Low Muscle and High Fat Percentages Are Associated with Low Natural Killer Cell Activity: A Cross-Sectional Study.

This study aimed to investigate whether body fat and muscle percentages are associated with natural killer cell activity (NKA). This was a cross-sectional study, conducted on 8058 subjects in a medical center in Korea. The association between the muscle and fat percentage tertiles and a low NKA, defined as an interferon-gamma level lower than 500 pg/mL, was assessed. In both men and women, the muscle mass and muscle percentage were significantly low in participants with a low NKA, whereas the fat percentage, white blood cell count, and C-reactive protein (CRP) level were significantly high in those with a low NKA. Compared with the lowest muscle percentage tertile as a reference, the fully adjusted odd ratios (ORs) (95% confidence intervals (CIs)) for a low NKA were significantly lower in T2 (OR: 0.69; 95% CI: 0.55-0.86) and T3 (OR: 0.74; 95% CI: 0.57-0.95) of men, and T3 (OR: 0.76; 95% CI: 0.59-0.99) of women. Compared with the lowest fat percentage tertile as a reference, the fully adjusted OR was significantly higher in T3 of men (OR: 1.31; 95% CI: 1.01-1.69). A high muscle percentage was significantly inversely associated with a low NKA in men and women, whereas a high fat percentage was significantly associated with a low NKA in men.

Prognostic value of natural killer cell activity for patients with HER2 + advanced gastric cancer treated with first-line fluoropyrimidine-platinum doublet plus trastuzumab.

BACKGROUND: We aimed to evaluate the prognostic value of natural killer (NK) cell activity for patients with HER2 + advanced gastric cancer (AGC) treated with first-line fluoropyrimidine-platinum doublet plus trastuzumab. METHODS: Forty-one patients with HER2 + AGC who received fluoropyrimidine-platinum doublet plus trastuzumab as first-line treatment were prospectively enrolled. NK cell activity was evaluated using the NK Vue®. RESULTS: The median age was 63.5 years, and 31 patients (75.6%) were male. Patients with low baseline NK cell activity (≤ median, n = 21) were associated worse progression-free survival (PFS) and overall survival (OS) compared with patients with high baseline NK cell activity (> median, n = 20) with a median PFS of 4.21 vs. 9.53 months (P < 0.001), and median OS of 8.15 months vs. 17.82 months (P = 0.025), respectively. In the multivariate analysis, low baseline NK cell activity was independently associated with poor PFS (HR 4.35, P = 0.007). NK cell activity recovered to a normal range in nine patients (47.4%) with a low baseline NK cell activity (n = 19) after two cycles of treatment. The median PFS and OS among patients with recovered NK cell activity were significantly better than that among patients with persistently low NK cell activity (PFS, P = 0.038; OS, P = 0.003). CONCLUSION: Our results demonstrated the prognostic value of baseline NK cell activity for patients with HER2 + AGC treated with fluoropyrimidine-platinum doublet plus trastuzumab. The association between treatment outcomes and dynamic changes in NK cell activity suggests that NK cell treatment may improve treatment outcomes, especially for patients with low baseline NK cell activity.

Modulatory effect of resveratrol and melatonin on natural killer cell activity and adrenomedullin in diabetic rats.

BACKGROUND: Epidemiological evidence suggests that diabetes poses a high risk for many chronic diseases, especially cardiovascular diseases, and cancer by stimulating many inflammatory and immunological pathogenic mediators and affecting natural killer (NK)-cell activity. In this study, the effects of melatonin and resveratrol on IL-6, TNF-alpha, oxidant/antioxidant capacity, NK-cell activity, and mid-regional proadrenomedullin (MR-proADM) levels of diabetic rats were investigated. METHODS: In the study, 28 Sprague Dawley rats were randomly divided into the control group (group I) and 3 streptozotocininduced diabetes mellitus (DM) groups (group II, III, and IV), each group consisting of 7 rats. Five mg/kg/day melatonin to group III and 5 mg/kg/day resveratrol (intraperitoneal) to group IV was given. At the end of 3 weeks, NK-cell activity, total antioxidant/oxidant capacity, MR-proADM, IL-6, and TNF-alpha levels were measured in intracardiac blood taken under anesthesia. RESULTS: NK-cell activity of group II was found lower than group I, group III, and group IV (7.4 ± 2.0 vs. 22.5 ± 11.9, 30.6 ± 22.5 and 20.4 ± 9.1 pg/mL; p = 0.0018, respectively). The difference was more prominent in diabetic rats receiving melatonin (p < 0.01). TNF-alpha levels of group II were higher than the group I (p < 0.05). The MR-proADM levels of group II were found to be lower than the group I and group III (6.4 ± 3.6 vs. 14.4 ± 3.2 and 14.0 ± 4.2 ng/L; p < 0.05, respectively). In addition, NK-cell activity was moderately correlated with MR-proADM (r = 0.5618, p = 0.0019).

Lower postoperative natural killer cell activity is associated with positive surgical margins after radical prostatectomy.

BACKGROUND/PURPOSE: The inflammatory milieu has been firmly established to affect cancer progression. However, the connection between natural killer (NK) cells and prostate cancer (PCa) has not been elucidated. METHODS: Prospective data on NK cell activity (NKA) and NK cell subset distribution patterns were evaluated from 51 patients treated with robot-assisted laparoscopic radical prostatectomy. Whole-blood samples were collected from patients preoperatively and 4-6 weeks postoperatively. The samples were subjected to NKA tests, NK cell number counts, determination of the NKG2D (activating receptor of NK cells), NKG2A (inhibiting receptor), and other surface markers. All the analyses were compared to the clinicopathological characteristics of patients. NKA was estimated by measuring interferon-γ (IFN-γ) levels after stimulation of the peripheral blood with PROMOCA™, which specifically stimulates the release of IFN-γ from NK cells. RESULTS: NKA was lower in patients with PCa than in healthy participants (484.66 vs. 1550 pg/mL). A paired comparison revealed significantly higher NKA postoperatively than preoperatively (1054 vs. 484.66 pg/mL; p = 0.011). Patients with negative surgical margins exhibited significantly higher postoperative NKA and NKA ratio (postoperative NKA/preoperative NKA) than those with positive margins (557 vs. 1921 pg/mL, p < 0.001; 3.6 vs. 1.59, p = 0.024). However, there was no difference in the postoperative NK cell number or the CD56bright/CD16-/CD3- or CD56dim/CD16+/CD3- cell numbers between the negative and positive margin groups. Postoperative NKA was significantly higher in lower-stage (1/2) than in higher-stage (3/4) PCa (1365 vs. 594 pg/mL, p = 0.014). CONCLUSION: NKA was significantly higher postoperatively than preoperatively. Patients with positive surgical margins had lower postoperative NKA than those with negative margins. Lower postoperative NKA was also observed in higher-stage PCa. NKA could be used as a supplemental marker for detecting the remaining tumor cells after prostatectomy in combination of PSA.

Mindfulness based stress reduction provides psychological benefit and restores immune function of women newly diagnosed with breast cancer: A randomized trial with active control.

BACKGROUND: Women newly diagnosed with breast cancer experience psychological distress, accompanied by reduced Natural Killer Cell Activity (NKCA) and altered levels of cytokines, which may compromise cancer control. Few studies have evaluated psycho-immune outcomes of mindfulness-based stress reduction (MBSR) for women newly diagnosed with breast cancer in comparison to an active control condition. OBJECTIVE: The purpose of this study was to determine whether MBSR benefits psychological, behavioral, and immunological function in women recently diagnosed with breast cancer. DESIGN: After confirmation of breast cancer staging, women diagnosed with early-stage breast cancer (n = 192) were randomized to an 8-week MBSR program or an 8-week active control condition (ACC). The ACC consisted of a series of cancer recovery and health education classes. Both MBSR and the ACC were administered in group format. METHODS: Women completed psychometric instruments and provided blood for NKCA and cytokine levels at pre-, mid-, and completion of program, as well as at 1- and 6-months post-program. One hundred and twenty four women completed all five-assessments (MBSR, n = 63; ACC, n = 61). Hierarchical linear modeling was used to analyze trajectories of outcomes over time and between groups. RESULTS: Compared to the ACC group, women randomized to MBSR exhibited decreasing trajectories of perceived stress, fatigue, sleep disturbance, and depressive symptoms. Further, compared to women randomized to ACC, MBSR women exhibited trajectories demonstrating significantly more rapid restoration of NKCA, accompanied by lower circulating TNF-alpha levels, lower IL-6 production, and greater IFN-gamma production. CONCLUSIONS: These results demonstrate early provision of MBSR for women newly diagnosed with breast cancer provides not only psychological benefit, but also optimizes immune function supportive of cancer control.

Clinical factors associated with pregnancy outcome in women with recurrent pregnancy loss.

The aim of this prospective cohort study was to evaluate clinical factors associated with pregnancy outcomes in women with recurrent pregnancy loss (RPL). Women with a history of two or more pregnancy losses underwent workups for clinical factors of RPL and their pregnancies were followed-up with informed consent. Two hundred eleven (81.5%) of 259 women with RPL became pregnant. The multivariable analyses demonstrated that age (p < .01, OR 0.9, 95%CI 0.97-0.83), uterine abnormality (p < .05, OR 0.3, 95%CI 0.11-0.8), and protein C (PC) deficiency (p < .01, OR 0.14, 95%CI 0.03-0.6) were independent factors for becoming pregnancy in women with RPL. The number of previous pregnancy loss (p < .01, OR 0.57, 95%CI 0.43-0.75) and natural killer (NK) cell activity ≥33% (p < .01, OR 0.31, 95%CI 0.13-0.73) were independent factors for live birth in the subsequent pregnancy. Advanced age, the presence of uterine abnormality, and PC deficiency were risk factors for reduced pregnancy rate in women with RPL. Increased number of previous pregnancy loss and high NK cell activity were risk factors for miscarriage in the subsequent pregnancy. These results involve important information and are helpful for clinical practitioners.

Natural Killer Cell Function Tests by Flowcytometry-Based Cytotoxicity and IFN-γ Production for the Diagnosis of Adult Hemophagocytic Lymphohistiocytosis.

Although natural killer (NK) cell function is a hallmark of hemophagocytic lymphohistiocytosis (HLH), there is no standard method or data on its diagnostic value in adults. Thus, we performed a single-center retrospective study of 119 adult patients with suspected HLH. NK cell function was determined using both flowcytometry-based NK-cytotoxicity test (NK-cytotoxicity) and NK cell activity test for interferon-gamma (NKA-IFNγ). NK cell phenotype and serum cytokine levels were also tested. Fifty (42.0%) HLH patients showed significantly reduced NK cell function compared to 69 non-HLH patients by both NK-cytotoxicity and NKA-IFNγ (p < 0.001 and p = 0.020, respectively). Agreement between NK-cytotoxicity and NKA-IFNγ was 88.0% in HLH patients and 58.0% in non-HLH patients. NK-cytotoxicity and NKA-IFNγ assays predicted HLH with sensitivities of 96.0% and 92.0%, respectively. The combination of NKA-IFNγ and ferritin (>10,000 µg/L) was helpful for ruling out HLH, with a specificity of 94.2%. Decreased NK-cytotoxicity was associated with increased soluble IL-2 receptor levels and decreased CD56dim NK cells. Decreased NKA-IFNγ was associated with decreased serum cytokine levels. We suggest that both NK-cytotoxicity and NKA-IFNγ could be used for diagnosis of HLH. Further studies are needed to validate the diagnostic and prognostic value of NK cell function tests.

Association between natural killer cell activity and the risk of colorectal neoplasia.

BACKGROUND AND AIM: Low activity of natural killer (NK) cells is known to be associated with higher risk of cancer, especially with poor prognosis and the presence of colorectal cancer (CRC). We investigated whether NK cells activity differs between subjects with and without colorectal neoplasia (CRN). METHODS: A cross-sectional study was performed on 1818 asymptomatic examinees aged ≥ 30 years who underwent NK cell activity test (which quantitates the amount of interferon-γ secreted into the plasma by NK cells) and a colonoscopy as part of a health checkup. RESULTS: The mean age of the study population was 41.4 years. The proportion of overall CRN and advanced CRN was 13.5% (n = 246) and 0.7% (n = 13), respectively. Only one subject was diagnosed with CRC. The median level of NK cell activity was lower in subjects with CRN than in those without CRN (1205 vs 1515 pg/mL, P = 0.009). It was also lower in subjects with non-advanced CRN than in those without CRN (1221 vs 1515 pg/mL; P = 0.036). Moreover, it was lower in subjects with advanced CRN than in those with non-advanced CRN (480 vs 1221 pg/mL; P = 0.028). Subjects with low levels of NK cell activity (< 250 pg/mL) had a higher prevalence of overall CRN (19.0% vs 12.9%, P = 0.024) and advanced CRN (3.4% vs 0.4%, P = 0.001) than those who demonstrated higher level (≥ 250 pg/mL). CONCLUSIONS: Natural killer cell activity seemed to decrease along with CRC progression toward the later stages in the adenoma-carcinoma sequence. Its activity may be depressed in relation to progression of neoplasia, even at precancerous stage.

Enhancement of natural killer activity and IFN-γ production in an IL-12-dependent manner by a Brassica rapa L.

Certain food components possess immunomodulatory effects. The aim of this study was to elucidate the mechanism of the immunostimulatory activity of Brassica rapa L. We demonstrated an enhancement of natural killer (NK) activity and interferon (IFN)-γ production in mice that were orally administered an insoluble fraction of B. rapa L. The insoluble fraction of B. rapa L. significantly induced IFN-γ production in mouse spleen cells in an interleukin (IL)-12-dependent manner, and NK1.1+ cells were the main cells responsible for producing IFN-γ. Additionally, the results suggested that the active compounds in the insoluble fraction were recognized by Toll-like receptor (TLR) 2, TLR4, and C-type lectin receptors on dendritic cells, and they activated signaling cascades such as MAPK, NF-κB, and Syk. These findings suggest that B. rapa L. is a potentially promising immuno-improving material, and it might be useful for preventing immunological disorders such as infections and cancers by activating innate immunity.

Enhancing the natural killer cell activity and anti-influenza effect of heat-treated Lactobacillus plantarum nF1-fortified yogurt in mice.

Influenza A virus (IAV) infection is a global public health concern. It causes respiratory diseases ranging from mild illness to fatal disease. Natural killer (NK) cells are an innate immune component that kill infected cells and secrete cytokines to modulate the adaptive immune system; they constitute the first-line defense and play important roles in controlling IAV infection. This study evaluated the effect of daily administration of heat-treated Lactobacillus plantarum nF1-fortified yogurt on immunity and protection against IAV infection. Mice administered with heat-treated L. plantarum nF1-fortified yogurt showed elevated NK cell-related cytokine expression levels. Daily administration of the L. plantarum nF1-fortified yogurt before IAV infection also enhanced splenic NK activity, lung inflammatory cytokine responses, and survival rate. Thus, daily administration of nF1-fortified yogurt enhances host immunity and helps prevent IAV infection.

Age-related alteration of expression and function of TLRs and NK activity in oral candidiasis.

OBJECTIVE: Roles of aging or immune responses mediated by Toll-like receptors and natural killer cell in the onset or progression of human candidiasis remain unclear. This study was designed to elucidate the roles using peripheral blood mononuclear cells from healthy donors and patients with oral candidiasis. SUBJECTS AND METHODS: Subjects tested were healthy volunteers and patients who visited Dental Clinical Division of Hokkaido University Hospital. The patients with oral candidiasis included 39 individuals (25-89 years of age) with major complaints on pain in oral mucosa and/or dysgeusia. Healthy volunteers include students (25-35 years of age) and teaching staffs (50-65 years of age) of Hokkaido University Graduate School of Dental Medicine. RESULTS: Functions of Toll-like receptors 2 and 4 were downregulated significantly and the natural killer activity was slightly, but not significantly downregulated in aged healthy volunteers compared with healthy young volunteers. Functions of Toll-like receptors 2 and 4 and the natural killer activity were significantly downregulated in patients with oral candidiasis compared with healthy volunteers. CONCLUSION: Downregulation of functions of Toll-like receptors 2 and 4 as well as natural killer activity is suggested to be associated with the onset or progression of oral candidiasis in human.

Decreased natural killer cell activity as a potential predictor of hypertensive incidence.

Introduction: Blood pressure is closely linked with immune function. This study examined the association between natural killer (NK) cell activity (NKA) and blood pressure and the development of hypertension according to NKA levels. Methods: This study enrolled 1543 adults who underwent NKA measurement and serial health check-ups at a medical center in Korea. NKA was estimated as the concentration of IFN-γ in the incubated whole blood containing a patented stimulatory cytokine. The participants were categorized into quartiles according to their NKA levels. Participants without hypertension were followed up, and the development of hypertension was compared according to the quartiles. Results: The prevalence of hypertension was not different among the NKA quartiles, whereas blood pressures significantly decreased, followed by an increment of quartiles (systolic blood pressure of 119.0 in Q1 and 117.0 in Q4, P-trend = 0.018). Over a mean follow-up period of 2.13 years, hypertension developed in 156 of 1170 individuals without baseline hypertension. The hazard ratio of Q4 compared with Q1 was 0.625 (95% CI: 0.397-0.983; p = 0.042). Conclusion: In conclusion, our findings indicate a correlation between lower NKA and higher blood pressure and the development of incident hypertension. This may suggest a potential protective role of NK cells against endothelial dysfunction. Further research is necessary to elucidate the specific relationship between immune functions and endothelial function.

Porcine Brain Enzyme Hydrolysate Enhances Immune Function and Antioxidant Defense via Modulation of Gut Microbiota in a Cyclophosphamide-Induced Immunodeficiency Model.

This study examined how consuming porcine brain enzyme hydrolysate (PBEH) affects the immune function and composition of the gut microbiota in an immunodeficient animal model. Male Wistar rats aged 6 weeks were fed casein (control), 100 mg/kg body weight (BW), red ginseng extract (positive-control), and 6, 13, and 26 mg PBEH per kg BW (PBEH-L, PBEH-M, and PBEH-H, respectively) daily for 4 weeks. At 30 min after consuming assigned compounds, they were orally administered cyclophosphamide (CTX; 5 mg/kg BW), an immunosuppressive agent, to suppress the immune system by inhibiting the proliferation of lymphocytes. The normal-control rats were fed casein and water instead of CTX. Natural killer cell activity and splenocyte proliferation induced by 1 µg/mL lipopolysaccharide were lower in the control group than the normal-control group, and they significantly increased with PBEH consumption, particularly at high doses. The PBEH consumption increased dose-dependently in the Th1/Th2 ratio compared to the control. The lipid peroxide contents were lower in the PBEH group than in the control group. Moreover, PBEH m and PBEH-H consumption mitigated white pulp cell damage, reduced red pulp congestion, and increased spleen mast cells in the histological analysis. Intestinal microbiota composition demonstrated differences between the groups at the genus levels, with Akkermansia being more abundant in the control group than the normal-control group and the PBEH-H group showing a decrease. However, Bifidobacterium decreased in the control group but increased in the PBEH-H group. The ß-diversity revealed distinct microbial communities of PBEH and positive-control groups compared to the control group (p < 0.05). The metagenome predictions revealed that PBEH-H influenced amino acid metabolism, antioxidant defense, insulin sensitivity, and longevity pathways. In conclusion, PBEH-H intake boosted immune responses and reduced lipid peroxides by modulating gut microbiota composition. These findings suggest that PBEH-H has the potential as a dietary supplement for improving immune function and gut health in individuals with immunodeficiency.

Euglena gracilis (Euglena) powder supplementation enhanced immune function through natural killer cell activity in apparently healthy participants: A randomized, double-blind, placebo-controlled trial.

Euglena gracilis (Euglena) is a microalgae found in most freshwater environments that produces paramylon, an insoluble ß-1,3-glucan linked to human immunity. We hypothesized that Euglena powder has effects on immune function in apparently healthy adults. The study included male or female volunteers between the ages of 20 and 70 years who had white blood cell counts ranging from 4 × 103/µL to 10 × 103/µL, a "severe" rating on the stress questionnaire from the Korea National Health and Nutrition Examination Survey, and at least 2 upper respiratory infections with cold-like symptoms in the previous year. Participants received either a placebo or 700 mg of Euglena powder daily for 8 weeks. The study measured natural killer cell activity, cytokine concentrations, and blood lipid profiles to confirm the immune effect of Euglena consumption. In conclusion, Euglena improved immunological function through natural killer cell activity. Safety assessment showed no significant changes in vital signs or clinical chemistry indicators, and there were no adverse events associated with Euglena consumption. Euglena supplementation may help boost the immune systems of healthy individuals.

Relationship between Serum Cortisol, Dehydroepiandrosterone Sulfate (DHEAS) Levels, and Natural Killer Cell Activity: A Cross-Sectional Study.

The adrenal steroid hormones, cortisol and dehydroepiandrosterone sulfate (DHEAS), are associated with the immune system in opposite actions. This study aimed to investigate the relationship between cortisol and DHEAS serum concentrations, their ratio (CDR), and natural killer cell activity (NKA). This cross-sectional study included 2275 subjects without current infection or inflammation in the final analyses. NKA was estimated by measuring the amount of interferon-gamma (IFN-γ) released by activated natural killer cells; low NKA was defined as IFN-γ level < 500 pg/mL. Cortisol, DHEAS levels, and CDRs were categorized by quartiles in men, premenopausal women, and postmenopausal women. Compared with the lowest quartile as reference, the adjusted odd ratios (ORs) and 95% confidence intervals (CIs) for low NKA of the highest cortisol and CDR group were 1.66 (1.09-2.51) and 1.68 (1.11-2.55) in men, 1.58 (1.07-2.33) and 2.33 (1.58-3.46) in premenopausal women, and 2.23 (1.28-3.87) and 1.85 (1.07-3.21) in postmenopausal women. Only in premenopausal women, the highest DHEAS group showed significantly lower risk of low NKA (OR: 0.51, 95% CI: 0.35-0.76). HPA axis activation indicated as high cortisol level, CDR was significantly associated with low NKA, while high DHEAS levels were inversely associated with low NKA in premenopausal women.

Immunotoxicity of N-butylbenzenesulfonamide: impacts on immune function in adult mice and developmentally exposed rats.

N-butylbenzenesulfonamide (NBBS) is a high-production volume plasticizer that is an emerging contaminant of concern for environmental and human health. To understand the risks and health effects of exposure to NBBS, studies were conducted in adult-exposed mice and developmentally exposed rats to evaluate the potential for NBBS to modulate the immune system. Beginning between 8 and 9 weeks of age, dosed feed containing NBBS at concentrations of 0, 313, 625, 1250, 2500, and 5000 ppm was continuously provided to B6C3F1/N female mice for 28 days. Dosed feed was also continuously provided to time-mated Harlan Sprague Dawley (Sprague Dawley SD) rats at concentrations of 0-, 250-, 500-, and 1000-ppm NBBS from gestation day 6 to postnatal day 28 and in F1 rats until 11-14 weeks of age. Functional assessments of innate, humoral, and cell-mediated immunity were conducted in adult female mice and F1 rats following exposure to NBBS. In female mice, NBBS treatment suppressed the antibody-forming cell (AFC) response to SRBC with small increases in T-cell responses and natural killer (NK)-cell activity. In developmentally exposed rats, NBBS treatment-related immune effects were sex dependent. A positive trend in NK-cell activity occurred in male F1 rats while a negative trend occurred in female F1 rats. The AFC response to SRBC was decreased in female F1 rats but not in male F1 rats. These data provide evidence that oral exposure to NBBS has the potential to produce immunomodulatory effects on both innate and adaptive immune responses, and these effects appear to have some dependence on species, sex, and period of exposure (developmental vs adult).

Enzyme-derived deer velvet extract activate the immune response in cyclophosphamide-induced immunosuppressive mice.

Deer velvet (DV) is an oriental traditional medicine used to treat various diseases. The present study examined the effect of flavourzyme-derived DV extract (YC-1101) on macrophages and an immunosuppressed mouse model. YC-1101 induced activation of macrophages as measured by nitric oxide production, cell proliferation, and cytokine release via concentration-dependent phosphorylation of c-Jun N-terminal kinase, extracellular signal-regulated kinase, and AKT, and nuclear translocation of p65 in macrophages. In addition, oral YC-1101 administration significantly increased splenocyte proliferation and natural killer cell activity in the immunosuppressed mouse model. Moreover, the levels of immune-related cytokines such as tumor necrotic factor-α, interferon-γ, and interleukin-2 were significantly increased by YC-1101 treatment comparable to the control group. Thus, these results suggest that YC-1101 is an efficient natural ingredient that has an immune-enhancing effect, and it might be a potential functional food for improving immunity.

Anti-tumor effect of Wasabi component, 6-(methylsulfinyl) hexyl isothiocyanate, against endometrial carcinoma cells.

PURPOSE: Wasabi is a traditional plant seasoning with an anti-septic function. Recent studies revealed several functions of Wasabi, such as anti-inflammation; however, the anti-tumor effect against endometrial carcinoma (EMC) cells has not been examined. In the present study, we investigated the anti-tumor effect of 6-(methylsulfinyl) hexyl isothiocyanate (6-MITC), a major chemical compound of Wasabi, against various EMC cell lines in vitro and in vivo. METHODS: The effect of 6-MITC on cell viability was measured by the WST-1 assay in EMC and HUVEC cells. The impact of 6-MITC oral administration in nude mice was measured to assess the growth of the EMC xenograft and natural killer (NK) cell activity in the spleen. RESULTS: The addition of 6-MITC suppressed the proliferation of EMC cells (Ishikawa, HEC265, HEC108, KLE, and HEC1B) dose-dependently, but not HUVEC cells. 6-MITC (5 µM) enhanced the cisplatin sensitivity of EMC cells. 6-MITC induced apoptosis in a dose-dependent fashion in EMC cells other than HEC1B cells and was associated with increased expression of cleaved-caspase3 and decreased expression of BCL2. Oral administration of 6-MITC (2 and 4 µmol/kg) to Ishikawa and HEC1B xenografting mice resulted in a reduced tumor volume compared with the control (P < 0.05, 4 µmol/kg). Immunohistochemical staining of resected tumors revealed increased expression of Ki-67 and reduced cleaved-caspase3. Furthermore, 6-MITC treatment enhanced NK cell activity, especially when administered before tumor xenografting. CONCLUSION: These results indicate that 6-MITC has a marked anti-tumor effect against EMC cells and a novel effect to enhance NK cell activity. These effects suggest the therapeutic potential of 6-MITC.

Peripheral blood natural killer cell cytotoxicity in recurrent miscarriage: a systematic review and meta-analysis.

Dysregulated natural killer (NK) cells have been associated with recurrent miscarriages (RM). Studies have suggested that high peripheral blood NK cell cytotoxicities (pNKCs) are associated with an increased risk of RM. The aim of this systematic review (SR) and meta-analysis (MAs) is to investigate the difference in pNKC between nonpregnant and pregnant women with RM and controls and determine whether pNKC is reduced by immunotherapy. We searched the PubMed/Medline, Embase, and Web of Science databases. The MAs were conducted to compare pNKCs between women with and without RM before and during pregnancy as well as pre- and post-immunotherapy. Risk of bias in nonrandomized studies was assessed by the Newcastle-Ottawa Scale. Statistical analysis was performed using the Review Manager software. A total of 19 studies were included in the SR and 14 studies in the MAs. The MAs revealed higher pNKCs among nonpregnant women with RM compared to controls (MD, 7.99 95 %CI 6.40-9.58; p < 0.00001). pNKCs were also higher in pregnant women with RM than in pregnant controls (MD, 8.21 95 %CI 6.08-10.34; p < 0.00001). Women with RM showed significantly decreased pNKCs after the immunotherapy compared to before (MD, -8.20 95 %CI -10.20 - -6.19; p < 0, 00001). Additionally, there is an association between high pNKCs and the risk of pregnancy loss in women with RM. However, included studies showed substantial heterogeneities regarding the inclusion criteria of patients, techniques measuring pNKC, and types of immunotherapies. More studies are needed to evaluate the clinical efficiency of pNKCs in managing RM.