Efficacy and safety of tacrolimus in older adults with ulcerative colitis: a retrospective study.

BACKGROUND/AIMS: The prevalence of ulcerative colitis (UC) has been increasing, also in older adults. Here, we retrospectively compared the efficacy and safety of tacrolimus (TAC) in older and younger patients with UC. METHODS: We included younger (age < 65 years; n = 116) and older patients (age ≥ 65 years; n = 21) with UC who received TAC from April 2009 through December 2022(mean follow-up, 1230 ± 175 days) and achieved remission. Evaluations included age at onset, laboratory values, estimated glomerular filtration rate (eGFR), use of 5-aminosalicylic acid (5-ASA), biological experience, colonoscopy scores, remission at 1 month after treatment initiation, and adverse events. Treatment duration and renal function were assessed in patients with follow-up data (younger patients, n = 110; older patients, n = 19). RESULTS: Older patients had a higher age at onset and treatment initiation but less 5-ASA use and biological experience. Before treatment, hemoglobin, albumin, and eGFR were significantly lower in the older group and CRP was significantly higher. The remission rate was 80.1% in the younger group and 66.6% in the older group (P = 0.1862). Adverse events were similar in both groups. The older group had a shorter treatment duration and significantly less change in renal function at all time points. DISCUSSION: Rates of TAC-induced remission and adverse events were similar in older and younger adults with UC. CONCLUSION: TAC can be used safely in elderly patients with moderate to severe UC with careful monitoring.

A retrospective study to investigate the efficacy and safety of granulocyte and monocyte adsorptive apheresis in patients with primary sclerosing cholangitis with ulcerative colitis.

BACKGROUND AND AIMS: Primary sclerosing cholangitis has a poor prognosis and can be accompanied by ulcerative colitis. Infection control is essential, so immunosuppressive drugs should ideally be preferably. Granulocyte and monocyte adsorptive apheresis does not suppress the immune system and is used to treat ulcerative colitis. Therefore, this study investigated the efficacy and safety of granulocyte and monocyte adsorptive apheresis in patients with primary sclerosing cholangitis and ulcerative colitis. METHODS: We retrospectively evaluated data from patients with primary sclerosing cholangitis with ulcerative colitis who visited our hospital from April 2000 to December 2022 and underwent granulocyte and monocyte adsorptive apheresis (n = 10, number of treatment cycles = 15). Study endpoints were remission induction rate and safety, assessed as changes in liver functions and adverse events. RESULTS: Seven of the 10 patients were male. The median (min-max) age was 23 (18-77) years. The most common disease type was right-dominant pancolitis. Remission occurred after 86.6% of cycles (13/15). Serum alkaline phosphatase and Aspartate transaminase were significantly lower after treatment (P = .0124, P = .002), and no negative effects on liver function were seen. The only adverse events were headache (n = 1) and decreased blood pressure (n = 1). CONCLUSIONS: Granulocyte and monocyte adsorptive apheresis has high efficacy for intestinal lesions and improves alkaline phosphatase and aspartate transaminase levels (high levels are a poor prognosis factor). It appears to be a treatment option in patients with primary sclerosing cholangitis associated with ulcerative colitis.

Recovery of phosphorus, magnesium, and potassium from surplus activated sludge using existing sludge treatment facilities and thickened primary sludge.

The separation of P, K, and Mg from surplus activated sludge (SAS) was investigated using existing sludge treatment facilities and the thickened primary sludge (TPS). The addition of the TPS to the SAS storage tank accelerated the anaerobic release of the three elements from SAS with maximum efficiencies of about 60%. The efficiency of P release showed a significant correlation with the oxidation-reduction potential. Increasing the total solid concentration increased the release of elements. The released elements could be transferred to a separate liquid (SL) from a screw-press thickener, and maximum concentrations of P, K, and Mg were about 200, 60, and 35 mg/L, respectively. The addition of CaCl2 and NaOH solutions to SL precipitated P as hydroxyapatite. However, no precipitation of K and Mg occurred simultaneously with P, even when the pH of SL was increased to 9. These findings suggest that about 60% of P, K, and Mg can be separated from SAS into SL using existing sludge treatment facilities and TPS; however, a method other than precipitation would be needed to recover P and K from SL simultaneously.

Nano-displacement sensing by phase-diversity optical digital coherent detection utilizing alternating quadrature phase-modulated reference light.

We have introduced a nanometer-scale non-contact displacement sensing method that relies on phase-diversity optical digital coherent detection. In our prior work, we used a conventional setup involving a 90°optical hybrid, two balanced amplified photodetectors (BAPs), and a narrow-linewidth (NLW) laser, which is complex and costly. However, in this paper, we have streamlined the system configuration by employing alternating quadrature phase modulation (AQPM) reference light, implemented using a phase modulator and a BAP. Moreover, we've employed an economical distributed feedback (DFB) laser, enabling us to achieve displacement sensing at 1.6 nm with a resolution of 0.6 nm. It is notable that there is some degradation in the performance due to the phase noise compared to the NLW laser, which achieves a displacement sensing down to 0.6 nm with a 0.2 nm resolution. Nevertheless, the DFB-AQPM system holds a significant potential for cost-effective, high-resolution nanometer-scale sensing applications.

Unlocking fertilization potential of anaerobically digested sewage sludge centrate for protein-rich rice cultivation with composted sludge amendment.

The use of composted sewage sludge (CSS) and centrate as alternatives to synthetic fertilizers in rice cultivation holds great promise. This study aims to determine the effects of varying doses and timings of centrate derived from anaerobically digested sewage sludge on rice yield, nutrient quality, and soil fertility when applied as a topdressing to rice fields fertilized with CSS. At the panicle initiation (PI) stage, 100, 300, and 500 kg N ha-1 of centrate topdressing (CT100, CT300, and CT500, respectively) was applied. In addition, different topdressing timings at a total dose of 500 kg N ha-1 were evaluated, including a two-split application (40% at active tillering (AT) and 60% at PI; CT500S2) and a three-split application (40% at AT + 40% at PI + 20% at heading; CT500S3). At a rate of 160 kg N ha-1, CSS was used as a base fertilizer in all treatments. A control treatment received synthetic fertilizers at a rate of 160 kg N ha-1 as a base application and 100 kg N ha-1 as a topdressing. Results showed that CSS-treated rice plants exhibited a lower N status and leaf chlorophyll content during the vegetative growth stage; however, the split application of centrate topdressing improved plant N status, resulting in an increase in biomass and grain yield. Centrate and CSS tended to increase the mineral content of rice; nevertheless, a significant accumulation of As in grains raised concerns about food safety. Combining CSS and centrate has the potential to increase rice production, improve grain nutritional value, and decrease reliance on synthetic fertilizers. However, it is essential to optimize this fertilization, mitigate environmental risks, and ensure food safety by employing appropriate fertilization dosing and timing as well as appropriate field management strategies.

Statistical model of trajectories of reduced mobility in older people with locomotive disorders: a prospective cohort study with group-based trajectory model.

BACKGROUND: Today we experience "Super-aged society", and a drastic increase in the number of older people needing assistance is an urgent matter for everyone from medical and socio-economical standpoints. Locomotive organ dysfunction due to musculoskeletal disorders is one of the main problems in these patients. Although the concepts of frailty and sarcopenia have been proposed for functional decline, pain remains the main and non-negligible complaint in these of such disorders. This prospective cohort study aimed to observe the changes of reduced mobility in patients with locomotive disorders and to determine the risk factors for functional deterioration of those patients using statistical modeling. METHODS: A cohort of older adults with locomotive disorders who were followed up every 6 months for up to 18 months was organized. Pain, physical findings related to the lower extremities, locomotive function in performing daily tasks, and Geriatric Locomotive Function Scale-25 (GLFS-25) score were collected to predict the progress of deterioration. Group-based trajectory analysis was used to identify subgroups of changes of GLFS-25 scores, and multinomial logistic regression analysis was performed to investigate potential predictors of the GLFS-25 trajectories. RESULTS: Overall, 314 participants aged between 65 and 93 years were included. The participants were treated with various combinations of orthopedic conservative treatments on an outpatient basis. The in-group trajectory model analysis revealed a clear differentiation between the four groups. The mild and severe groups generally maintained their GLFD-25 scores, while the moderate group included a fluctuating group and a no change group.　This study showed that comorbidity of osteoporosis was related to GLFS-25 score over 18 months. Age was a weak factor to be moderate or severe group, but gender was not. In addition, the number of pain locations, number of weak muscles, one-leg standing time, grip strength and BMI significantly contributed to the change in GLFS-25 score. CONCLUSIONS: This study proposes an effective statistical model to monitor locomotive functions and related findings. Pain and comorbid osteoporosis are significant factors that related to functional deterioration of activities. In addition, the study shows a patient group recovers from the progression and their possible contributing factors.

CD98 expression can be a predictive factor of resistance to radiotherapy in head and neck squamous cell carcinoma.

CD98 is a marker of cancer stem cells, and it regulates radiosensitivity in head and neck squamous cell carcinoma (HNSCC). The current study aimed to investigate whether CD98 can be used as a prognostic factor and marker of radioresistance. CD98 immunostaining was performed using biopsy specimens collected from patients diagnosed with HNSCC. The average period of postoperative monitoring was 31.6 months. The treatment options were radiation therapy with either cisplatin or cetuximab, and surgery. The participants were divided into groups of low and high fluorescence intensity. CD98 was an independent prognostic factor of radioresistance. In total, 103 patients were treated with chemoradiotherapy or bioradiotherapy. The overall survival rates of patients receiving chemoradiotherapy or bioradiotherapy were 69.2% in the low group and 36.2% in the high group. The progression-free survival rates were 60.0% and 24.6%, respectively. CD98 expression was considered an independent prognostic factor of overall survival and progression-free survival. In total, 99 patients underwent surgical treatment. The surgery group did not differ according to CD98 expression. Via CD98 immunostaining, sensitivity to radiotherapy can be determined in advance. In HNSCC, knowledge about sensitivity to radiotherapy can significantly improve prognosis.

Degradation of sulfamonomethoxine in solution using pulsed plasma discharge - identification of by-products and toxicity of treated solution to green algae.

This study investigated the degradation of sulfamonomethoxine (SMM) by pulsed plasma discharge. SMM was successfully degraded following the first-order kinetics model. The percentage removal of SMM was estimated by the total input energy of plasma discharge, which was dependent on the initial SMM concentration. In addition, three types of by-products were observed at an early reaction time, which were then degraded. In contrast, the ecotoxicity of the treated solution by plasma discharge was assessed by an acute toxicity test using the green alga Raphidocelis subcapitata. The plasma discharge in water generated hydrogen peroxide with a concentration higher than the EC50 for R. subcapitata. It is therefore necessary to remove H2O2 or prevent the generation of H2O2 for the degradation of antibiotics in solutions using plasma discharge.

Effect of dissolved soil organic matter on cesium adsorption by zeolite and illite.

In controlled landfill sites, soil layers are installed around radioactive waste to prevent the leaching of radioactive cesium (Cs). The Cs retention capacity of soil has been reported to be enhanced by mixing clay minerals. However, several studies have indicated that dissolved soil organic matter (DSOM) inhibits the Cs sorption by clay minerals. Therefore, this study assesses the effect of DSOM on the Cs sorption by zeolite and illite. Excitation emission matrix fluorescence spectroscopy was used for DSOM in the soil solution before and after contact with clay minerals. The results show that DSOM sorption onto clay minerals, particularly fulvic acid, inhibited Cs sorption. Batch sorption tests were conducted to obtain the sorption isotherms using two sample solutions, namely, soil and ionic solutions. Soil solution, which contained DSOM, was prepared by mixing soil and ultrapure water and filtration using a 0.3-µm glass fiver filter. Ionic solution was prepared by removing DSOM larger than 500 Da from the soil solution using dialysis. The amount of sorbed Cs in the soil solution was lower than that in the ionic solution. Comparing the Freundlich coefficients (KF) between the soil and ionic solutions, we found that the KF values of zeolite and illite for the ionic solution accounted for 6.4- and 4.4-fold higher than that for the soil solution, respectively.

Safety and effectiveness of adalimumab in Japanese patients with juvenile idiopathic arthritis: Results from a real-world postmarketing study.

OBJECTIVES: This study was conducted to assess the real-world safety and effectiveness of adalimumab in patients with juvenile idiopathic arthritis (JIA). METHODS: In this all-case, postmarketing surveillance study (NCT01412021) conducted in Japan, patients receiving adalimumab for JIA affecting multiple joints were observed for 24 weeks. The safety (adverse drug reactions [ADRs]/serious ADRs) and effectiveness (4-variable Disease Activity Score in 28 joints using erythrocyte sedimentation rate [DAS28-4/ESR] remission rate) were assessed. RESULTS: In the safety population (n = 356), 90.3% (65/72; weight, ≥15-<30 kg) of patients received adalimumab 20 mg every 2 weeks (q2w) and 98.3% (236/240; weight ≥30 kg) received 40 mg q2w. Incidence of ADRs and serious ADRs was 29.8% (106/356) and 3.4% (12/356), respectively. Incidence of ADRs was significantly higher in patients aged <15 years vs. ≥15 years (34.6% vs. 21.1%, p = .0072), those with comorbidities vs. without (38.3% vs. 25.7%, p = .0155), and those receiving dose <40 mg q2w vs. ≥40 mg q2w (38.8% vs. 26.9%, p = .0418). DAS28-4/ESR remission rate improved from 21.7% (36/166) at baseline to 74.7% (112/150) at week 24. CONCLUSIONS: Adalimumab was well tolerated and had acceptable safety and effectiveness in patients with JIA in the real-world setting.

Relationship between mucosal healing by tacrolimus and relapse of refractory ulcerative colitis: a retrospective study.

BACKGROUND: Tacrolimus (TAC) is a powerful remission-inducing drug for refractory ulcerative colitis (UC). However, it is unclear whether mucosal healing (MH) influences relapse after completion of TAC.We investigated whether MH is related to relapse after TAC. PATIENTS: Among 109 patients treated with TAC, 86 patients achieved clinical remission and 55 of them underwent colonoscopy at the end of TAC. These 55 patients were investigated. METHODS: Patients with MH at the end of TAC were classified into the MH group (n = 41), while patients without MH were classified into the non-MH group (n = 14). These groups were compared with respect to 1) clinical characteristics before treatment, 2) clinical characteristics on completion of treatment, and 3) the relapse rate and adverse events rates. This is a retrospective study conducted at a single institution. RESULTS: 1) There was a significant difference in baseline age between the two groups before TAC therapy, but there were no significant differences in other clinical characteristics. The NMH group was younger (MH group: 48.1 (23-79) years, NMH group: 36.3 (18-58) years, P = 0.007). Endoscopic scores showed significant differences between the 2 groups at the end of TAC. There were also significant differences in the steroid-free rate after 24 weeks (MH group: 85.3%, NMH group 50%, P = 0.012). There was no significant difference in the relapse rate between the 2 groups at 100 days after remission, but a significant difference was noted at 300 days (17% vs. 43%), 500 days (17% vs. 75%), and 1000 days (17% vs. 81%) (all P < 0.05). CONCLUSIONS: TAC is effective for refractory ulcerative colitis. However, even if clinical remission is achieved, relapse is frequent when colonoscopy shows that MH has not been achieved. It is important to evaluate the mucosal response by colonoscopy on completion of TAC.

Comparison of Lewis Score and Capsule Endoscopy Crohn's Disease Activity Index in Patients with Crohn's Disease.

BACKGROUND/AIMS: Small bowel capsule endoscopy (SBCE) is used to visualize mucosal inflammatory changes in the small intestine of patients with Crohn's disease (CD). The Lewis score (LS) and Capsule Endoscopy Crohn's Disease Activity Index (CECDAI) are used to evaluate the visualized images. We determined the score disagreement between LS and CECDAI in patients with CD. METHODS: We evaluated 184 SBCE procedures in 102 CD patients with small bowel lesions. Patients were classified according to the Montreal classification. LS and CECDAI were calculated, and cases with disagreement between the two scores were identified. We investigated the characteristics of disagreement, and analyzed the relationships with the Crohn's Disease Activity Index (CDAI) and C-reactive protein. RESULTS: LS (504 ± 1160) correlated strongly with CECDAI (6 ± 5.4) (Spearman's rank correlation coefficient ρ = 0.81, p < 0.0001). LS values of 135 and 790 were equivalent to CECDAI values of 4.9 and 6.9, respectively. The inflammatory changes by LS were significantly observed in several tertiles in the CECDAI discrepancy group (LS < 135, CECDAI ≥ 4.9) compared with the normal agreement group (LS < 135, CECDAI < 4.9) (p < 0.0001). In both groups, CDAI was also significantly different between Montreal L1 and L3 groups (p = 0.0232, p = 0.0196, respectively). LS inflammation score was 0 in six cases in the LS discrepancy group (LS ≥ 135, CECDAI ≤ 4.9, n = 10); the high LS scores were in patients with high stricture scores. CONCLUSIONS: Discrepancies between the LS and CECDAI scores were observed in some patients. Cases with high CECDAI alone exhibited extensive inflammation and high disease activity (clinical symptoms and biomarker levels). CECDAI seems to better reflect active intestinal inflammation than LS.

Evaluation of Intestinal Patency with the Patency Capsule: The Twenty-Four Hour Assessment Method.

INTRODUCTION: Confirmation of intestinal patency using the patency capsule (PC) in 30-33 h may result in a complex testing schedule. The aim of this study was to perform and evaluate a 24-h PC procedure for potential use as a simple and easy-to-apply intestinal patency assessment method. SUBJECT AND METHODS: The study included 342 patients who were assessed 24 h after ingesting a PC for assessment of intestinal patency. The PC elimination rate and the distribution of elimination time were evaluated. RESULTS: Assessment of intestinal patency was conducted in 308 (90%) patients. Self-confirmed PC elimination within 24 h was possible in 104 (30.4%) patients. The PC was considered to have been already eliminated in 38 (11.1%) patients. Thus, the extracorporeal elimination rate was 41.5%. Among 200 patients with non-extracorporeal elimination, the PC reached the large intestine in 166 patients (48.5% of the total patients). Small-bowel capsule endoscopy (CE) was performed in all 308 patients, and the entire small bowel could be observed in 98.4%. Capsule retention was not observed in any of the patients. CONCLUSION: The 24-h assessment method, in which the PC can be ingested using the same procedure as that for CE capsule, can be handled more easily and is more useful clinically.

Efficacy and safety of granulocyte adsorption apheresis in elderly patients with ulcerative colitis.

BACKGROUND: Elderly ulcerative colitis (UC) is increasing. Elderly UC differ from younger UC with respect to the course of their disease. Granulocyte adsorption apheresis (CAP) is often used to treat elderly UC. We retrospectively analyzed the cases of elderly UC who underwent CAP for remission induction therapy in a comparison with younger UC. METHODS: 96 patients with UC underwent CAP. Patients who concurrently received tacrolimus, biological agents, or high-dose steroid therapy were excluded. The remaining 80 patients were evaluated. We divided them into an elderly group (aged ≥65 years) and a younger group, and then we compared the groups' (1) clinical characteristics, (2) the efficacy and adverse effects of CAP, and (3) the complications of PSL. RESULTS: The remission rate was 70.8% in the elderly group and 87.5% in the younger group. There were significant differences between the two groups with respect to the age at the onset of UC, the estimated glomerular filtration rate on admission, underlying diseases, and complications of PSL therapy. Adverse effects of CAP included headache, complications of blood reinfusion, heparin allergy, hypotension, and failure of blood removal. There were significant differences between the two groups with respect to the complications of PSL therapy (all P < .05). CONCLUSIONS: Although the elderly group had longer durations of UC, a higher prevalence of underlying diseases, and a higher frequency of adverse events due to PSL therapy. No serious adverse effects of CAP occurred in either group. Thus, CAP was safe and effective in both younger and elderly UC.

Cesium and strontium loads into a combined sewer system from rainwater runoff.

In this study, combined sewage samples were taken with time in several rain events and sanitary sewage samples were taken with time in dry weather to calculate Cs and Sr loads to sewers from rainwater runoff. Cs and Sr in rainwater were present as particulate forms at first flush and the particulate Cs and Sr were mainly bound with inorganic suspended solids such as clay minerals in combined sewage samples. In addition, multiple linear regression analysis showed Cs and Sr loads from rainwater runoff could be estimated by the total amount of rainfall and antecedent dry weather days. The variation of the Sr load from rainwater to sewers was more sensitive to total amount of rainfall and antecedent dry weather days than that of the Cs load.

Activation of apoptosis by caspase-3-dependent specific RelB cleavage in anticancer agent-treated cancer cells: involvement of positive feedback mechanism.

DTCM-glutarimide (DTCM-G) is a newly found anti-inflammatory agent. In the course of experiments with lymphoma cells, we found that DTCM-G induced specific RelB cleavage. Anticancer agent vinblastine also induced the specific RelB cleavage in human fibrosarcoma HT1080 cells. The site-directed mutagenesis analysis revealed that the Asp205 site in RelB was specifically cleaved possibly by caspase-3 in vinblastine-treated HT1080 cells. Moreover, the cells stably overexpressing RelB Asp205Ala were resistant to vinblastine-induced apoptosis. Thus, the specific Asp205 cleavage of RelB by caspase-3 would be involved in the apoptosis induction by anticancer agents, which would provide the positive feedback mechanism.

Tongue pressure during swallowing in adults with down syndrome and its relationship with palatal morphology.

In individuals with Down syndrome, hypotonicity of the tongue and an underdeveloped maxilla may lead to poor oral motor coordination, which adversely affects the oral phase of swallowing. This study aimed to evaluate the characteristics of pressure produced by the tongue against the hard palate during swallowing in individuals with Down syndrome. In addition, the relationship between tongue pressure and palatal morphology was examined. We studied nine adults with Down syndrome and ten healthy adults as controls. Tongue pressure while swallowing 5 mL water was recorded by a sensor sheet system with five measuring points attached to the hard palate. Palatal length, depth, width, curvature, and slope were measured by three-dimensional digital maxillary imaging. The order of onset of tongue pressure on the median line of the hard palate was the same in all participants, except for three with Down syndrome. The duration and maximal magnitude of tongue pressure on the median line in nine participants with Down syndrome were significantly shorter and lower than those of controls. In participants with Down syndrome, significant positive correlations were observed between the duration of tongue pressure at the mid-median part of the hard palate and palatal depth and width, and between the duration and maximal magnitude of tongue pressure at the posterior-median part and palatal length. These findings suggest that impaired tongue activity, poor tongue control, and constrained tongue motion due to a short and narrow palate contribute to swallowing difficulty in individuals with Down syndrome.

Efficacy of serum leucine-rich alpha-2 glycoprotein in predicting findings of Crohn's disease small bowel lesion in capsule endoscopy.

Background/Aims: Small bowel capsule endoscopy (SBCE) is an evaluation method for small bowel (SB) lesions in Crohn's disease (CD). However, the relationship between SBCE findings and the serological biomarker leucine-rich alpha-2 glycoprotein (LRG) remains unclear. We aimed to establish appropriate cutoff values of LRG to predict the presence of SB lesions in CD through SBCE. Methods: Patients with CD with SB lesions who had undergone SBCE and LRG measurements 1 month before and after the SBCE were included. The LRG values for ulcers ≥0.5 cm and other inflammatory lesions noted in SBCE were determined using the Youden Index, and the sensitivity and specificity were calculated. Additionally, the correlation between the SBCE scores (CD Activity in Capsule Endoscopy) and LRG values was evaluated. Results: Forty patients without active colorectal lesions were included in the study. When the cutoff value of LRG for SB ulcers ≥ 0.5 cm was set at 14 µg/mL, the sensitivity was 92.3%, specificity was 81.5%, positive predictive value (PPV) was 70.6%, and negative predictive value (NPV) was 95.7%. In contrast, an LRG cutoff value of 12 µg/mL without inflammatory findings had a sensitivity of 91.7%, specificity of 82.1%, PPV of 68.8%, and NPV of 95.8%. CD Activity in Capsule Endoscopy correlated well with LRG values (Spearman's rank correlation coefficient ρ = 0.681, P< 0.001). Conclusions: An LRG cutoff value of 14 µg/mL may be useful in predicting the presence of SB ulcers ≥ 0.5 cm, and an LRG cutoff value of 12 µg/mL may be useful in predicting the absence of SB inflammatory findings.

Inhibition of NO-induced ß-cell death by novel NF-κB inhibitor (-)-DHMEQ via activation of Nrf2-ARE pathway.

Excessive nitric oxide (NO) plays a pivotal role in the progression of ß-cell apoptosis in type 1 diabetes mellitus. We used mouse insulinoma Min6 cells as a model of ß cells in this research. We found that (-)-DHMEQ, an NF-κB inhibitor, rescued ß cells from NO-induced apoptosis, and then studied the mechanism of apoptosis inhibition. (-)-DHMEQ activated Nrf2 and induced transcription of Nrf2-target genes following the increase of antioxidant response element (ARE) reporter activity. Similarly, tert-butyl hydroquinone (tBHQ), a known activator of Nrf2, inhibited NO-induced cell death along with the transcriptional activation of ARE. RNAi-mediated knockdown of Nrf2 lowered the cytoprotective effect of (-)-DHMEQ against NO, suggesting that (-)-DHMEQ inhibited NO-induced cell death via Nrf2 activation. Furthermore, overexpression of Nrf2 rendered cells to be more resistant to NO, indicating that Nrf2 activation provides critical defense function against NO in Min6 cells. Taken together, we conclude that (-)-DHMEQ may be a useful therapeutic agent for type 1 diabetes mellitus in the onset of disease by protecting ß cells from apoptosis.

Direct binding of calmodulin to the cytosolic C-terminal regions of sweet/umami taste receptors.

Sweet and umami taste receptors recognize chemicals such as sugars and amino acids on their extracellular side and transmit signals into the cytosol of the taste cell. In contrast to ligands that act on the extracellular side of these receptors, little is known regarding the molecules that regulate receptor functions within the cytosol. In this study, we analysed the interaction between sweet and umami taste receptors and calmodulin, a representative Ca2+-dependent cytosolic regulatory protein. High prediction scores for calmodulin binding were observed on the C-terminal cytosolic side of mouse taste receptor type 1 subunit 3 (T1r3), a subunit that is common to both sweet and umami taste receptors. Pull-down assay and surface plasmon resonance analyses showed different affinities of calmodulin to the C-terminal tails of distinct T1r subtypes. Furthermore, we found that T1r3 and T1r2 showed the highest and considerable binding to calmodulin, whereas T1r1 showed weaker binding affinity. Finally, the binding of calmodulin to T1rs was consistently higher in the presence of Ca2+ than in its absence. The results suggested a possibility of the Ca2+-dependent feedback regulation process of sweet and umami taste receptor signaling by calmodulin.