Levels of 4-1BB transcripts and soluble 4-1BB protein are elevated in the adipose tissue of human obese subjects and are associated with inflammatory and metabolic parameters.

BACKGROUND: 4-1BB, a member of the TNF receptor superfamily, has a role in various inflammatory pathologies through its interaction with 4-1BB ligand. We previously demonstrated that it participates in initiating and promoting obesity-induced adipose inflammation in a rodent model. OBJECTIVE: In this study, we examined whether 4-1BB is related to obesity-induced adipose inflammation and metabolic parameters in humans. METHODS: A total of 50 subjects, 25 obese (body mass index (BMI)≥25 kg m(-2)) and 25 lean (BMI<23 kg m(-2)) participated in the study. The levels of 4-1BB transcripts and soluble 4-1BB protein (s4-1BB) in subcutaneous adipose tissue were measured by quantitative real-time PCR and enzyme-linked immunosorbent assay, respectively. Inflammatory and metabolic parameters were measured by enzymatic analysis and immunoassay. RESULTS: Obese subjects had higher levels of both 4-1BB transcripts and s4-1BB protein in subcutaneous adipose tissue than lean controls, and the levels were correlated with BMI and the expression of inflammatory markers, as well as with serum metabolic parameters. Moreover, s4-1BB was released from human adipocytes, and elicited chemotactic responses from human monocytes/T cells as well as enhancing their inflammatory activity, indicating that it may promote human adipose inflammation. DISCUSSION: Our data demonstrate that elevated levels of 4-1BB transcripts and s4-1BB in adipose tissue are closely associated with obesity-induced inflammation and metabolic dysregulation. They suggest that both 4-1BB transcripts and s4-1BB could serve as novel biomarkers and/or therapeutic targets for obesity-induced inflammation and metabolic syndrome in humans.

Two-hour post-load plasma glucose levels are associated with carotid intima-media thickness in subjects with normal glucose tolerance.

AIMS: Elevated post-load plasma glucose levels may increase the risk of cardiovascular disease, even when they are within the normoglycaemic range. We examined the association of carotid artery intima-media thickness, a marker of early atherosclerosis, with glycaemic variables, including post-load plasma glucose levels, in Japanese subjects with normal glucose tolerance. METHODS: The study participants were 663 Japanese subjects with normal glucose tolerance (565 men, mean age 47 ± 9 years) who underwent both a 75-g oral glucose tolerance test and carotid artery intima-media thickness measurement by B-mode ultrasonography during a health examination. Associations between maximal common carotid artery intima-media thickness and fasting plasma glucose, 1-h and 2-h plasma glucose during an oral glucose tolerance test, and HbA1c were examined. RESULTS: The carotid artery intima-media thickness gradually increased across the tertiles of 1-h plasma glucose, 2-h plasma glucose and HbA1c . In multiple linear regression analysis, 2-h plasma glucose (ß = 0.09, P = 0.012), as well as age, male gender, hypertension, dyslipidaemia, and current smoking were independent determinants of carotid artery intima-media thickness. In contrast, other glycaemic variables were not independent determinants of carotid artery intima-media thickness. The carotid artery intima-media thickness in hypertensive subjects with the highest tertile of 2-h plasma glucose [0.70 (95% CI 0.64-0.76) mm] was significantly greater than in normotensive subjects, with the lowest tertile of 2-h plasma glucose [0.60 (95% CI 0.58-0.63) mm, P = 0.037], even after adjusting for the multiple potential confounders. CONCLUSIONS: The 2-h plasma glucose during an oral glucose tolerance test was positively and independently associated with carotid artery intima-media thickness in Japanese subjects with normal glucose tolerance. In particular, the combination of elevated 2-h plasma glucose and hypertension may contribute to an increased carotid artery intima-media thickness.

Carbamate pesticide-induced apoptosis and necrosis in human natural killer cells.

We previously found that ziram, a carbamate fungicide, significantly induced apoptosis and necrosis in human NK-92MI, a natural killer cell line. To investigate whether other carbamate pesticides also induce apoptosis and necrosis in human natural killer cell, we conducted further experiments with NK-92CI, a human natural killer cell line using a more sensitive assay. NK-92CI cells were treated with ziram, thiram, maneb or carbaryl at 0.031-40 microM for 2-24 h in the present study. Apoptosis and necrosis were determined by FITC-Annexin-V/PI staining. To explore the mechanism of apoptosis, intracellular levels of active caspases 3 and mitochondrial cytochrome-c release were determined by flow cytometry. We found that ziram and thiram also induced apoptosis and necrosis in a time- and dose-dependent manner; however, maneb and carbaryl induced apoptosis and necrosis only at higher doses in NK-92CI cells. The strength of the apoptosis-inducing effect differed among the pesticides, and the order was as follows: thiram > ziram greater than maneb greater than carbaryl. NK-92CI was more sensitive to ziram than NK-92MI. Moreover, ziram and thiram significantly increased the intracellular level of active caspase 3 in NK-92CI and caspase inhibitor significantly inhibited the apoptosis. Ziram and thiram significantly caused mitochondrial cytochrome-c release in NK-92CI. These findings indicate that carbamate pesticides can induce apoptosis in natural killer cells, and the apoptosis is mediated by both the caspase-cascade and mitochondrial cytochrome-c pathways.

Does subjective evaluation of the frequency of salty food intake predict the risk of incident hypertension? A 4-year follow-up study in a middle-aged population.

BACKGROUND: Excess salt intake increases blood pressure (BP). Identifying individuals with excess salt intake is, therefore, important for the prevention of hypertension. AIM: To examine the predictive value of subjective evaluation of salty foods intake for the risk of incident hypertension in a middle-aged population. METHODS: A total of 970 non-hypertensive workers (mean age, 44 ± 6 years) was followed for a maximum period of 4 years, and their BP was measured annually. At baseline, all participants were asked about their subjective frequency of salty foods intake (seldom, sometimes or always), and they were divided into three groups according to their answers. Hypertension was defined as systolic/diastolic BP ≥ 140/90 mmHg or use of antihypertensive medications. RESULTS: There were no significant differences in the 4-year cumulative incident rate of hypertension among the 'seldom', 'sometimes' and 'always' groups (15.8%, 14.3% and 10.3%, respectively, log-rank test P = 0.44). In a multivariate Cox proportional hazards model, age, body mass index and the baseline BP category were independent predictors for developing hypertension, whereas the frequency of salty foods intake was not a predictor (adjusted hazard ratio (95% confidence interval), 0.99 (0.64-1.54) in the 'sometimes' group and 0.64 (0.33-1.28) in the 'always' group as compared with the 'seldom' group). CONCLUSION: The subjective evaluation of salty foods intake did not predict the 4-year risk of incident hypertension in this study population. Further investigations with a longer follow-up period are needed to clarify whether the present insignificant results are maintained for more than 4 years.

Influence of non-steroidal anti-inflammatory drugs on antiplatelet effect of aspirin.

WHAT IS KNOWN AND OBJECTIVE: It has been reported that ibuprofen interferes with the antiplatelet effect of low-dose aspirin. This interaction is ascribed to steric hindrance at the active site of cyclooxygenase-1 by ibuprofen, when aspirin is administered after ibuprofen. However, whether other non-steroidal anti-inflammatory drugs (NSAIDs) interact with aspirin similarly is not well defined. The aim of this study was to assess the influence of nine NSAIDs on the antiplatelet effect of aspirin. METHODS: We investigated the antiplatelet effect of NSAIDs using steady-state plasma concentration reported after usual doses. We studied the in vitro antiplatelet effect of NSAID alone, aspirin alone, aspirin before NSAID addition and aspirin after NSAID addition to platelet-rich plasma. The rates of platelet aggregation induced by collagen were determined. The final concentration of aspirin used was the 50% effective concentration (EC(50)) previously estimated in vitro. RESULTS AND DISCUSSION: Ibuprofen and mefenamic acid interfere with the antiplatelet effect of aspirin when added before the latter. The rate of platelet aggregation was reduced by 48·1% and 22·7%, respectively. The other NSAIDs tested did not significantly affect the aspirin antiplatelet effect when exposure was prior to aspirin. None of the nine NSAIDs altered the aspirin effect if administration followed that of aspirin. WHAT IS NEW AND CONCLUSION: Naproxen and flurbiprofen have significant antiplatelet effects at plasma concentrations seen with usual doses. Our in vitro model suggests that the antiplatelet effect of aspirin is significantly diminished when taken after, but not before, ibuprofen or mefenamic acid. None of the other NSAIDs tested had any effect irrespective of the timing of dosing.

Mechanism of ziram-induced apoptosis in human natural killer cells.

We previously found that ziram, a dithiocarbamate fungicide, significantly inhibited natural killer (NK) activity in a dose-dependent manner. To explore the mechanism of this inhibition, we investigated ziram-induced apoptosis in human NK cells. Human NK-92MI cells were treated with ziram at 0.0625-4 µM for 2-64 h. Apoptosis was determined by FITC-Annexin-V/PI staining. To explore the mechanism of apoptosis, intracellular levels of active caspases 3, 3/7, 8, and 9 and pan-caspase and mitochondrial cytochrome-c release were determined by flow cytometry. Disruption to mitochondrial transmembrane potential was determined with a MitoLight? Apoptosis Detection Kit. It was found that ziram induced apoptosis in a dose- and time-dependent manner in human NK cells. Ziram increased the intracellular levels of active caspases 3, 3/7, 8, and 9 and pan-caspase in a dose-dependent manner, and a caspase-3 inhibitor, Z-DEVD-FMK, and a general caspase inhibitor, Z-VAD-FMK, partially but significantly inhibited the apoptosis. Ziram also disrupted mitochondrial transmembrane potential and caused mitochondrial cytochrome-c release in a dose-dependent manner. These findings indicate that ziram can induce apoptosis in human NK cells, and the apoptosis is at least mediated by both the caspase-cascade and the mitochondria/cytochrome-c pathways.

The current role of precision surgery in oligometastatic prostate cancer.

Oligometastatic prostate cancer (omPCa) is a novel intermediate disease state characterized by a limited volume of metastatic cells and specific locations. Accurate staging is paramount to unmask oligometastatic disease, as provided by prostate-specific membrane antigen-positron emission tomography. Driven by the results of prospective trials employing conventional and/or modern staging modalities, the treatment landscape of omPCa has rapidly evolved over the last years. Several treatment-related questions comprising the concept of precision strikes are under development. For example, beyond systemic therapy, cohort studies have found that cytoreductive radical prostatectomy (CRP) can confer a survival benefit in select patients with omPCa. More importantly, CRP has been consistently shown to improve long-term local symptoms when the tumor progresses across disease states due to resistance to systemic therapies. Metastasis-directed treatments have also emerged as a promising treatment option due to the visibility of oligometastatic disease and new technologies as well as treatment strategies to target the novel PCa colonies. Whether metastases are present at primary cancer diagnosis or detected upon biochemical recurrence after treatment with curative intent, targeted yet decisive elimination of disseminated tumor cell hotspots is thought to improve survival outcomes. One such strategy is salvage lymph node dissection in oligorecurrent PCa which can alter the natural history of progressive PCa. In this review, we will highlight how refinements in modern staging modalities change the classification and treatment of (oligo-)metastatic PCa. Further, we will also discuss the current role and future directions of precision surgery in omPCa.