cFNB regimens on rehabilitation of patients after TKA. Patients and Methods: Sixty patients scheduled for TKA were enrolled in this trial. After surgery, patients in the 0.1%, 0.15%, and 0.2% groups received infusion of 10 mL of 0.1%, 6.7 mL of 0.15%, and 5 mL of 0.2% ropivacaine per hour, respectively (n=20), at the dose of 10 mg/h for 48 h. The primary endpoint was time to readiness for discharge. The secondary endpoints were time to first walk, manual muscle testing (MMT) scores, numerical rating scale (NRS) scores at rest and movement, morphine consumption, rescue analgesia, and the incidence of adverse events. Results: The time to readiness for discharge and the time to first walk of the 0.1% group were significantly longer than that of the 0.15% and 0.2% groups. MMT scores of the 0.2% group at 18 h after surgery were significantly lower than those of the 0.1% group. MMT scores of the 0.2% group at 24 and 48 h after surgery were also significantly lower than those of the 0.1% and 0.15% groups. NRS scores at rest and at movement in the 0.1% group were significantly higher than those in the 0.15% and 0.2% groups. Conclusion: Patients administered the regimens of 0.15% and 0.2% ropivacaine infusion for cFNB were ready for discharge earlier than the 0.1% group after TKA, at the dose of 10 mg/h for 48 h. The regimen of 0.15% ropivacaine, which is associated with less quadriceps muscle strength weakness than 0.2%, is recommended for postoperative analgesia after TKA.

7.
Int Immunopharmacol ; 84: 106543, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32353688

RESUMO

This study aimed to investigate the protective effect of GanodericacidA (GA) on myocardial ischemia-reperfusion (MIR) injury. The myocardial injury model in rats was established by ligating left anterior descending coronary artery. We measured cardiac hemodynamic, antioxidant enzyme activity, and various biochemical indexes of myocardial tissue, and evaluated myocardial infarction and damage. Further, the expression of JAK2/STAT3/NF-κB signaling pathway-related proteins in myocardial tissue was measured by western blot. The results showed that the myocardial infarction extention was obviously reduced upon GA treatment. Compared with the control group, ischemia-reperfusion rats showed significant increase in lactate dehydrogenase (LDH) and creatine Kinase (CK), which were significantly decreased in GA group. Besides, GA pretreatment effectively decreased the levels of inflammatory cytokines in serum. The phosphorylation of Janus Kinase 2 (JAK2), signal transducer and activator of transcription (STAT3)and Nuclear factor-κB (NF-κB) in reperfusion group were significantly higher than that in control group, which were reversed upon GA treatment. In conclusion, GA may reduce myocardial injury by regulating JAK2/STAT3/NF-κB pathway.


Assuntos
Ácidos Heptanoicos/uso terapêutico , Janus Quinase 2/metabolismo , Lanosterol/análogos & derivados , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , NF-kappa B/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Citocinas/sangue , Ácidos Heptanoicos/farmacologia , Lanosterol/farmacologia , Lanosterol/uso terapêutico , Masculino , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologia , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos
8.
Biomed Res Int ; 2020: 8959210, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32258155

RESUMO

Purposes: Cervical cancer (CC) is one of the highest frequently occurred malignant gynecological tumors with high rates of morbidity and mortality. Here, we aimed to identify significant genes associated with poor outcome. Materials and methods. Differentially expressed genes (DEGs) between CC tissues and normal cervical tissues were picked out by GEO2R tool and Venn diagram software. Database for Annotation, Visualization and Integrated Discovery (DAVID) was performed to analyze gene ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway. The protein-protein interactions (PPIs) of these DEGs were visualized by Cytoscape with Search Tool for the Retrieval of Interacting Genes (STRING). Afterwards, Kaplan-Meier analysis was applied to analyze the overall survival among these genes. The Gene Expression Profiling Interactive Analysis (GEPIA) was applied for further validation of the expression level of these genes. Results: The mRNA expression profile datasets of GSE63514, GSE27678, and GSE6791 were downloaded from the Gene Expression Omnibus database (GEO). In total, 76 CC tissues and 35 normal tissues were collected in the three profile datasets. There were totally 73 consistently expressed genes in the three datasets, including 65 up-regulated genes and 8 down-regulated genes. Of PPI network analyzed by Molecular Complex Detection (MCODE) plug-in, all 65 up-regulated genes and 4 down-regulated genes were selected. The results of the Kaplan-Meier survival analysis showed that 3 of the 65 up-regulated genes had a significantly worse prognosis, while 3 of the 4 down-regulated genes had a significantly better outcome. For validation in GEPIA, 4 of 6 genes (PLOD2, ANLN, AURKA, and AR) were confirmed to be significantly deregulated in CC tissues compared to normal tissues. Conclusion: We have identified three up-regulated (PLOD2, ANLN, and AURKA) and a down-regulated DEGs (AR) with poor prognosis in CC on the basis of integrated bioinformatical methods, which could be regarded as potential therapeutic targets for CC patients.


Assuntos
Biologia Computacional , Bases de Dados Genéticas , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Software , Neoplasias do Colo do Útero , Intervalo Livre de Doença , Feminino , Humanos , Taxa de Sobrevida , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/mortalidade
9.
Theranostics ; 10(8): 3793-3815, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32206123

RESUMO

Magnetic hyperthermia (MH) has been introduced clinically as an alternative approach for the focal treatment of tumors. MH utilizes the heat generated by the magnetic nanoparticles (MNPs) when subjected to an alternating magnetic field (AMF). It has become an important topic in the nanomedical field due to their multitudes of advantages towards effective antitumor therapy such as high biosafety, deep tissue penetration, and targeted selective tumor killing. However, in order for MH to progress and to realize its paramount potential as an alternative choice for cancer treatment, tremendous challenges have to be overcome. Thus, the efficiency of MH therapy needs enhancement. In its recent 60-year of history, the field of MH has focused primarily on heating using MNPs for therapeutic applications. Increasing the thermal conversion efficiency of MNPs is the fundamental strategy for improving therapeutic efficacy. Recently, emerging experimental evidence indicates that MNPs-MH produces nano-scale heat effects without macroscopic temperature rise. A deep understanding of the effect of this localized induction heat for the destruction of subcellular/cellular structures further supports the efficacy of MH in improving therapeutic therapy. In this review, the currently available strategies for improving the antitumor therapeutic efficacy of MNPs-MH will be discussed. Firstly, the recent advancements in engineering MNP size, composition, shape, and surface to significantly improve their energy dissipation rates will be explored. Secondly, the latest studies depicting the effect of local induction heat for selectively disrupting cells/intracellular structures will be examined. Thirdly, strategies to enhance the therapeutics by combining MH therapy with chemotherapy, radiotherapy, immunotherapy, photothermal/photodynamic therapy (PDT), and gene therapy will be reviewed. Lastly, the prospect and significant challenges in MH-based antitumor therapy will be discussed. This review is to provide a comprehensive understanding of MH for improving antitumor therapeutic efficacy, which would be of utmost benefit towards guiding the users and for the future development of MNPs-MH towards successful application in medicine.


Assuntos
Hipertermia Induzida/métodos , Nanopartículas de Magnetita , Neoplasias/terapia , Animais , Fenômenos Químicos , Terapia Combinada/métodos , Quimioterapia Combinada , Humanos , Nanopartículas de Magnetita/química , Nanopartículas de Magnetita/uso terapêutico , Camundongos
10.
J Pain Res ; 13: 57-64, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32021395

RESUMO

Purpose: Serratus anterior plane (SAP) block is effective for analgesia after breast surgery. Whether a higher local anesthetic concentration prolongs sensory block duration and improves postoperative analgesia remains unclear. The aim of this study was to compare the analgesic effects of SAP block with different concentrations of ropivacaine. Patients and Methods: Sixty patients scheduled for breast surgery were enrolled in this randomized double-blind trial. SAP block was induced with 20 mL of 0.375%, 0.5%, or 0.75% ropivacaine in Group R0.375, Group R0.5, and Group R0.75, respectively. The primary endpoint was the area under the curve (AUC) of numerical rating scale (NRS) pain intensity scores at rest over time. The secondary endpoints were AUC of NRS pain intensity scores on movement over time, active sensory block duration, tramadol consumption, and the elapsed time between completion of surgery and the first administration of rescue analgesia. Results: The AUC of NRS pain intensity scores at rest of Group R0.375 was significantly higher than that of Groups R0.5 and R0.75 (P=0.025, and P=0.001). The AUC of NRS pain intensity scores on movement of Group R0.375 was also significantly higher than that of Groups R0.5 and R0.75 (both P<0.001). At higher ropivacaine concentrations, the duration of SAP sensory block increased (P<0.001). Tramadol consumption and the elapsed time between completion of surgery and the first administration of rescue analgesia were similar in the three groups (P>0.05). Conclusion: A comparison of 0.5% and 0.75% ropivacaine showed no significant difference in postoperative analgesia, but both were superior to 0.375% ropivacaine, although higher ropivacaine concentration lengthened the duration of SAP block. Therefore, SAP block with 0.5% ropivacaine is recommended for postoperative analgesia in breast surgery.

11.
Exp Cell Res ; 389(1): 111879, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32017928

RESUMO

Coordinated regulation of autophagy and apoptosis helps to enhance the antitumor effects of sodium selenite. However, the potential molecules that act as switch nodes in the crosstalk between autophagy and apoptosis is still elusive. Phospholipid scramblase 1 (PLSCR1) has been shown to regulate leukocyte differentiation, while its role in autophagy/apoptosis toggle switch remains unexplored. In this study, we showed that sodium selenite switched protective autophagy to apoptosis in p53-wild type NB4 cells without obvious caspase-8/apoptosis-inducing factor (AIF) axis activation, while induced autophagy-dependent caspase-8/AIF axis activation in p53-mutant Jurkat cells. Additionally, p53 was demonstrated as a positive regulator of PLSCR1. p53-dependent up-regulation of PLSCR1 accounted for the differential regulation of autophagy and apoptosis induced by sodium selenite. Furthermore, sodium selenite induced the release of AIF from mitochondria to cytosol with the facilitation of caspase-8 in Jurkat cells, while not in NB4 cells. The released AIF further enhanced autophagy flux through interacting with PLSCR1, which hereby resulting in the disassociation of PLSCR1 from Atg5-Atg12 complex. Our results indicate that PLSCR1 plays a critical role in p53-dependent regulation of autophagy and apoptosis in sodium selenite-treated leukemia cells. Manipulation of p53-PLSCR1 cascade might be beneficial to enhance the anti-tumor effects of sodium selenite.


Assuntos
Apoptose , Autofagia , Leucemia/patologia , Proteínas de Transferência de Fosfolipídeos/genética , Selenito de Sódio/farmacologia , Proteína Supressora de Tumor p53/fisiologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Autofagia/efeitos dos fármacos , Autofagia/genética , Linhagem Celular Tumoral , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Células Jurkat , Leucemia/genética , Camundongos
12.
ACS Nano ; 14(2): 1936-1950, 2020 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-31961656

RESUMO

In this study, a magnetothermodynamic (MTD) therapy is introduced as an efficient systemic cancer treatment, by combining the magnetothermal effect and the reactive oxygen species (ROS)-related immunologic effect, in order to overcome the obstacle of limited therapeutic efficacy in current magnetothermal therapy (MTT). This approach was achieved by the development of an elaborate ferrimagnetic vortex-domain iron oxide nanoring and graphene oxide (FVIOs-GO) hybrid nanoparticle as the efficient MTD agent. Such a FVIOs-GO nanoplatform was shown to have high thermal conversion efficiency, and it was further proved to generate a significantly amplified ROS level under an alternating magnetic field (AMF). Both in vitro and in vivo results revealed that amplified ROS generation was the dominant factor in provoking a strong immune response at a physiological tolerable temperature below 40 °C in a hypoxic tumor microenvironment. This was supported by the exposure of calreticulin (CRT) on 83% of the 4T1 breast cancer cell surface, direct promotion of macrophage polarization to pro-inflammatory M1 phenotypes, and further elevation of tumor-infiltrating T lymphocytes. As a result of the dual action of magnetothermal effect and ROS-related immunologic effect, impressive in vivo systemic therapeutic efficacy was attained at a low dosage of 3 mg Fe/kg with two AMF treatments, as compared to that of MTT (high dosage of 6-18 mg/kg under four to eight AMF treatments). The MTD therapy reported here has highlighted the inadequacy of conventional MTT that solely relies on the heating effect of the MNPs. Thus, by employing a ROS-mediated immunologic effect, future cancer magnetotherapies can be designed with greatly improved antitumor capabilities.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/terapia , Compostos Férricos/farmacologia , Grafite/farmacologia , Nanopartículas/química , Espécies Reativas de Oxigênio/imunologia , Termodinâmica , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/imunologia , Linhagem Celular Tumoral , Feminino , Compostos Férricos/administração & dosagem , Compostos Férricos/química , Grafite/administração & dosagem , Grafite/química , Campos Magnéticos , Camundongos , Camundongos Endogâmicos BALB C , Tamanho da Partícula , Células RAW 264.7 , Ratos , Ratos Sprague-Dawley , Propriedades de Superfície , Microambiente Tumoral/efeitos dos fármacos
13.
Sci Adv ; 5(9): eaax0937, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31523712

RESUMO

Carbonic anhydrase (CA) IX overexpresses exclusively on cell membranes of hypoxic tumors, regulating the acidic tumor microenvironment. Small molecules of CA inhibitor modified with short peptide successfully achieve CA IX-targeted self-assembly that localizes CA inhibitors on hypoxic cancer cell surfaces and enhances their inhibition efficacy and selectivity. CA IX-related endocytosis also promotes selective intracellular uptake of these nanofibers under hypoxia, in which nanofiber structures increase in size with decreasing pH. This effect subsequently causes intracellular acid vesicle damage and blocks protective autophagy. The versatility of tunable nanostructures responding to cell milieu impressively provokes selective toxicities and provides strategic therapy for hypoxic tumors. Moreover, in vivo tests demonstrate considerable antimetastatic and antiangiogenesis effects in breast tumors, and particularly remarkable enhancement of antitumor efficacy in doxorubicin administration. With its biocompatible components and distinctive hypoxia therapies, this nanomaterial advances current chemotherapy, providing a new direction for hypoxic cancer therapy.


Assuntos
Neoplasias da Mama , Inibidores da Anidrase Carbônica , Doxorrubicina , Nanofibras , Peptídeos , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Doxorrubicina/química , Doxorrubicina/farmacologia , Feminino , Humanos , Camundongos , Camundongos Nus , Nanofibras/química , Nanofibras/uso terapêutico , Peptídeos/química , Peptídeos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Anesth Analg ; 128(2): 256-263, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30113398

RESUMO

BACKGROUND: It is currently unknown whether bupivacaine-induced asystole is better resuscitated with lipid emulsion (LE) administered peripherally or centrally, and whether different LE regimens administered peripherally demonstrated similar effects. In this study, we compared the effects of various regimens of lipid administration in a rat model of bupivacaine-induced asystole. METHODS: Forty-five adult male Sprague-Dawley rats were subjected to bupivacaine-induced asystole and randomly divided into 3 lipid regimens groups: (1) 20% LE was administered continuously via the internal jugular vein (CV-infusion group); (2) 20% LE was administered continuously via the tail vein (PV-infusion group); and (3) 20% LE was administered as divided boluses via the tail vein (PV-bolus group). The maximum dose of LE did not exceed 10 mL·kg(-1). External chest compressions were administered until the return of spontaneous circulation (ROSC) or the end of a 40-minute resuscitation period. RESULTS: The survival rate, rate of ROSC, systolic blood pressure, heart rate, heart rate-blood pressure product, and coronary perfusion pressure during 2-40 minutes in the CV-infusion and PV-bolus groups were significantly higher than those in the PV-infusion group (P < .01), and the plasma total bupivacaine concentration and myocardial bupivacaine content were significantly lower (P < .05). Time to heartbeat return and time to ROSC in the CV-infusion and PV-bolus groups were significantly shorter than those in the PV-infusion group (P < .05). CONCLUSIONS: In the rat model of bupivacaine-induced asystole, a divided LE bolus regimen administered peripherally provided a better resuscitation outcome than that of a continuous LE infusion regimen peripherally, and performed in a similar fashion as the continuous LE infusion regimen administered centrally.


Assuntos
Anestésicos Locais/toxicidade , Bupivacaína/toxicidade , Modelos Animais de Doenças , Emulsões Gordurosas Intravenosas/administração & dosagem , Parada Cardíaca/induzido quimicamente , Parada Cardíaca/tratamento farmacológico , Animais , Parada Cardíaca/fisiopatologia , Infusões Intravenosas , Injeções Intravenosas , Masculino , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
15.
BMC Anesthesiol ; 18(1): 174, 2018 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-30458723

RESUMO

BACKGROUND: Successful resuscitation from asystole induced by bupivacaine requires the reestablishment of a sufficient coronary flow (CF) quickly. This study was designed to test whether levosimendan was superior to epinephrine in the reestablishment of crucial coronary flows after bupivacaine-induced asystole. METHODS: The isolated, perfused, nonrecirculating, Langendorff rat heart preparation was used. Bupivacaine 100 µmol/L was perfused into rat hearts to induce asystole, and then for 3 min thereafter. Three experimental groups were assessed after asystole with infusions as follow: (1) a mixture of 2% lipid emulsion and 40 µmol/L bupivacaine (control group), (2) a mixture of 0.15 µg/mL epinephrine combined with 2% lipid emulsion and 40 µmol/L bupivacaine (epinephrine group), and (3) a mixture of 5 µmol/L levosimendan combined with a 2% lipid emulsion and 40 µmol/L bupivacaine mixture (levosimendan group). Coronary flow (CF), the time to recovery (Trecovery), the number of ventricular arrhythmias, and cardiac function parameters were recorded for 40 min after heartbeat recovery. RESULTS: All hearts in the control, epinephrine and levosimendan groups had heartbeat recovery. The rank order of the mean CF from highest to lowest was the levosimendan group > the epinepgrine group > the control group (P < 0.05). The rank order of Trecovery from shortest to longest was the levosimendan group < the epinephrine group < the control group (P < 0.01). During the recovery phase, isolated rat hearts developed more ventricular arrhythmias in the epinephrine group than in the levosimendan group (P = 0.01). CONCLUSION: Levosimendan is superior to epinephrine in producing higher CFs and faster recovery when reversing bupivacaine-induced asystole in the isolated rat hearts.


Assuntos
Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Bupivacaína/administração & dosagem , Epinefrina/administração & dosagem , Emulsões Gordurosas Intravenosas/administração & dosagem , Parada Cardíaca/tratamento farmacológico , Simendana/administração & dosagem , Anestésicos Locais/administração & dosagem , Animais , Circulação Coronária/efeitos dos fármacos , Quimioterapia Combinada , Parada Cardíaca/fisiopatologia , Preparação de Coração Isolado/métodos , Masculino , Ratos , Ratos Sprague-Dawley , Ressuscitação/métodos
16.
Clin Ther ; 40(6): 1014-1022, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29793698

RESUMO

PURPOSE: This study tested the hypothesis that ultrasound-guided mid-forearm nerve block with 0.75% ropivacaine reduces the prevalence of moderate to severe pain after wrist and hand surgery, and provides prolonged postoperative analgesia with minimal motor blockade. METHODS: Thirty patients undergoing elective wrist and hand surgery were randomly assigned to 1 of 2 groups: group R (n = 15) and group NS (n = 15). We combined an ultrasound-guided supraclavicular brachial plexus block with mid-forearm median, radial, and ulnar nerve block in all patients. The supraclavicular brachial plexus was blocked with 20 mL of 1.5% lidocaine, and the mid-forearm nerves were blocked with 15 mL of either 0.75% ropivacaine (group R) or normal saline (5 mL each nerve) (group NS). A blinded observer provided a numeric rating pain score at 1, 2, 6, 12, 24, and 48 hours after surgery. The durations of sensory and motor blockade, patient satisfaction, morphine requirement for postoperative pain rescue, and adverse events were recorded. FINDINGS: The prevalence of moderate to severe pain in group R was significantly lower than that in group NS (33% vs 86%; P = 0.008). The highest mean (SD) numeric rating pain score (worst pain) in group R was lower than that in group NS (2.7 [1.9] vs 5.6 [2.9]; P = 0.004), and the median (Q1, Q3) amount of morphine required for postoperative pain rescue in group R was lower than that in group NS (0 [0, 6] vs 8 [6, 10]; P = 0.001]. Additionally, there were no differences in the durations of motor blockade between the 2 groups. IMPLICATIONS: Based on the findings from this study, ultrasound-guided mid-forearm nerve block with 0.75% ropivacaine significantly reduces the prevalence of moderate to severe pain after wrist and hand surgery, provides long-term postoperative analgesia, and facilitates the return of motor function in the upper limb. Chinese Clinical Trial Registry identifier: ChiCTR-IOR-15007278 (October 2015).


Assuntos
Anestésicos Locais/administração & dosagem , Mãos/cirurgia , Dor Pós-Operatória/tratamento farmacológico , Ropivacaina/administração & dosagem , Ultrassonografia , Adulto , Bloqueio do Plexo Braquial , Método Duplo-Cego , Feminino , Antebraço/diagnóstico por imagem , Humanos , Lidocaína/administração & dosagem , Masculino , Pessoa de Meia-Idade , Medição da Dor , Satisfação do Paciente
17.
Reg Anesth Pain Med ; 43(2): 174-179, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29278604

RESUMO

BACKGROUND AND OBJECTIVES: The analgesic effect and duration of a transversus abdominis plane (TAP) block remain controversial. Transversus abdominis plane blocks are effective for somatic/incisional pain but do not provide analgesia for visceral pain from intra-abdominal procedures. The purpose of this study was to assess the area and extent of cutaneous sensory blockade and the regression of dermatomal anesthesia after bilateral oblique subcostal TAP block. METHODS: This observational, prospective clinical study consisted of 12 healthy volunteers. All volunteers received a bilateral oblique subcostal TAP block under real-time ultrasound guidance with 20 mL of 0.375% ropivacaine. The anterior abdominal cutaneous area was divided into 3 parts (midabdomen, left-lateral abdomen, right-lateral abdomen) using 2 lines drawn in a parasagittal fashion 5 cm lateral to the midline. The area of cutaneous sensory blockade involving the anterior abdomen was assessed 30 minutes after institution of the block using a cold stimulus. This was followed by repeated measurements using a cold stimulus applied along parasagittal lines drawn 3 cm lateral to the midline at 0.5, 6, 10, 14, 18, 22, and 26 hours after blockade. RESULTS: The area of cutaneous sensory blockade of the abdomen was 332 (SD, 73) cm; that of the midabdomen was 253 (SD, 29) cm, which represented an average of 90% of the area of the midabdomen; and that of the lateral abdominal wall (combination of left-lateral abdomen and right-lateral abdomen) was 79 (SD, 62) cm, which represented an average of 26% of total lateral abdominal area. Dermatomes T7-T12 of the midabdomen were successfully blocked in all volunteers after using the bilateral oblique subcostal technique. However, T6 and L1 were only variably blocked. The area of cutaneous sensory block of the anterior abdomen regressed over the ensuing 22 hours in the following manner: 90%, 87%, 73%, 50%, 22%, 3%, and 0% at 0.5, 6, 10, 14, 18, 22, and 26 hours, respectively. CONCLUSIONS: Bilateral oblique subcostal TAP block produces a widespread cutaneous sensory blockade with a consistent dermatomal distribution in the midabdomen for a considerable effective duration.


Assuntos
Músculos Abdominais/inervação , Amidas/administração & dosagem , Anestésicos Locais/administração & dosagem , Bloqueio Nervoso/métodos , Limiar da Dor/efeitos dos fármacos , Pele/inervação , Músculos Abdominais/diagnóstico por imagem , Adulto , Amidas/efeitos adversos , Anestésicos Locais/efeitos adversos , China , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Bloqueio Nervoso/efeitos adversos , Manejo da Dor , Estudos Prospectivos , Recuperação de Função Fisiológica , Ropivacaina , Fatores de Tempo , Ultrassonografia de Intervenção
18.
Anesth Analg ; 123(5): 1116-1122, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27224931

RESUMO

BACKGROUND: Lipid infusions have been proposed to treat local anesthetic-induced cardiac toxicity. This study compared the effects of long-chain triglyceride (LCT) emulsions with those of long- and medium-chain triglyceride (LCT/MCT) emulsions on the pharmacokinetics of bupivacaine in a rat model. METHODS: After administration of intravenous infusion of bupivacaine at 2 mg·kg·min for 5 minutes in Sprague-Dawley (SD) rats, either Intralipid 20%, an LCT emulsion (LCT group, n = 6), or Lipovenoes 20%, an LCT/MCT emulsion (LCT/MCT group, n = 6), was infused at 2mg·kg·min for 5 minutes. The concentrations of total plasma bupivacaine and bupivacaine that were not bound by lipid (lipid unbound) were measured by a liquid chromatography-tandem mass spectrometric method. A 2-compartmental analysis was performed to calculate the lipid-bound percentage of bupivacaine and its pharmacokinetics. RESULTS: In the LCT group, the clearance (15 ± 2 vs 10 ± 1 mL·min·kg, P = .003) was higher; the volume of distribution (0.57 ± 0.10 vs 0.36 ± 0.11 L·kg, P = .007) and K21 (0.0100 ± 0.0018 vs 0.0070 ± 0.0020 min, P = .021, P' = .032) were larger; and the area under the blood concentration-time curve 0 - t; (605 ± 82 vs 867 ± 110 mgL·min, P =.001) and the area under the blood concentration-time curve (0 - ∞) (697 ± 111 vs 991 ± 121 mgL·min, P =.001) were less, when compared with the LCT/MCT group. CONCLUSIONS: LCT emulsions are more effective than LCT/MCT emulsions in the metabolism of bupivacaine through demonstration of a superior pharmacokinetic profile.


Assuntos
Anestésicos Locais/farmacocinética , Bupivacaína/farmacocinética , Emulsões Gordurosas Intravenosas/farmacocinética , Triglicerídeos/farmacocinética , Anestésicos Locais/administração & dosagem , Anestésicos Locais/sangue , Animais , Bupivacaína/administração & dosagem , Bupivacaína/sangue , Emulsões/administração & dosagem , Emulsões/farmacocinética , Emulsões Gordurosas Intravenosas/administração & dosagem , Infusões Intravenosas , Fosfolipídeos/administração & dosagem , Fosfolipídeos/sangue , Fosfolipídeos/farmacocinética , Ratos , Ratos Sprague-Dawley , Óleo de Soja/administração & dosagem , Óleo de Soja/sangue , Óleo de Soja/farmacocinética , Triglicerídeos/administração & dosagem , Triglicerídeos/sangue
19.
J Orthop Translat ; 7: 1-6, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30035083

RESUMO

Background/Objective: Asporin is associated with osteoarthritis and lumbar disk degeneration. Previous studies in chondrocytes showed that asporin can bind to transforming growth factor-ß1 (TGF-ß1) and downregulate matrix biosynthesis. However, this has not been studied in intervertebral disk (IVD) cells. This study aimed to inspect the expression of asporin under TGF-ß1 stimulation and its effect on TGF-ß1-induced matrix biosynthesis in human intervertebral annulus cells. Methods: Human intervertebral annulus cells were obtained from the pathological region of IVD in eight patients. After primary culture and redifferentiation in alginate beads, cells were reseeded and treated with different concentrations (5 ng/mL, 10 ng/mL, and 15 ng/mL) of TGF-ß1 for up to 24 hours. Total RNA extracted from the cells and those with asporin knockdown were subjected to real-time polymerase chain reaction analysis to examine the expression of asporin and extracellular matrix genes. Results: TGF-ß1 stimulation induces asporin transcription significantly in a dose- and time-dependent manner. Knockdown of endogenous asporin leads to the upregulated expression of collagen II alpha 1 and aggrecan. Conclusion: Our results have verified a functional feedback loop between TGF-ß1 and asporin in human intervertebral annulus cells indicating that TGF-ß1-induced annulus matrix biosynthesis can be significantly upregulated by knockdown of asporin. Therefore, asporin could be a potential new therapeutic target and inhibition of asporin could be adopted to enhance the anabolic effect of TGF-ß1 in human intervertebral annulus cells in degenerative IVD diseases.

20.
Oncol Rep ; 35(3): 1255-64, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26676801

RESUMO

In the present study, we aimed to investigate the relationship between autophagy and apoptosis in selenite­treated colorectal cancer (CRC) cells. The effects of selenite on HCT116 and SW480 cell apoptosis were investigated with an Annexin V/propidium iodide (PI) double staining kit by flow cytometry. The punctate of LC3 protein following treatment with selenite was observed by a laser scanning confocal microscope and by transmission electron microscopy. Using western blot assays, we detected the apoptotic and autophagic markers in both CRC cells and mouse xenograft tumor models. We found that sodium selenite induced autophagy in the two CRC cell lines. Consistent with the in vitro results, we observed that the expression of autophagy marker LC3 was increased. Finally, we discovered that modulation of reactive oxygen species by MnTMPyP inhibited autophagy, while H2O2 activated autophagy. These results help to elucidate the anticancer effect of selenium, providing further evidence to exploit novel anticancer drugs targeting selenium.


Assuntos
Autofagia/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Proteínas Associadas aos Microtúbulos/biossíntese , Selenito de Sódio/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Autofagia/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Humanos , Peróxido de Hidrogênio/administração & dosagem , Camundongos , Proteínas Associadas aos Microtúbulos/genética , Espécies Reativas de Oxigênio/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
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