Classically activated pro-inflammatory macrophages are generated from naive macrophages by pro-inflammatory cues that dynamically reprogram their fuel metabolism toward glycolysis. This increases ...their intracellular reactive oxygen species (ROS) levels, which then activate the transcription and release of pro-inflammatory mediators. Our study on mice that lack methionine sulfoxide reductase (Msr)-B1 shows that the resulting partial loss of protein methionine reduction in pro-inflammatory macrophages creates a unique metabolic signature characterized by altered fuel utilization, including glucose and pyruvate. This change also associates with hyper-inflammation that is at least partly due to sustained oxidation of an exposed methionine residue (M44) on glyceraldehyde 3-phosphate dehydrogenase (GAPDH), thereby inducing GAPDH aggregation, inflammasome activation, and subsequent increased interleukin (IL)-1β secretion. Since MsrB1-knockout mice exhibit increased susceptibility to lipopolysaccharide (LPS)-induced sepsis, the MsrB1-GAPDH axis may be a key molecular mechanism by which protein redox homeostasis controls the metabolic profile of macrophages and thereby regulates their functions.
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•MsrB1 plays critical roles in controlling pro-inflammatory macrophage activation•MsrB1 is a bona fide regulator of ROS-driven GAPDH methionine oxidation•MsrB1 depletion leads to GAPDH aggregation, which unleashes inflammasome activation•In a model for sepsis, hyper-inflammation is exacerbated by the lack of MsrB1
Yoo et al. show that upon MsrB1 depletion, glucose metabolism becomes dysregulated due to an exacerbated ROS-driven GAPDH aggregation, which leads to an increased NAD+/NADH ratio and mitochondrial ROS, thereby unleashing inflammasome activation and IL-1β secretion. Such an observation is recapitulated in MsrB1-KO mice displaying hyper-inflammation and increased susceptibility to sepsis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A polyethylene vinyl acetic acid (EVA) nanocomposite comprising of an intumescent agent that incorporates ammonium phosphate monobasic, mono-pentaerythritol, and melamine with a cationic nanoclay was ...set up through solution blending and melt blending to assess the fire retardancy utilizing a cone calorimeter. The results demonstrated that there was a significant reduction in the peak heat release rate of 70% contrasted with pure EVA. The fire retardancy of the clay-organic intumescent mixture framework composite was more successful than a same amount of additional nanoclay and intumescent agent. To check these outcomes, the residues of cone calorimeter samples were assessed alongside clay d-spacing changes amid utilization.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Although various in vitro assays have been developed to evaluate the cytochrome P450 (CYP)-inducing potential of drug candidates, there is a continuing need for the development of a reliable model in ...drug discovery. The objective of the present study was to compare CYP induction by chemicals in HepG2 cells with Huh7, NKNT-3, and reverted NKNT-3 cells. HepG2 cells showed more similarity to human liver than the other cell lines in comparisons of the expression of cellular proteins. In evaluation of basal CYP activity, Huh7 cells exhibited the highest CYP1A2 and CYP3A4 activity, and HepG2 cells showed the highest CYP2B6 activity. The inducibility of CYP1A2, CYP2B6, and CYP3A4 by prototypical inducers was determined using enzyme assay, immunoblot analysis, and real-time PCR. Among the cells tested, HepG2 cells were highly responsive to CYP inducers, such as 3-methylcholanthrene for CYP1A2 and phenobarbital for CYP2B6 and CYP3A4. Moreover, HepG2 cells were responsive to various CYP1A2, CYP2B6, and CYP3A4 inducers as determined using fluorogenic and LC–MS/MS substrates. Thus, HepG2 cells may be comparable to human hepatocytes for the evaluation of CYP induction or slightly less sensitive. These results suggest HepG2 cells as a cell-based model in screening for CYP inducers in drug discovery.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Purpose: Coronavirus disease 2019 (COVID-19) has affected many parts of daily life and healthcare, including cancer screening and diagnosis. The purpose of this study was to determine whether there ...was an upshift in the colorectal cancer stage at diagnosis due to delays related to the COVID-19 outbreak.Methods: From January to June of each year from 2017 to 2020, a total of 3,229 patients who were first diagnosed with colorectal cancer were retrospectively reviewed. Those enrolled from 2017 to 2019 were classified as the ‘pre-COVID’ group, and those enrolled in 2020 were classified as the ‘COVID’ group. The primary outcome was the rate of stage IV disease at the time of diagnosis.Results: There was no statistically significant difference in the proportion of stage IV patients between the pre-COVID and COVID groups (P=0.19). The median preoperative carcinoembryonic antigen level in the COVID group was higher than in the pre-COVID group in all stages (all P<0.05). In stage I, II patients who underwent radical surgery, the lymphatic invasion was more presented in COVID patients (P=0.009).Conclusion: We did not find significant stage upshifting in colorectal cancer during the COVID-19 outbreak. However, there were more initially unresectable stage IV colorectal cancer patients with a low conversion rate to resectable status, and more patients had factors related to poor prognosis. These results may become more apparent over time, so it is vital not to neglect cancer screening to not delay the diagnosis during the COVID-19 epidemic.
Lateral cervical lymph node (LCLN) metastasis, or pathologic N1b disease, is an important risk factor in papillary thyroid carcinoma (PTC). However, many patients have favorable prognosis even with ...pathologic N1b patients in clinical practice. The study aims to identify high- and intermediate-risk groups based on initial pathologic characteristics in these patients.
This study included 518 classical PTC patients confirmed as pathologic N1b at initial surgery between 2001 and 2010. All patients underwent a single fixed activity (5.6 GBq) of radioactive I-131 remnant ablation.
Patients with a primary tumor larger than 4 cm, gross extrathyroidal extension, metastatic LN larger than 3 cm, or greater than 10 metastatic LCLN were classified as high-risk group. These comprehensive pathologic criteria were retrieved from cox proportional hazard models. Twenty two percent of patients (n = 113) were classified as high-risk and 78% (n = 405) as intermediate-risk group. Successful ablation was identified in only 32% of the patients in the high-risk group and 61% in the intermediate-risk group (p < 0.001). The difference between the two risk groups was independent to gender. There was a significant difference in disease-free survival between the high- and intermediate- risk N1b groups during 5.1 years of median follow-up (84% vs. 59%, p < 0.001). Distant metastasis was more prevalent in the high-risk group (20%) than in the intermediate-risk group (4%, p < 0.001).
The prognosis of PTC patients with LCLN metastasis varies depending on initial pathologic characteristics. We proposed the comprehensive pathologic criteria for sub-classification of N1b into high- and intermediate-risk groups and this sub-classification may permit personalized management of N1b PTC patients.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Peritoneal fibrosis (PF) is an intractable complication of peritoneal dialysis (PD) that leads to peritoneal membrane failure. This study investigated the role of suppression of tumorigenicity (ST)2 ...in PF using patient samples along with mouse and cell‐based models. Baseline dialysate soluble (s)ST2 level in patients measured 1 month after PD initiation was 2063.4 ± 2457.8 pg/mL; patients who switched to haemodialysis had elevated sST2 levels in peritoneal effluent (1576.2 ± 199.9 pg/mL, P = .03), which was associated with PD failure (P = .04). Baseline sST2 showed good performance in predicting PD failure (area under the receiver operating characteristic curve = 0.780, P = .001). In mice with chlorhexidine gluconate‐induced PF, ST2 was expressed in fibroblasts and mesothelial cells within submesothelial zones. In primary cultured human peritoneal mesothelial cells (HPMCs), transforming growth factor‐β treatment increased ST2, fibronectin, β‐galactosidase and Snail protein levels and decreased E‐cadherin level. Anti‐ST2 antibody administration reversed the up‐regulation of ST2 and fibronectin expression; it also reduced fibrosis induced by high glucose (100 mmol/L) in HPMCs. Thus, high ST2 level in dialysate is a marker for fibrosis and inflammation during peritoneal injury, and blocking ST2 may be an effective therapeutic strategy for renal preservation.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Although the antimyeloma effect of lenalidomide is associated with activation of the immune system, the exact in vivo immunomodulatory mechanisms of lenalidomide combined with low-dose dexamethasone ...(Len-dex) in refractory/relapsed multiple myeloma (RRMM) patients remain unclear. In this study, we analyzed the association between immune cell populations and clinical outcomes in patients receiving Len-dex for the treatment of RRMM. Peripheral blood samples from 90 RRMM patients were taken on day 1 of cycles 1 (baseline), 2, 3, and 4 of Len-dex therapy. Peripheral blood CD3
+
, CD4
+
, and CD8
+
cell frequencies were significantly decreased by 3 cycles of therapy, whereas NK cell frequency was significantly increased after the 3rd cycle. For the myeloid-derived suppressor cell (MDSC) subset, the frequency of granulocytic MDSCs transiently increased after the 1st cycle, whereas there was an increase in monocytic MDSC (M-MDSC) frequency after the 1st and 3rd cycles. Among 81 evaluable patients, failure to achieve a response of VGPR or greater was associated with a decrease in CD8
+
cell frequency and increase in M-MDSC frequency after 3 cycles of Len-dex treatment. A high proportion of natural killer T (NKT)-like cells (CD3
+
/CD56
+
) prior to Len-dex treatment might predict a longer time to progression. In addition, patients with a smaller decrease in the frequency of both CD3
+
cells and CD8
+
cells by 3 cycles exhibited a longer time to the next treatment. These results demonstrated that early changes in immune cell subsets are useful immunologic indicators of the efficacy of Len-dex treatment in RRMM.
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EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UL, UM, UPUK, VKSCE, ZAGLJ
The primary purpose of this study was to investigate the differences in the serum brain-derived neurotrophic factor (BDNF) level between elderly Korean people over 65 years with and without dementia.
...171 individuals over 65 years were enrolled in this study. Screening for cognitive impairments was carried out using the Mini-Mental Status Examination-Korean version (MMSE-KC). One hundred thirty-two subjects scored below 1.5 standard deviations (SD) of the mean MMSE-KC score, and these were evaluated using the Consortium to Establish a Registry for Alzheimer's Disease, Korean version (CERAD-K) and the Geriatric Depression Scale (GDS). The Clinical Dementia Rating Scale (CDRS) and the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) diagnostic criteria were used for further evaluation. Subjects with a CDRS score of 1 or higher were classified as having Alzheimer's disease (AD), and subjects with a CDRS score of 0.5 were classified as having a mild cognitive impairment (MCI). Subjects with a CDRS score of 0 were classified as having aging-associated cognitive decline (AACD). Serum BDNF levels were analyzed using the enzyme-linked immunosorbent assay (ELISA) method.
The serum BDNF levels were significantly lower in the subjects with MCI and AD compared with the healthy controls (p<0.01). A significant correlation was found between the total MMSE-KC score and serum BDNF level (r=0.295; p<0.01). However, no significant correlation was observed between the severity of MMSE-KC and the total GDS score. A significant difference was found in the total score of GDS between the AACD group and subjects with AD (p<0.05).
This study suggested that BDNF might be involved in the pathophysiology of cognitive decline in elderly people.
Background: Stair-climbing (SC) is an essential daily life skill, and stair-climbing exercise (SCE) serves as a valuable method for promoting physical activity in older adults. This study aimed to ...compare the impact of SCEs with heel contact (HC) and heel off (HO) during SC on functional mobility and trunk muscle (TM) activation amplitudes in community-dwelling older adults. Methods: In the pilot randomized controlled trial, participants were randomly allocated to either the HC group (n = 17; mean age 75.9 ± 6.3 years) or the HO group (n = 17; mean age 76.5 ± 4.6 years). The HC participants performed SCE with the heel of the ankle in contact with the ground, while the HO participants performed SCE with the heel of the ankle off the ground during SC. Both groups participated in progressive SCE for one hour per day, three days per week, over four consecutive weeks (totaling 12 sessions) at the community center. We measured timed stair-climbing (TSC), timed up and go (TUG), and electromyography (EMG) amplitudes of the TMs including rectus abdominis (RA), external oblique (EO), transverse abdominus and internal oblique abdominals (TrA-IO), and erector spinae (ES) during SC before and after the intervention. Results: Both groups showed a significant improvement in TSC and TUG after the intervention ( P < .01, respectively), with no significant difference between the groups. There was no significant difference in the EMG activity of the TMs between the groups after the intervention. The amplitude of TMs significantly decreased after the intervention in both groups ( P < .01, respectively). Conclusion: Both SCE methods could improve balance and SC ability in older adults while reducing the recruitment of TMs during SC. Both SCE strategies are effective in improving functional mobility and promoting appropriate posture control during SC in older adults.
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