A novel macrolide derivative ameliorates smoke-induced inflammation and emphysema by inhibiting NF-κB activation.

Although inflammation and emphysema in patients with chronic obstructive pulmonary disease (COPD) can be ameliorated by antibiotics such as erythromycin, the impact of drug resistance is still controversial. We aimed to evaluate the role of F528, a new macrolide derivative without antibacterial effect, in cigarette smoke (CS)-induced pulmonary inflammation and emphysema in a mouse model, as well as in a macrophage cell line. The inflammatory cell number and cell type in the BALF were counted, and the levels of cytokines in the BALF and cultured cell medium were measured by ELISA. The degree of emphysema and apoptosis was evaluated by H&E and immunohistochemical staining, respectively. The lung function of the mice was evaluated by a small animal lung function meter. Furthermore, the expression levels of MMP-2, MMP-9, and phospho-NF-κB in the cells and lung tissue were measured by Western blot and qRT-PCR. In the BALF of the CS-induced pulmonary inflammation and emphysema model, the numbers of inflammatory cells and cytokines were significantly decreased after F528 intervention. F528 intervention also significantly protected lung function from CS-induced emphysema, while the mean lining interception (MLI) of the F528-treated CS group was significantly lower than that of the vehicle-treated CS group. In addition, F528 treatment reduced the phosphorylation of NF-κB induced by smoke, and the expression of MMP-2 and MMP-9 was also obviously decreased by F528 treatment. We therefore conclude that F528 reduces cigarette smoke-induced inflammation and emphysema in vivo and in vitro through inhibition of the activation of NF-κB.

RANKL Mediates Muscle Atrophy and Dysfunction in a Cigarette Smoke-induced Model of Chronic Obstructive Pulmonary Disease.

Skeletal muscle dysfunction is one of the important comorbidities of chronic obstructive pulmonary disease (COPD); however, the underlying mechanisms remain largely unknown. RANKL (receptor activator of nuclear factor κB ligand), a key mediator in osteoclast differentiation, was also found to play a role in skeletal muscle pathogenesis. Whether RANKL is involved in COPD-related skeletal muscle dysfunction is as-of-yet unknown. We examined the expression of RANKL/RANK in skeletal muscles from mice exposed to cigarette smoke (CS) for 24 weeks. Grip strength and exercise capacity as well as muscular morphology were evaluated in CS-exposed mice with or without anti-RANKL treatment. The expressions of protein synthesis- or muscle growth-related molecules (IGF-1, myogenin, and myostatin), muscle-specific ubiquitin E3 ligases (MuRF1 and atrogin-1), and the NF-κb inflammatory pathway were also evaluated in skeletal muscles. The effect of CS extract on RANKL/RANK expression and that of exogenous RANKL on the ubiquitin-proteasome pathway in C2C12 myotubes were investigated in vitro. Long-term CS exposure induced skeletal muscle dysfunction and atrophy together with upregulation of RANKL/RANK expression in a well-established mouse model of COPD. RANKL neutralization prevented skeletal muscle dysfunction and atrophy. RANKL inhibition decreased expressions of myostatin and MuRF1/Atrogin1 and suppressed the NF-κb pathway in skeletal muscles from CS-exposed mice. In in vitro experiments with C2C12 myotubes, CS extract induced expression of RANKL/RANK, and exogenous RANKL induced activation of the ubiquitin-proteasome pathway and NF-κb pathway via RANK. Our results revealed an important role of the RANKL/RANK pathway in muscle atrophy induced by CS exposure, suggesting that RANKL may be a potential therapeutic target in COPD-related skeletal muscle dysfunction.

Overexpression of MAP3K3 promotes tumour growth through activation of the NF-κB signalling pathway in ovarian carcinoma.

Mitogen-activated protein kinase kinase kinase 3 (MAP3K3), a member of the serine/threonine protein kinase family, is ubiquitously expressed and acts as an oncogene. However, the expression and exact molecular mechanism of MAP3K3 in ovarian carcinoma (OC) remain unclear. Here, we found that MAP3K3 protein was highly expressed in 70.5% of high-grade serous ovarian carcinoma (HGSOC) samples. MAP3K3 overexpression was significantly associated with the FIGO stage and chemotherapy response. Additionally, MAP3K3 overexpression was associated with reduced disease-free survival and overall survival. In vitro experiments showed that MAP3K3 overexpression promoted cell proliferation, inhibited apoptosis, and enhanced the migration and invasion of OC cells. Moreover, in vivo tumourigenesis experiments confirmed that silencing MAP3K3 significantly reduced the growth rate and volume of transplanted tumours in nude mice. Drug sensitivity experiments demonstrated that differential expression of MAP3K3 in OC cell lines correlates with chemotherapy resistance. Functionally, the MAP3K3 gene regulated the malignant biological behaviour of OC cells by mediating NF-κB signalling pathways, affecting the downstream epithelial-mesenchymal transition and cytoskeletal protein expression. Our results unveiled the role of MAP3K3 in mediating NF-κB signalling to promote the proliferation, invasion, migration, and chemotherapeutic resistance of OC cells, highlighting a potential new therapeutic and prognostic target.

[The expression of interleukin-25 in blood and nasal tissue of patients with chronic rhinosinusitis with nasal polyps].

OBJECTIVE: To explore the expression of interleukin-25 (IL-25) in chronic rhinosinusitis with nasal polyps (CRSwNP) and its potential significance in pathogenesis. METHOD: IL-25 expression in blood was detected by enzyme-linked immunosorbent assay (ELISA). IL-25 expression in tissue was detected by immunohistochemistry (LSAB method) from polyps (68 CRSwNP patients) and 55 inferior turbinate mucosa from patients with deviation of nasal septum served as control. Complete blood count and HE staining of blood and tissue eosinophil infiltration degree. RESULT: IL-25 expression in CRSwNP group were significantly higher than the control group, the difference was statistically significant (P < 0.01). IL-25 expression in local organizations was positively correlated with the number of eosinophil infiltration in CRSwNP group (r = 0.679, P < 0.01). CONCLUSION: The expression of IL-25 in CRSwNP patients mutually reinforcing and might increase eosinophil infiltration and play an important role in the development of CRSwNP.

[Change of coagulation functions and its significance in acute exacerbation of chronic obstructive pulmonary disease].

OBJECTIVE: To explore the changes and clinical significances of plasma D-dimer, factor X and tissue factor in acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and analyze the in-depth changes of these indicators in AECOPD with co-current deep venous thrombosis (DVT). METHODS: A total of 56 AECOPD patients were divided into the DVT and non-DVT subgroups (n = 28 each). And 60 normal control subjects were recruited according to age and gender. For each subject, 2.7 ml whole blood was drawn and then the plasma levels of D-dimer, factor X and tissue factor were detected. The results were statistically analyzed with the software SPSS 13.0. And the analysis of variance was performed between the groups. RESULTS: There was no significant difference between the distribution of the AECOPD group and the control group by gender and age. Therefore two groups were comparable. And in the AECOPD group, there was no significant difference between the distribution of DVT and non-DVT subgroups by gender and age. Therefore these two subgroups were comparable as well. The value of D-dimer in the AECOPD patients was significantly higher than that in the normal control [(0.76 ± 0.30) vs (0.29 ± 0.11) mg/L, P < 0.01]; and in the AECOPD group, the value of D-dimer in the DVT subgroup was significantly higher than that in the non-DVT subgroup [(0.85 ± 0.29) vs (0.67 ± 0.28) mg/L, P < 0.05]. In the AECOPD group, the value of tissue factor was (238 ± 68) mg/L and the value of factor X (1181 ± 337) mg/L. While in the normal control group, the values were (124 ± 30) and (998 ± 260) mg/L respectively. As for tissue factor and factor X, there were significant differences between two groups (all P < 0.01). Yet in AECOPD patients, neither indicator had significant differences between the DVT and non-DVT subgroups (all P > 0.05). CONCLUSION: The blood of AECOPD patients is in a hypercoagulatory state. And an obvious rise in their plasma level of D-dimer suggests that it may be complicated with DVT.