Changes in the tumor necrosis factor-α level after an ultrasound-guided femoral nerve block in elderly patients with a hip fracture / Alterações no nível de TNF-α após bloqueio do nervo femoral guiado por ultrassom em idosos com fratura de quadril

Abstract Background and objectives: An ultrasound guided femoral nerve block is an established analgesic method in patients with a hip fracture. Elevated cytokine levels correlate with poor patient outcomes after surgery. Hence, the aim of the study was to describe the levels of tumor necrosis factor-α after an ultrasound-guided femoral nerve block in elderly patients having a femoral neck fracture. Methods: A total of 32 patients were allocated into two treatment groups: 16 patients (femoral nerve block group; ultrasound-guided femoral nerve block with up to 20 mL of 0.3 mL.kg−1 of 0.5% bupivacaine and intravenous tramadol) and 16 patients (standard management group; up to 3 mL of 0.9% saline in the femoral sheath and intravenous tramadol). Tumor necrosis factor-α and visual analogue scale scores were evaluated immediately before the femoral nerve block and again at 4, 24, and 48 h after the femoral nerve block. All surgery was performed electively after 48 h of femoral nerve block. Results: The femoral nerve block group had a significantly lower mean tumor necrosis factor-α level at 24 (4.60 vs. 8.14, p < 0.001) and 48 h (5.05 vs. 8.56, p < 0.001) after the femoral nerve block, compared to the standard management group. The femoral nerve block group showed a significantly lower mean visual analogue scale score at 4 (3.63 vs. 7.06, p < 0.001) and 24 h (4.50 vs. 5.75, p < 0.001) after the femoral nerve block, compared to the standard management group. Conclusions: Ultrasound-guided femoral nerve block using 0.3 mL.kg−1 of 0.5% bupivacaine up to a maximum of 20 mL resulted in a significant lower tumor necrosis factor-α level.

Resumo Justificativa e objetivos: O bloqueio do nervo femoral guiado por ultrassom é um método analgésico estabelecido em pacientes com fratura de quadril. Níveis elevados de citocinas estão correlacionados com resultados desfavoráveis para o paciente após a cirurgia. Portanto, o objetivo do estudo foi descrever os níveis do fator de necrose tumoral alfa após bloqueio do nervo femoral guiado por ultrassom em pacientes idosos com fratura do colo de fêmur. Métodos: No total, 32 pacientes foram alocados em dois grupos de tratamento: 16 pacientes (grupo bloqueio do nervo femoral; bloqueio do nervo femoral guiado por ultrassom com até 20 mL de bupivacaína a 0,5% (0,3 mL.kg−1) e tramadol intravenoso) e 16 pacientes (grupo tratamento padrão, até 3 mL de solução salina a 0,9% na bainha femoral e tramadol intravenoso). Os escores do fator de necrose tumoral alfa e da Escala Visual Analógica foram avaliados imediatamente antes do bloqueio do nervo femoral e novamente em 4, 24 e 48 horas pós-bloqueio do nervo femoral. Todas as cirurgias foram realizadas de forma eletiva após 48 horas de bloqueio do nervo femoral. Resultados: O grupo bloqueio do nervo femoral teve um nível médio de fator de necrose tumoral alfa significativamente menor em 24 (4,60 vs. 8,14, p < 0,001) e 48 horas (5,05 vs. 8,56, p < 0,001) pós-bloqueio do nervo femoral, comparado com o grupo tratamento padrão. O grupo bloqueio do nervo femoral apresentou uma média significativamente menor no escore da Escala Visual Analógica em 4 (3,63 vs. 7,06, p < 0,001) e 24 horas (4,50 vs. 5,75, p < 0,001) pós-bloqueio do nervo femoral, em comparação com o grupo tratamento padrão. Conclusões: O bloqueio do nervo femoral guiado por ultrassom utilizando 0,3 mL.kg−1 de bupivacaína a 0,5% até o máximo de 20 mL resultou em um nível significativamente menor de fator de necrose tumoral alfa.

Effect of anthracycline and taxane on the expression of programmed cell death ligand-1 and galectin-9 in triple-negative breast cancer.

This study identified chemotherapeutic agents that up-regulate programmed cell death ligand-1 (PD-L1) and galectin-9 (Gal-9) in breast cancer cells. Immunohistochemical (IHC) staining was used to evaluate changes in PD-L1 and Gal-9 expression in the tumor tissue of triple-negative breast cancer (TNBC) patients who received anthracycline- and taxane-based neoadjuvant chemotherapy. To determine whether PD-L1 and Gal-9 expression changes were attributable directly to chemotherapeutics, MDA-MB-231 cells and HS578T cells were treated with different concentrations of anthracycline and taxane. Expression levels of PD-L1 and Gal-9 were evaluated and the activation status of NFκB in MDA-MB-231 and HS578T cells was determined to identify the PD-L1 and Gal-9 up-regulation mechanism. Three cases of increased PD-L1 expression and two of increased Gal-9 expression were observed among the TNBC patients. PD-L1 and Gal-9 expression were up-regulated by anthracycline and taxane in MDA-MB-231 cells, but not in HS578T cells. Increased nuclear levels of NFκB were observed in MDA-MB-231 cells treated with 0.5 µM epirubicin. Anthracycline and taxane up-regulated PD-L1 and Gal-9 expression in some subtypes of TNBC. This study provides useful reference data for clinical trials investigating combination treatments with immune checkpoint inhibitors and chemotherapy.

[Changes in the tumor necrosis factor-α level after an ultrasound-guided femoral nerve block in elderly patients with a hip fracture]. / Alterações no nível de TNF­α após bloqueio do nervo femoral guiado por ultrassom em idosos com fratura de quadril.

BACKGROUND AND OBJECTIVES: An ultrasound guided femoral nerve block is an established analgesic method in patients with a hip fracture. Elevated cytokine levels correlate with poor patient outcomes after surgery. Hence, the aim of the study was to describe the levels of tumor necrosis factor-α after an ultrasound-guided femoral nerve block in elderly patients having a femoral neck fracture. METHODS: A total of 32 patients were allocated into two treatment groups: 16 patients (femoral nerve block group; ultrasound-guided femoral nerve block with up to 20mL of 0.3mL.kg-1 of 0.5% bupivacaine and intravenous tramadol) and 16 patients (standard management group; up to 3mL of 0.9% saline in the femoral sheath and intravenous tramadol). Tumor necrosis factor-α and visual analogue scale scores were evaluated immediately before the femoral nerve block and again at 4, 24, and 48h after the femoral nerve block. All surgery was performed electively after 48h of femoral nerve block. RESULTS: The femoral nerve block group had a significantly lower mean tumor necrosis factor-α level at 24 (4.60 vs. 8.14, p<0.001) and 48h (5.05 vs. 8.56, p<0.001) after the femoral nerve block, compared to the standard management group. The femoral nerve block group showed a significantly lower mean visual analogue scale score at 4 (3.63 vs. 7.06, p<0.001) and 24h (4.50 vs. 5.75, p<0.001) after the femoral nerve block, compared to the standard management group. CONCLUSIONS: Ultrasound-guided femoral nerve block using 0.3mL.kg-1 of 0.5% bupivacaine up to a maximum of 20mL resulted in a significant lower tumor necrosis factor-α level.

A PI3K p110α-selective inhibitor enhances the efficacy of anti-HER2/neu antibody therapy against breast cancer in mice.

Combination therapies with phosphoinositide 3-kinase (PI3K) inhibitors and trastuzumab (anti-human epidermal growth factor receptor [HER]2/neu antibody) are effective against HER2+ breast cancer. Isoform-selective PI3K inhibitors elicit anti-tumor immune responses that are distinct from those induced by inhibitors of class I PI3K isoforms (pan-PI3K inhibitors). The present study investigated the therapeutic effect and potential for stimulating anti-tumor immunity of combined therapy with an anti-HER2/neu antibody and pan-PI3K inhibitor (GDC-0941) or a PI3K p110α isoform-selective inhibitor (A66) in mouse models of breast cancer. The anti-neu antibody inhibited tumor growth and enhanced anti-tumor immunity in HER2/neu+ breast cancer TUBO models, whereas GDC-0941 or A66 alone did not. Anti-neu antibody and PI3K inhibitor synergistically promoted anti-tumor immunity by increasing functional T cell production. In the presence of the anti-neu antibody, A66 was more effective than GDC-0941 at increasing the fraction of CD4+, CD8+, and IFN-γ+CD8+ T cells in the tumor-infiltrating lymphocyte population. Detection of IFN-γ levels by enzyme-linked immunospot assay showed that the numbers of tumor-specific T cells against neu and non-neu tumor antigens were increased by combined PI3K inhibitor plus anti-neu antibody treatment, with A66 exhibiting more potent effects than GDC-0941. In a TUBO (neu+) and TUBO-P2J (neu-) mixed tumor model representing immunohistochemistry 2+ tumors, A66 suppressed tumor growth and prolonged survival to a greater extent than GDC-0941 when combined with anti-neu antibody. These results demonstrate that a PI3K p110α-isoform-selective inhibitor is an effective adjunct to trastuzumab in the treatment of HER2-positive breast cancer.

Characteristics of upper limb muscular strength in male wheelchair tennis players.

The purpose of this study was to identify the characteristics of muscular strength in upper limb and to present the preliminary information for development of sports injury prevention program and exercise rehabilitation program in wheelchair tennis players. Participants were 12 male wheelchair tennis players. Muscular strength was measured in shoulder and elbow joints with isokinetic dynamometer. Ipsilateral (IR) and bilateral (BR) balance ratio were calculated with isokinetic strength at 60°/sec. As a result, extension strength (ES) was significantly higher than flexion strength (FS) (P< 0.001), and IR in both sides and BR in ES were maintained within normal range whereas BR in FS was lower than normal range in shoulder joint. In elbow joint FS was significantly higher than ES (P< 0.05), and IR and BR were lower than normal range. Consequently, the different tendency in IR between shoulder and elbow joints and lower IR and BR in elbow joints could be the characteristics in male wheelchair tennis players. It is suggested that flexor strengthening program in nondominant shoulder joint, extensor strengthening program in both elbow joint, and flexor strengthening program in non-dominant elbow joint should be introduced for male wheelchair tennis players.

Potent anti-inflammatory effect of a novel furan-2,5-dione derivative, BPD, mediated by dual suppression of COX-2 activity and LPS-induced inflammatory gene expression via NF-κB inactivation.

BACKGROUND AND PURPOSE: We previously reported that 3-(benzo[d]-1,3-dioxol-5-yl)-4-phenylfuran-2,5-dione (BPD) showed strong inhibitory effects on PGE(2) production. However, the exact mechanism for the anti-inflammatory effect of BPD is not completely understood. In this study, we investigated the molecular mechanism involved in the effects of BPD on inflammatory mediators in LPS-stimulated macrophages and animal models of inflammation. EXPERIMENTAL APPROACH: The expressions of COX-2, inducible NOS (iNOS), TNF-α, IL-6 and IL-1ß, in LPS-stimulated RAW 264.7 cells and murine peritoneal macrophages, were determined by Western blot and/or qRT-PCR, respectively. NF-κB activation was investigated by EMSA, reporter gene assay and Western blotting. Anti-inflammatory effects of BPD were evaluated in vivo in carrageenan-induced paw oedema in rats and LPS-induced septic shock in mice. KEY RESULTS: BPD not only inhibited COX-2 activity but also reduced the expression of COX-2. In addition, BPD inhibited the expression of iNOS, TNF-α, IL-6 and IL-1ß at the transcriptional level. BPD attenuated LPS-induced DNA-binding activity and the transcription activity of NF-κB; this was associated with a decrease in the phosphorylation level of inhibitory κB-α (IκB-α) and reduced nuclear translocation of NF-κB. Furthermore, BPD suppressed the formation of TGF-ß-activated kinase-1 (TAK1)/TAK-binding protein1 (TAB1), which was accompanied by a parallel reduction of phosphorylation of TAK1 and IκB kinase (IKK). Pretreatment with BPD inhibited carrageenan-induced paw oedema and LPS-induced septic death. CONCLUSION AND IMPLICATIONS: Taken together, our data indicate that BPD is involved in the dual inhibition of COX-2 activity and TAK1-NF-κB pathway, providing a molecular basis for the anti-inflammatory properties of BPD.

Fraxinellone inhibits lipopolysaccharide-induced inducible nitric oxide synthase and cyclooxygenase-2 expression by negatively regulating nuclear factor-kappa B in RAW 264.7 macrophages cells.

Fraxinellone is formed by the natural degradation of limonoids isolated from the root bark of Dictamnus dasycarpus. Fraxinellone has been reported to possess neuroprotective and vasorelaxing activities, but the effects and the mechanism of fraxinellone in inflammation have not been fully characterized. In the present study, the anti-inflammatory effect of fraxinellone was evaluated in lipopolysaccharide (LPS)-treated RAW 264.7 macrophages. Fraxinellone was found to inhibit LPS-induced nitric oxide (NO) and prostaglandin E(2) (PGE(2)) production, and to reduce the LPS-induced expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at the mRNA and protein levels in a dose-dependent manner. Furthermore, fraxinellone significantly attenuated LPS-induced DNA binding activity and the transcription activity of nuclear factor-kappa B (NF-kappaB). Consistent with these findings, pretreatment with fraxinellone significantly suppressed the LPS-stimulated phosphorylation of inhibitory kappa B-alpha (IkappaB-alpha) and the subsequent translocation of p65 to the nucleus. Fraxinellone also suppressed the IkappaB kinase (IKK) activity and the phosphorylation of extracellular-signal-related kinase (ERK1/2), whereas the phosphorylations of Jun N-terminal kinase (JNK1/2) and p38 were unaffected. These results suggest that the anti-inflammatory properties of fraxinellone are related to the down-regulations of iNOS and COX-2 due to NF-kappaB inhibition through the negative regulations of IKK and ERK1/2 phosphorylations in RAW 264.7 cells.

Bis-(3-hydroxyphenyl) diselenide inhibits LPS-stimulated iNOS and COX-2 expression in RAW 264.7 macrophage cells through the NF-kappaB inactivation.

OBJECTIVES: Previously, we reported that diaryl diselenide compounds have strong inhibitory effects on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in macrophages. In this study, we investigated the molecular mechanisms underlying NO suppression and prostaglandin E(2) (PGE(2)) production by diaryl diselenide compounds, bis-(2-hydroxyphenyl) diselenide (DSE-A), bis-(3-hydroxyphenyl) diselenide (DSE-B), bis-(4-hydroxyphenyl) diselenide (DSE-C), dipyridyl diselenide (DSE-D) and diphenyl diselenide (DSE-E). METHODS: The effect of these compounds on NO suppression and PGE(2) production was investigated in RAW 264.7 macrophages. KEY FINDINGS: Our data indicate that of the above, DSE-B most potently inhibits NO and PGE(2) production, and that it also significantly reduces the releases of tumour necrosis factor (TNF)-alpha, interleukin(IL)-1beta and IL-6. Consistent with these observations, DSE-B also reduced the protein levels of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), and the mRNA levels of iNOS, COX-2, TNF-alpha, IL-1beta and IL-6. Furthermore, DSE-B inhibited LPS-induced nuclear factor-kappaB (NF-kappaB) activation, which was associated with the prevention of the inhibitor kappaB-alpha (IkappaB-alpha) degradation and a subsequent reduction in nuclear p65 protein levels. CONCLUSIONS: Taken together, our data suggest that the anti-inflammatory properties of DSE-B are due to reduction in the expression of iNOS, COX-2, TNF-alpha, IL-1beta and IL-6 through the down-regulation of NF-kappaB binding activity.

Anti-inflammatory effects of sinapic acid through the suppression of inducible nitric oxide synthase, cyclooxygase-2, and proinflammatory cytokines expressions via nuclear factor-kappaB inactivation.

To investigate the anti-inflammatory potential of sinapic acid as well as the underlying mechanism involved, we studied the inhibitory effect of sinapic acid on the production of pro-inflammatory mediators in vitro and then evaluated its in vivo anti-inflammatory effect. Sinapic acid inhibited lipopolysaccharide (LPS)-induced nitric oxide (NO), prostaglandin E 2 (PGE 2), tumor necrosis factor (TNF)-alpha, and interleukin (IL)-1beta production in a dose-dependent manner. Consistent with these findings, sinapic acid inhibited LPS-induced expressions of inducible nitric oxide synthase (iNOS) and cyclooxygase (COX)-2 at the protein levels, and iNOS, COX-2, TNF-alpha, and IL-1beta mRNA expression in RAW 264.7 macrophages, as determined by Western blotting and reverse-transcribed polymerase chain reaction, respectively. Sinapic acid suppressed the LPS-induced activation of nuclear factor-kappaB (NF-kappaB), a transcription factor pivotal necessary for pro-inflammatory mediators, such as iNOS, COX-2, TNF-alpha, and IL-1beta. This effect was accompanied by a parallel reduction of the nuclear translocation of p65 and p50 NF-kappaB subunits, as well as IkappaB-alpha degradation and phosphorylation. The effects of sinapic acid on acute phase inflammation were investigated on serotonin- and carrageenan-induced paw edema and compared with indomethacin (10 mg/kg, p.o.) or ibuprofen (100 mg/kg, p.o.). Maximum inhibitions of 34.2 and 44.5% were observed at a concentration of 30 mg/kg for serotonin- and carrageenan-induced paw edema, respectively. These results suggest that the suppressions of the expressions of iNOS, COX-2, TNF-alpha, and IL-1beta via NF-kappaB inactivation are responsible for the anti-inflammatory effects of sinapic acid.

Isoliquiritigenin isolated from the roots of Glycyrrhiza uralensis inhibits LPS-induced iNOS and COX-2 expression via the attenuation of NF-kappaB in RAW 264.7 macrophages.

In this study, the anti-inflammatory effects of flavonoids isolated from the roots of Glycyrrhiza uralensis (Leguminosae), namely, isoliquiritin (the glycoside of isoliquirigenin) and isoliquiritigenin (the aglycone of isoliquiritin) were evaluated on lipopolysaccharide (LPS)-treated RAW 264.7 macrophages. Isoliquiritigenin (ILG) more potently inhibited LPS-induced nitric oxide (NO) and prostaglandin E(2) (PGE(2)) production than isoliquiritin (ILT). Consistent with these findings, ILG reduced the LPS-induced expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at the protein and mRNA levels in a concentration-dependent manner, as determined by Western blotting and RT-PCR, respectively. In addition, the release of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), and the mRNA expression levels of these cytokines were reduced by ILG in a dose-dependent manner. Moreover, ILG attenuated the LPS-induced DNA binding activity and the transcription activity of nuclear factor-kappa B (NF-kappaB), and this was associated with a decrease in inhibitory kappa B-alpha (IkappaB-alpha) phosphorylation and in the subsequent blocking of p65 and p50 protein translocations to the nucleus. Furthermore, ILG suppressed the phosphorylations of IkappaB kinase (IKK), ERK1/2, and p38, whereas the phosphorylation of JNK1/2 was unaffected. These results suggest that the anti-inflammatory properties of ILG are caused by iNOS, COX-2, TNF-alpha, and IL-6 down-regulation due to NF-kappaB inhibition via the suppression of IKK, ERK1/2 and p38 phosphorylation in RAW 264.7 cells.