Several studies have shown physiological functions of interleukin (IL)-32, a novel cytokine. However, the role of IL-32 in cancer development has not been reported. In this study, we showed that IL-32γ inhibited tumor growth in IL-32γ-overexpressing transgenic mice inoculated with melanoma as well as colon tumor growth in xenograft nude mice inoculated with IL-32γ-transfected colon cancer cells (SW620). The inhibitory effect of IL-32γ on tumor growth was associated with the inhibition of constitutive activated nuclear transcription factor-κB (NF-κB) and of signal transducer and activator of transcription 3 (STAT3). The expression of antiapoptotic, cell proliferation and tumor-promoting genes (bcl-2, X-chromosome inhibitor of apoptosis protein (IAP), cellular IAP and cellular FADD-like IL-1β-converting enzyme-inhibitory protein, cyclin D), cyclin-dependent kinase 4, cycolooxygenase-2 and inducible nitric oxide synthase was decreased, whereas the expression of apoptotic target genes (caspase-3 and -9, bax) increased. In tumor, spleen and blood, the number of cytotoxic CD8+ T cells and CD57+ natural killer cells and the levels of IL-10 increased, but that of tumor necrosis factor-α (TNF-α), IL-1β and IL-6 decreased. We also found that forced overexpression of IL-32γ inhibited colon cancer cell (SW620 and HCT116) growth accompanied with the inhibition of activated NF-κB and STAT3 in vitro. In addition, when IL-32γ was knocked down by small interfering RNA (siRNA) or neutralized with an anti-IL-32γ antibody, IL-32γ-induced colon cancer cell growth inhibition, the IL-32γ-induced decrease of TNF-α, IL-1 and IL-6 production, and the increase of IL-10 production were abolished. However, siRNA of NF-κB and STAT3 augmented IL-32γ-induced colon cancer cell growth inhibition. These findings indicate significant pathophysiological roles of IL-32γ in cancer development.
Cardiomyocyte apoptosis is an important pathogenic mechanism in myocardial ischemia/reperfusion (I/R) injury. It has been shown that nitric oxide (NO) and the renin-angiotensin system (RAS) are closely related, and both systems regulate apoptotic cell death. However, the effects of NO modulation on myocardial apoptotic cell death and changes in the RAS in the I/R-injured myocardium have not been studied. Female Sprague-Dawley rats were randomized into three groups: NO synthesis inhibitor, N(G)-nitro-L-arginine-methyl ester (L-NAME, 10mg/kg); NO precursor, L-arginine (540mg/kg); and vehicle. The rats were then subjected to 45 min coronary occlusion followed by 4 h reperfusion. The TdT-mediated in situ nick and labeling (TUNEL) indices were 39.9%+/-0.8% at the border and 30.9%+/-1.2% at the center of the I/R area in the vehicle group. L-NAME administration significantly increased these TUNEL-positive cells to 45.3%+/-1.9% and 37.9%+/-1.3%, respectively (P < 0.05 each). L-arginine administration reduced the TUNEL index at the border zone with marginal significance (P = 0.08 vs vehicle group). I/R injury significantly reduced the angiotensin-converting enzyme (ACE) mRNA expression in the left (ventricular) free wall of vehicle group rats. However, ACE mRNA expression was 1.9 times greater in the L-NAME group than that in the vehicle group (P < 0.05). This study showed that the inhibition of NO synthesis increased apoptotic cardiomyocyte death and local ACE mRNA expression in the I/R-injured myocardium. Our observations indicate that NO, ACE, and apoptotic cardiomyocyte death are related to each other during I/R injury.
Background Atrial fibrillation or flutter (AFF) is common in both patients with myocardial infarction (MI) and those with heart failure (HF). However, its impact on the risk of adverse outcomes in MI complicated by either reduced LVEF and/or transient pulmonary congestion is less known. Purpose To assess the relationship between AFF and outcomes and whether AFF modified the treatment response to sacubitril/valsartan in the PARADISE-MI (Prospective ARNI versus ACEi trial to determine superiority in reducing HF events after MI) trial. Methods 5656 patients enrolled in the PARADISE-MI trial were divided into 3 groups: no known AFF, history of AFF without AFF at enrolment, and AFF occurring with the index MI event. We assessed outcomes and the treatment response to sacubitril/valsartan in all groups. The primary outcome of the PARADISE-MI trial was death from cardiovascular (CV) causes or incident HF. The outcome analyses were adjusted for the number of risk augmenting factors, age, pulmonary congestion, percutaneous coronary intervention, LVEF and hypertension. Results 259 patients (4.6%) had only a history of AFF, 525 patients (9.3%) had AFF associated with index MI. Patients with a history of AFF and AFF with index MI were older, with a higher rate of pulmonary congestion and hypertension, lower eGFR values but lower rates of diabetes, compared with those without AFF (Table 1). In unadjusted analyses, history of AFF and AFF with index MI were associated with a significant increase in the risk of the primary outcome (hazard ratio (HR): 1.76; 95% confidence interval (CI): 1.32–2.35 and HR 1.69, 95% CI 1.37–2.10, respectively), remaining significant after adjustment only in those with AFF with index MI (HR=1.40, 95% CI 1.12–1.74) (Fig. 1). This was primarily driven by an increase in the crude and adjusted risk of incident HF, both in those with a history of AFF and AFF with index MI (adjusted HR=1.56, 95% CI 1.10–2.22 and HR=1.55, 95% CI 1.18–2.03, respectively). An increase in the crude risk of CV death was present in patients with a history of AFF and AFF with index MI (HR=1.57, 95% CI 1.04–2.39 and HR=1.66, 95% CI 1.23–2.24, respectively), yet did not remain significant after adjustment. The risk of the composite outcome of death from coronary heart disease, non-fatal MI, hospitalisation for angina or coronary was not associated with either a history of AFF or AFF with index MI, in unadjusted or adjusted analyses (adjusted HR=0.83, 95% CI 0.57–1.19 and HR=1.00, 95% CI 0.78–1.29, respectively) (Fig. 1). Neither history of AFF nor AFF with index MI modified the treatment effect of sacubitril/valsartan (p>0.05). Conclusions In this post-MI cohort, history of AFF and AFF occurring with the index MI event were associated with an increased risk of CV death or incident heart failure, primarily driven by an increased risk of incident HF. However, the risk of the composite coronary outcome was not associated with AFF status, compared to other studied outcomes. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): The PARADISE-MI trial was funded by Novartis
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