Long-chain polyunsaturated omega-3 fatty acids reduce multiple myeloma exosome-mediated suppression of NK cell cytotoxicity

BackgroundDespite the advances in the treatment of multiple myeloma (MM), complete remission is usually challenging. The interactions between tumor and host cells, in which exosomes (EXs) play critical roles, have been shown to be among the major deteriorative tumor-promoting factors herein. Therefore, any endeavor to beneficially target these EX-mediated interactions could be of high importance.Objectivesa) To investigate the effects of myeloma EXs on natural killer (NK) cell functions. b) To check whether treatment of myeloma cells with eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), two polyunsaturated omega-3 fatty acids with known anti-cancer effects, can modify myeloma EXs in terms of their effects on natural killer functions.MethodsL363 cells were treated with either EPA or DHA or left untreated and the released EXs (designated as E-EX, D-EX and C-EX, respectively) were used to treat NK cells for functional studies.ResultsMyeloma EXs (C-EXs) significantly reduced NK cytotoxicity against K562 cells (P ≤ 0.05), while the cytotoxicity suppression was significantly lower (P ≤ 0.05) in the (E-EX)- and (D-EX)-treated NK cells compared to the (C-EX)-treated cells. The expression of the activating NK receptor NKG2D and NK degranulation, after treatment with the EXs, were both altered following the same pattern. However, C-EXs could increase IFN-γ production in NK cells (P < 0.01), which was not significantly affected by EPA/DHA treatment. This indicates a dual effect of myeloma EXs on NK cells functions.ConclusionOur observations showed that myeloma EXs have both suppressive and stimulatory effects on different NK functions. Treatment of myeloma cells with EPA/DHA can reduce the suppressive effects of myeloma EXs while maintaining their stimulatory effects. These findings, together with the previous findings on the anti-cancer effects of EPA/DHA, provide stronger evidence for the repositioning of the currently existing EPA/DHA supplements to be used in the treatment of MM as an adjuvant treatment.Graphical abstract Open in a separate windowEXs released from L363 (myeloma) cells in their steady state increase IFN-γ production of NK cells, while reduce their cytotoxicity against the K562 cell line (right blue trace). EXs from L363 cells pre-treated with either EPA or DHA are weaker stimulators of IFN-γ production. These EXs also increase NK cytotoxicity and NKG2D expression (left brown trace) compared to the EXs obtained from untreated L363 cells. Based on these findings, myeloma EXs have both suppressive and stimulatory effects on different NK functions depending on the properties of their cells of origin, which can be exploited in the treatment of myeloma.     

Effectiveness of Group Resiliency Training on Anxiety,Depression, and Marital Satisfaction in Mothers of Children with Attention Deficit Hyperactivity Disorder

Many studies have been reported that higher levels of depression and anxiety in parents of children with attention deficit hyperactivity disorder. The objective of this study was to evaluate the effectiveness of group resiliency training on anxiety, depression, and marital satisfaction in mothers of children with attention deficit hyperactivity disorder. This study was an experimental, pretest—post-test study with control group. Participants included 54 mothers of children with attention deficit hyperactivity disorder. Mothers were randomly divided to experimental and control groups. The experimental group received 8 group resiliency training sessions and then compared in changes in Beck depression and anxiety scale and the Enrich marital satisfaction scale. Results of multivariate analysis of covariance showed significant change in depression, anxiety, and marital satisfaction. Our study indicates that resiliency training can be considered as one the effective intervention for anxiety, depression, and marital satisfaction in these mothers.     

IL-8 production by macrophages is synergistically enhanced when cigarette smoke is combined with TNF-α

Macrophages are key inflammatory cells in chronic obstructive pulmonary disease (COPD). The pathophysiology of cigarette smoke-induced lung emphysema is complex but there is a clear role for reactive oxygen species (ROS, such as peroxynitrite), tumor necrosis factor (TNF-α) and interleukin (IL)-8. We investigated whether TNF-α or cigarette smoke medium (CSM) alone or in combination induces the production of IL-8 by human macrophages or monocyte lymphoma U937. CSM and TNF-α induce a dose- and time-dependent increase in IL-8 production. Interestingly, when sub-threshold concentrations of CSM and TNF-α were co-incubated, a 1500% increase in IL-8 production was observed compared to either of the compounds alone. Similar results were obtained with TNF-α and the peroxynitrite donor SIN-1. Moreover, the overproduction of IL-8 was associated with an enhanced increase in the translocation of NF-κB and an enhanced decrease in glutathione levels. Preincubation of the cells with antioxidants, such as N-acetyl-l-cysteine (NAC), prevented the overproduction of IL-8 and activation of NF-κB.In conclusion, CSM exposure of macrophages up-regulates the expression and the production of IL-8 via reactive oxygen species and NF-κB activation. Moreover, CSM dramatically enhances the production of IL-8 in combination with TNF-α. Based upon the strong synergistic action, a combination therapy directed against ROS and TNF-α could be a new approach to stop the progression in lung damage during emphysema.     

Socioeconomic inequality in childhood obesity and its determinants: a Blinder–Oaxaca decomposition

Objective

Childhood obesity has become a priority health concern worldwide. Socioeconomic status is one of its main determinants. This study aimed to assess the socioeconomic inequality of obesity in children and adolescents at national and provincial levels in Iran.

Characterization of pharmacoresistance to benzodiazepines in the rat Li-pilocarpine model of status epilepticus

Status epilepticus is usually initially treated with a benzodiazepine such as diazepam. During prolonged seizures, however, patients often lose their sensitivity to benzodiazepines, thus developing pharmacoresistant seizures. In rats, administration of LiCl followed 20–24 h later by pilocarpine induces a continuous, self-sustained, and reproducible form of status epilepticus that can be terminated with diazepam when it is administered soon after the pilocarpine injection. However, when administered after a 45 min delay, diazepam is less effective. Previous findings have suggested that the development of pharmacoresistance is related to the stage of status epilepticus. In the present study, we characterized the seizure stage-dependence of diazepam pharmacoresistance. Following administration of different doses of diazepam at varying time intervals after specific behaviorally- and electrographically-defined seizure stages, stage-, time-, and dose-dependent pharmacoresistance to diazepam developed. We also studied two other antiepileptic drugs commonly used in the treatment of status epilepticus, phenobarbital and phenytoin. Consistent with previous studies, our results indicated a similar relationship between stage, time and dose for phenobarbital, but not for phenytoin. Our data are consistent with rapid modulation of GABA_A receptors during status epilepticus that may result in pharmacoresistance to antiepileptic drugs that enhance GABA_A receptor-mediated inhibition.     

Comparison of an ESAT-6/CFP-10 peptide-based enzyme-linked immunospot assay to a tuberculin skin test for screening of a population at moderate risk of contracting tuberculosis

Screening for latent tuberculosis infection (LTBI) with the Mantoux tuberculin skin test (TST) has many limitations including false-positive results due to Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccination. Three hundred ninety adult inmates with normal screening chest radiographs in a county jail were evaluated for LTBI using TST and an ESAT-6/CFP-10 peptide-based enzyme-linked immunospot assay (T-SPOT.TB). LTBI prevalence rates were 19.0% and 8.5% by T-SPOT.TB and TST, respectively. Overall agreement between test results was 82.8% (kappa = 0.29). Positive T-SPOT.TB results were significantly associated with increased age (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.01 to 1.06) and intravenous drug use history (OR, 2.92; 95% CI, 1.36 to 6.27). Positive TST results were significantly associated with increased age (OR, 1.06; 95% CI, 1.02 to 1.09) and foreign birth (OR, 6.61; 95% CI, 1.98 to 22.01). Discordant covariates between the assay results included increased age (OR, 0.96; 95% CI, 0.94 to 0.99) and intravenous drug use history (OR, 0.41; 95% CI, 0.19 to 0.88). T-SPOT.TB reactivity is unaffected by prior BCG vaccination. T-SPOT.TB may be more sensitive than TST in diagnosing LTBI among a moderate risk population of inmates, particularly those with intravenous drug use history. Longitudinal studies are needed to assess the positive predictive value of T-SPOT.TB in identifying those most likely to convert to active disease in general populations as well as in high-risk subpopulations.     

The effect of bovine rotavirus and its nonstructural protein 4 on ER stress-mediated apoptosis in HeLa and HT-29 cells

Tumor Biology - Endoplasmic reticulum (ER) plays important roles in multiple cellular processes as well as cell survival and apoptosis. Perturbation of ER functions leads to ER stress and unfolded...     

The effect of dexamethasone on postoperative vomiting and oral intake after adenotonsillectomy

OBJECTIVE: Vomiting is one of the most important postoperative complications of adenotonsillectomy. This study was designed to determine the effectiveness of preoperative intravenous dexamethasone on postoperative emesis. METHODS: In a double-blind, placebo-controlled clinical trial, 100 patients aged 5-15 years, ASA classes I and II were randomly selected to receive either 0.5 mg/kg IV dexamethasone (n=50), as study group or an equivalent volume of saline preoperatively, as control group. The anesthetic regimen and surgical procedures were standardized for all patients. The incidence of early and late vomiting, the time to first oral intake and duration of intravenous hydration were compared in both groups. RESULTS: Data analysis showed that the overall incidence of early and late vomiting was significantly lesser in dexamehasone group than the control one. The time to first oral intake and duration of IV therapy were also significantly shorter in dexamethasone group. CONCLUSION: A single dose of dexamethasone significantly decreased the incidence of postoperative vomiting in early and late recovery phase and shortened the time to first oral intake and the duration of IV therapy.