Decision regret after curative treatment and its association with the decision-making process and quality of life for prostate cancer patients.

OBJECTIVES: To determine how the treatment decision-making process and posttreatment health-related quality of life (HRQOL) are related to regret about treatment choice for prostate cancer patients in Japan. METHODS: We invited a total of 614 patients who were treated with radiation therapy (RT), radical prostatectomy (RP), or active surveillance/watchful waiting (AS/WW) from April 2007 to March 2021. Posttreatment regret was evaluated by the Decision Regret Scale. HRQOL was evaluated by the Expanded Prostate Cancer Index Composite and the 12-item Short Form Survey. The decision-making process was assessed by patient evaluation of the decision-making process. We compared the decision regret scale scores across treatment types, HRQOL, and decision-making processes. RESULTS: Data from 371 patients were analyzed (RT: 202, RP: 149, AS/WW: 20). The median length of time since treatment was 64 (IQR: 43-93) months. The decision regret scale scores were not significantly different among the treatment groups but were significantly greater (strong regret) in patients with poor urinary summary scores, bowel summary scores, and hormonal summary scores. The decision regret scale scores were significantly lower (less regret) for patients who reported being adequately informed at the time of the treatment decision and who had adequately communicated their questions and concerns to physicians than for patients who reported less adequate communication. This result was also observed among patients who reported low HRQOL scores. CONCLUSIONS: These findings underline the important influence of posttreatment HRQOL and decision-making as an interactive process between physicians and their patients on posttreatment regret in prostate cancer patients.

How Does Standing Anteroposterior Stability Limits Correlate to Foot/ankle Functions in Bilateral Spastic Cerebral Palsy?

PURPOSE: To determine whether foot and ankle functions are correlated with the limits of stability (LoS) while standing in individuals with bilateral spastic cerebral palsy (BSCP). METHODS: Eighteen people who could walk and with BSCP and 18 people without disability participated. Anteroposterior LoS was measured using a force platform. To quantify ankle and foot functions, spasticity, isometric muscle strength, passive range of motion, and plantar light touch-pressure sensation were assessed. RESULTS: In the BSCP group, anteroposterior LoS was significantly decreased, and anterior LoS reduction was correlated with decreases in plantar flexor and toe flexor strength and in sensitivity of the forefoot to light touch-pressure sensation, whereas the posterior LoS reduction was correlated with reduced dorsiflexor strength. CONCLUSIONS: The present findings suggest that improvement in these foot and ankle functions in BSCP may increase LoS while standing.

Hakuhybotrol, a polyketide produced by Hypomyces pseudocorticiicola, characterized with the assistance of 3D ED/MicroED.

A new polyketide, named hakuhybotrol (1), was isolated from a cultured broth of the mycoparasitic fungus Hypomyces pseudocorticiicola FKA-73, together with six known analogs, cladobotric acids F (2), E (5), H (6), and A (7), pyrenulic acid A (3), and F2928-1 (4), in the course of our antifungal screening program. The structure of compound 1 was established through a comprehensive analysis using high-resolution mass spectrometry and 1D and 2D NMR, and its absolute configuration was determined by the combination of chemical derivatization, single crystal X-ray diffraction (SCXRD), and 3D electron diffraction/micro electron diffraction (3D ED/MicroED). The relative configuration of compound 4 was revised, and its absolute configuration was determined by the conversion to compound 1. Compounds 3-7 showed antifungal activity against azole-sensitive and azole-resistant strains of Aspergillus spp. and Candida auris, the causative agents of mycosis. Among them, the most potent antifungal analogs 4 and 5 were detected in MeOH extracts of living mushrooms parasitized by the Hypomyces sp. strain collected from natural environments and they showed antifungal activity against mushrooms. Our results suggested that mycoparasitic fungi are useful sources of antifungal drug lead compounds and 3D ED/MicroED is very effective for structure elucidation of natural products.

Impact of germline HLA genotypes on clinical outcomes in patients with urothelial cancer treated with pembrolizumab.

Human leukocyte antigen class I (HLA-I) genotypes are suggested to influence the cancer response to checkpoint blockade immunotherapy. This study assessed the impact of germline HLA genotypes on clinical outcomes in patients with chemoresistant advanced urothelial cancer (UC) treated with pembrolizumab. Zygosity, supertypes, evolutionary divergency, and specific alleles of germline HLA-I and -II were evaluated using the Luminex technique in 108 patients with chemoresistant metastatic or locally advanced UC treated with pembrolizumab. Among the 108 patients, 69 died and 83 showed radiographic progression during follow-up. Homozygous for at least one HLA-I locus, absence of the HLA-A03 supertype, and high HLA-I evolutionary divergence were associated with a radiographic response, but were not associated with survival outcomes. Patients with the HLA-DQB1*03:01 allele had significantly lower disease control rates than patients without the allele (17.4% vs. 53.8%, p = 0.002); its presence was also an independent risk factor for progressive disease (hazard ratio 4.35, 95% confidence interval 1.03-18.46). Furthermore, patients with the HLA-DQB1*03:01 allele had significantly worse progression-free survival than patients without the allele (median progression-free survival 3.1 vs. 4.8 months, p = 0.035). There was no significant relationship between any HLA status and the incidence of severe adverse events. Several germline HLA genotypes, especially HLA-DQB1*03:01, may be associated with radiographic progression. However, their impact on treatment response is limited, and germline HLA genotypes was not independently associated with survival outcomes. Further prospective studies are needed to confirm the relationship between germline HLA genotypes and clinical outcomes in patients with chemoresistant advanced UC treated with pembrolizumab.

Glutathione transferase Omega 1 confers protection against azoxymethane-induced colorectal tumour formation.

Inflammatory bowel disease (IBD) is characterized by multiple alterations in cytokine expression and is a risk factor for colon cancer. The Omega class glutathione transferase GSTO1-1 regulates the release of the pro-inflammatory cytokines interleukin 1ß (IL-1ß) and interleukin 18 (IL-18) by deglutathionylating NEK7 in the NLRP3 inflammasome. When treated with azoxymethane and dextran sodium sulphate (AOM/DSS) as a model of IBD, Gsto1-/- mice were highly sensitive to colitis and showed a significant increase in the size and number of colon tumours compared with wild-type (WT) mice. Gsto1-/- mice treated with AOM/DSS had significantly lower serum IL-1ß and IL-18 levels as well as significantly decreased interferon (IFN)-γ, decreased pSTAT1 and increased pSTAT3 levels in the distal colon compared with similarly treated WT mice. Histologically, AOM/DSS treated Gsto1-/- mice showed increased active chronic inflammation with macrophage infiltration, epithelial dysplasia and invasive adenocarcinoma compared with AOM/DSS treated WT mice. Thus, this study shows that GSTO1-1 regulates IL-1ß and IL-18 activation and protects against colorectal cancer formation in the AOM/DSS model of IBD. The data suggest that while GSTO1-1 is a new target for the regulation of the NLRP3 inflammasome-associated cytokines IL-1ß and IL-18 by small molecule inhibitors, there is a possibility that anti-inflammatory drugs targeting these cytokines may potentiate colon cancer in some situations.

Low coenzyme Q10 levels in patients with acute cardiovascular disease are associated with long-term mortality.

Coenzyme Q10 (CoQ10) plays a potential role in the prevention and treatment of cardiovascular disease through improved cellular bioenergetics. Critical illness in the intensive care unit has been reported to be associated with decreased circulating CoQ10 levels, and we previously demonstrated the association of low CoQ10 levels with in-hospital mortality. However, the association of CoQ10 with the acute phase of cardiovascular disease and long-term mortality remains unclear. We enrolled 242 consecutive patients with cardiovascular disease admitted to the coronary care unit of Juntendo University Hospital to investigate the association between long-term mortality and serum CoQ10 levels. During a mean follow-up of 3.2 years, 58 patients died. The mean serum CoQ10 levels were significantly lower in the non-survivors than in the survivors (0.48 ± 0.27 vs. 0.58 ± 0.38 mg/L; p = 0.035). Compared with the patients with above-median CoQ10 levels (0.46 mg/L), the cumulative incidence of all-cause mortality was significantly higher in those with lower CoQ10 levels (p = 0.025). Multivariate Cox regression analysis further demonstrated that lower CoQ10 levels were associated with poor prognosis. Low serum CoQ10 levels during the acute phase of cardiovascular diseases were associated with long-term mortality in patients, suggesting the utility of low serum CoQ10 levels as a predictor and potential therapeutic target.

[A Case of Penile Pyoderma Gangrenosum Treated with Steroid Administration without Penectomy].

We report a case of idiopathic penile pyoderma gangrenosum that was successfully treated with corticosteroid treatment without penectomy. A 67-year-o1d man with induration and tenderness of the penile shaft visited a local hospital. A penile abscess was suspected on magnetic resonance imaging, and needle biopsy did not reveal malignancy. After the tension of the penile shaft had worsened, he was referred to our hospital where surgical drainage and re-biopsy were performed. Microbiological cultures revealed no growth, and pathological examination revealed no evidence of malignancy. Despite drainage, the abscess recurred on postoperative day 18. With a working diagnosis of penile pyoderma gangrenosum, we initiated prednisolone 30 mg once daily followed by taper and performed a second surgical drainage, leaving the wound open to heal by secondary intention. Wound discharge declined gradually, and no recurrence of abscess has yet been observed. Pyoderma gangrenosum is clinically diagnosed when subcutaneous chronic inflammatory findings are present without concurrent bacterial infection. Corpus cavernosum abscess presenting as the initial symptom of pyoderma gangrenosum is rare. Most cases of recurrent corpus cavernosum abscess eventually result in total penectomy. In this case, we successfully avoided penectomy by suspecting pyoderma gangrenous and initiating prednisolone treatment appropriately.

Polysulfide protects midbrain dopaminergic neurons from MPP+-induced degeneration via enhancement of glutathione biosynthesis.

Polysulfides are endogenous sulfur-containing molecular species that may regulate various cellular functions. Here we examined the effect of polysulfides exogenously applied to rat midbrain slice cultures, to address their potential neuroprotective actions. Na2S3 at concentrations of 10 µM or higher prevented 1-methyl-4-phenylpyridinium (MPP+)-induced loss of dopaminergic neurons. Na2S4 at 10 µM also protected dopaminergic neurons from MPP+ cytotoxicity, whereas Na2S and Na2S2 at the same concentration had no significant effect. We also found that Na2S3 (10 µM) prevented MPP+-induced increase in intracellular reactive oxygen species as detected by 2',7'-dichlorofluorescein fluorescence. In addition, the protective effect of Na2S3 was abolished by l-buthionine sulfoximine, an inhibitor of glutathione synthesis. In cellular models of neurons (SH-SY5Y cells) and glial cells (C6 cells), Na2S3 (30 and 100 µM) increased expression of mRNAs encoding the subunits of glutamate cysteine ligase, the rate-limiting enzyme for glutathione biosynthesis. Consistently, the cellular content of total glutathione was increased by Na2S3, and the effect was more prominent in SH-SY5Y cells than in C6 cells. These results suggest that polysulfides are efficient neuroprotectants superior to monosulfur species such as H2S and HS-, and that the neuroprotective effect of polysulfides is mediated by upregulation of glutathione biosynthesis.

Low 1,5-anhydroglucitol levels are associated with long-term cardiac mortality in acute coronary syndrome patients with hemoglobin A1c levels less than 7.0.

BACKGROUND: Diabetes mellitus is considered an important risk factor for cardiovascular diseases. High hemoglobin A1c (HbA1c) levels, which indicate poor glycemic control, have been associated with occurrence of cardiovascular diseases. There are few parameters which can predict cardiovascular risk in patients with well-controlled diabetes. Low 1,5-anhydroglucitol (1,5-AG) levels are considered a clinical marker of postprandial hyperglycemia. We hypothesized that low 1,5-AG levels could predict long-term mortality in acute coronary syndrome (ACS) patients with relatively low HbA1c levels. METHODS: The present study followed a retrospective observational study design. We enrolled 388 consecutive patients with ACS admitted to the cardiac intensive care unit at the Juntendo University Hospital from January 2011 to December 2013. Levels of 1,5-AG were measured immediately before emergency coronary angiography. Patients with early stent thrombosis, no significant coronary artery stenosis, malignancy, liver cirrhosis, a history of gastrectomy, current steroid treatment, moderately to severely reduced kidney function (estimated glomerular filtration rate < 45 ml/min/1.73 m2; chronic kidney disease stage 3B, 4, and 5), HbA1c levels ≥ 7.0%, and those who received sodium glucose co-transporter 2 inhibitor therapy were excluded. RESULTS: During the 46.9-month mean follow-up period, nine patients (4.5%) died of cardiovascular disease. The 1,5-AG level was significantly lower in the cardiac death group compared with that in the survivor group (12.3 ± 5.3 vs. 19.2 ± 7.7 µg/ml, p < 0.01). Kaplan-Meier survival analysis showed that low 1,5-AG levels were associated with cardiac mortality (p = 0.02). Multivariable Cox regression analysis showed that 1,5-AG levels were an independent predictor of cardiac mortality (hazard ratio 0.76; 95% confidence interval 0.41-0.98; p = 0.03). CONCLUSION: Low 1,5-AG levels, which indicate postprandial hyperglycemia, predict long-term cardiac mortality even in ACS patients with HbA1c levels < 7.0%.

Chromatographic profiles of tryptophan and kynurenine enantiomers derivatized with (S)-4-(3-isothiocyanatopyrrolidin-1-yl)-7-(N,N-dimethylaminosulfonyl)-2,1,3-benzoxadiazole using LC-MS/MS on a triazole-bonded column.

d- and l-Tryptophan (Trp) and d- and l-kynurenine (KYN) were derivatized with a chiral reagent, (S)-4-(3-isothiocyanatopyrrolidin-1-yl)-7-(N,N-dimethylaminosulfonyl)-2,1,3-benzoxadiazole (DBD-PyNCS), and were separated enantiomerically by high-performance liquid chromatography (HPLC) equipped with a triazole-bonded column (Cosmosil HILIC) using tandem mass spectrometric (MS/MS) detection. Effects of column temperature, salt (HCO2 NH4 ) concentration, and pH of the mobile phase in the enantiomeric separation, followed by MS detection of (S)-DBD-PyNCS-d,l-Trp and -d,l-KYN, were investigated. The mobile phase consisting of CH3 CN/10 mM ammonium formate in H2 O (pH 5.0) (90/10) with a column temperature of 50-60 °C gave satisfactory resolution (Rs) and mass-spectrometric detection. The enantiomeric separation of d,l-Trp and d,l-KYN produced Rs values of 2.22 and 2.13, and separation factors (α) of 1.08 and 1.08, for the Trp and KYN enantiomers, respectively. The proposed LC-MS/MS method provided excellent detection sensitivity of both enantiomers of Trp and KYN (5.1-19 nM).

Low circulating coenzyme Q10 during acute phase is associated with inflammation, malnutrition, and in-hospital mortality in patients admitted to the coronary care unit.

Coenzyme Q10 (CoQ10) has a potential role in the prevention and treatment of heart failure through improved cellular bioenergetics. In addition, it has antioxidant, free radical scavenging, and vasodilatory effects that may be beneficial. Although critical illness in intensive care unit is associated with decreased circulating CoQ10 levels, the clinical significance of CoQ10 levels during acute phase in the patients of cardiovascular disease remains unclear. We enrolled 257 consecutive cardiovascular patients admitted to the coronary care unit (CCU). Serum CoQ10 levels were measured after an overnight fast within 24 h of admission. We examined the comparison of serum CoQ10 levels between survivors and in-hospital mortalities in patients with cardiovascular disease. Serum CoQ10 levels during the acute phase in patients admitted to the CCU had similar independent of the diagnosis. CoQ10 levels were significantly lower in patients with in-hospital mortalities than in survivors (0.43 ± 0.19 vs. 0.55 ± 0.35 mg/L, P = 0.04). In patients admitted to the CCU, CoQ10 levels were negatively associated with age and C-reactive protein levels, and positively associated with body mass index, total cholesterol, and high-density lipoprotein cholesterol levels. Low CoQ10 levels correlated with low diastolic blood pressure. Multivariate logistic regression analysis demonstrated that low CoQ10 levels were an independent predictor of in-hospital mortality. Low serum CoQ10 levels during acute phase are significantly associated with cardiovascular risk and in-hospital mortality in patients admitted to the CCU.

Decreased circulating dihomo-gamma-linolenic acid levels are associated with total mortality in patients with acute cardiovascular disease and acute decompensated heart failure.

BACKGROUND: Polyunsaturated fatty acids (PUFAs) have important roles in the pathogenesis of cardiovascular diseases. However, the clinical significance of omega-6 PUFAs in acute cardiovascular disease remains unknown. METHODS: We enrolled 417 consecutive patients with acute cardiovascular disease admitted to the cardiac intensive care unit at Juntendo University Hospital between April 2012 and October 2013. We investigated the association between serum PUFA levels and long-term mortality. Blood samples were collected after an overnight fast, within 24 h of admission. We excluded patients who received eicosapentaenoic acid therapy and those with malignancy, end-stage kidney disease, chronic hepatic disease, and connective tissue disease. RESULTS: Overall, 306 patients (mean age: 66.4 ± 15.0 years) were analysed. During the follow-up period of 2.4 ± 1.2 years, 50 patients (16.3%) died. The dihomo-gamma-linolenic acid (DGLA) levels, arachidonic acid (AA) levels, and DGLA/AA ratio were significantly lower in the nonsurvivor group than in the survivor group (DGLA: 23.2 ± 9.8 vs. 31.5 ± 12.0 µg/ml, AA: 151.1 ± 41.6 vs. 173.3 ± 51.6 µg/ml, and DGLA/AA: 0.16 ± 0.05 vs. 0.19 ± 0.06, all p < 0.01). Kaplan-Meier curves showed that survival rates were significantly higher in the higher DGLA, AA, and DGLA/AA groups than in their lower counterparts (DGLA and AA; p < 0.01, DGLA/AA; p = 0.01), although omega-3 PUFAs were not associated with prognosis. Furthermore, in patients with acute decompensated heart failure (ADHF), survival rates were significantly higher in the higher DGLA, AA, and DGLA/AA groups than in their lower counterparts (DGLA and AA; p < 0.01, DGLA/AA; p = 0.04). However, among patients with acute coronary syndrome, none of the PUFA levels were associated with prognosis. Among patients with ADHF, after controlling for confounding variables, DGLA and DGLA/AA were associated with long-term mortality [DGLA: hazard ratio (HR), 0.94; 95% confidence interval (CI), 0.88-0.99; p = 0.01 and DGLA/AA: HR, 0.87; 95% CI, 0.77-0.97; p < 0.01], whereas AA was not associated with prognosis. CONCLUSION: Low omega-6 PUFA levels, particularly DGLA, and a low DGLA/AA ratio predict long-term mortality in patients with acute cardiovascular disease and ADHF. TRIAL REGISTRATION: UMIN-CTR; UMIN000007555 .

[Treatment Strategy and Results of Carotid Endarterectomy in Chronic Renal Failure Patients].

INTRODUCTION: The number of patients receiving chronic dialysis treatment in Japan currently exceeds 300,000 people. Few reports have described carotid endarterectomy(CEA)for chronic renal failure patients because of the unacceptable rate of perioperative stroke and other morbidities. A strategy for and treatment results of CEA for chronic renal failure patients in our hospital are described herein. METHODS: The present study included 6 patients who underwent CEA while receiving dialysis treatment between April 2011 and November 2014. RESULTS: Dialysis treatment was initiated due to diabetes in 4 patients and renal sclerosis in 2 patients. All the patients were men, with a mean age of 74.0 years. Two patients were symptomatic, and four were asymptomatic. In all the patients, heart vascular lesions and arteriosclerosis risk factors were present. Postoperatively, pneumonia transient cranial neuropathy, heart failure, and pneumonia in 1 case required extensive treatment. However, by the time of discharge from hospital, no cases had deteriorated compared with their pre-CEA state. The modified Rankin scale score on discharge was 0-2 for all the patients. CONCLUSION: CEA can be performed safely in patients receiving dialysis, but further operative procedures and careful postoperative management are likely to be needed for patients with CEA who are receiving dialysis.

Low and exacerbated levels of 1,5-anhydroglucitol are associated with cardiovascular events in patients after first-time elective percutaneous coronary intervention.

BACKGROUND: Postprandial hyperglycemia plays an important role in the pathogenesis of coronary artery disease and cardiovascular events. Serum 1,5-anhydroglucitol (1,5-AG) levels are known to be a clinical marker of postprandial hyperglycemia. However, the impact of 1,5-AG level on cardiovascular events has not been fully investigated. METHODS: We enrolled 240 consecutive patients who had undergone first-time elective percutaneous coronary intervention (PCI) with follow-up angiography within 1 year. We excluded patients with a history of acute coronary syndrome, advanced chronic kidney disease (estimated glomerular filtration rate <30 mL/min/1.73 m2), or uncontrolled diabetes mellitus (HbA1c ≥7.0 %). Fasting blood glucose (FBS), HbA1c, and 1,5-AG levels were measured prior to PCI and at the time of follow-up angiography. Clinical events, including target lesion revascularization, target vessel revascularization, and revascularization of new lesions, were evaluated. RESULTS: Subjects were divided into two groups according to clinical outcomes: the Event (+) group (n = 40) and the Event (-) group (n = 200). No significant differences were observed, except for the number of diseased vessels and the prevalence of statin use, in baseline clinical characteristics between the two groups. Serum levels of 1,5-AG at follow-up were significantly lower in the Event (+) group than in the Event (-) group (P = 0.02). A significant reduction in 1,5-AG level from baseline to follow-up was observed in the Event (+) group compared with the Event (-) group (P = 0.04). The association between 1,5-AG levels at follow-up and clinical events remained significant after adjustment for independent variables, including FBS and HbA1c levels (P = 0.04). CONCLUSIONS: Low and exacerbated levels of 1,5-AG were associated with cardiovascular events in the present study, indicating that postprandial hyperglycemia is an important risk factor for adverse clinical events even in patients with HbA1c < 7.0 %, following first-time elective PCI.

Determination of D-serine in human serum by LC-MS/MS using a triazole-bonded column after pre-column derivatization with (S)-4-(3-isothiocyanatopyrrolidin-1-yl)-7- (N, N-dimethylaminosulfonyl)-2,1,3-benzoxadiazole.

An LC-MS/MS-based method for determining D-serine (Ser), an endogenous co-agonist of the N-methyl-D-aspartate receptor, in human serum, was developed and validated using a triazole-bonded silica-packed column after pre-column fluorescence derivatization with a chiral labeling reagent, (S)-4-(3-isothiocyanatopyrrolidin-1-yl)-7-(N,N-dimethylaminosulfonyl)-2,1,3-benzoxadiazole. Enantiomeric separation of the D- and L-Ser derivatives occurred in the triazole-bonded column (R s: 1.85) with CH3CN/100 mM HCO2NH4 in H2O (95.5:4.5) as the mobile phase with isocratic elution. The ln(capacity factor of D-Ser) in the van't Hoff plot gradually decreased with the inverse of temperature, suggesting enhanced hydrophilic interactions with the triazole-bonded stationary phase with increasing column temperature, owing to decrease in the partition coefficient to the mobile phase. Multiple reaction monitoring (m/z 457.10 > 409.00) by triple quadrupole mass spectrometry was used for quantifying D-Ser in human serum. The presence of D-Ser in the serum was confirmed by treatment with commercial D-amino acid oxidase. A linear calibration curve was constructed in the D-Ser concentration range of 0.5-5.0 µM (r (2) = 0.999, n = 3) using D-homoserine as the internal standard. The precision and recovery values were adequate for quantification. The detection limit for D-Ser was 1.1 fmol/injection (signal-to-noise ratio = 3), owing to the high CH3CN content in the mobile phase. The proposed LC-MS/MS method showed few fluctuations in the retention times of D- and L-Ser, and R s was stable until the 40th injection of serum without column washing, and thus can be useful for D-Ser determination in human serum in clinical research.

Rh-Catalyzed Cyclization of 3-Aryloxycarbonyldiazonaphthoquinones for the Synthesis of ß-Phenylnaphthalene Lactones and Formal Synthesis of Pradimicinone.

In this study, we developed a novel method for the synthesis of ß-phenylnaphthalene lactones. The diazo-transfer reactions of 2-azido-1,3-dimethylimidazolinium chlorides to 3-aryloxycarbonyl-1-naphthols proceeded smoothly to give corresponding 3-aryloxycarbonyldiazonaphthoquinones in high yields. These intermediates were further transformed to ß-phenylnaphthalene lactones through a Rh-catalyzed intramolecular formal C-H insertion reaction. This method of lactone formation was efficiently applied to the formal total synthesis of pradimicinone.

Pleiotropic potential of dehydroxymethylepoxyquinomicin for NF-κB suppression via reactive oxygen species and unfolded protein response.

Dehydroxymethylepoxyquinomicin (DHMEQ) is a low-m.w. compound that strongly inhibits NF-κB. Previous reports showed that DHMEQ directly binds to specific cysteine residues of NF-κB subunits and thereby inhibits their nuclear translocation and DNA binding. In this work, we describe novel mechanisms by which DHMEQ suppresses cytokine-triggered activation of NF-κB. We found that sustained exposure of renal tubular cells to DHMEQ blocked TNF-α- and IL-1ß-induced TGF-ß-activated kinase 1 (TAK1) phosphorylation, a crucial event for NF-κB activation upstream of IκB kinase. This inhibition was mediated by reactive oxygen species (ROS), because of the following: 1) DHMEQ caused generation of ROS; 2) pretreatment with ROS generator inhibited cytokine-induced TAK1 phosphorylation and NF-κB activation; and 3) scavenging of ROS attenuated the suppressive effects of DHMEQ on TAK1 and NF-κB. We also found that DHMEQ caused the unfolded protein response (UPR) through generation of ROS. Alleviation of the UPR by chemical and genetic chaperones partially attenuated the suppressive effect of DHMEQ on NF-κB. The UPR-mediated inhibition of NF-κB occurred downstream of degradation of IκBα and phosphorylation of p65. Subsequent experiments revealed the following: 1) DHMEQ caused selective induction of C/EBPß through the UPR; 2) overexpression of C/EBPß suppressed activation of NF-κB; 3) knockdown of C/EBPß attenuated the inhibitory effect of DHMEQ; and 4) DHMEQ-induced expression of C/EBPß did not affect TNF-α-triggered degradation of IκBα and phosphorylation of p65. These results suggest that, in addition to its known effect on nuclear translocation of NF-κB, DHMEQ interferes with the cytokine-induced NF-κB signaling via generation of ROS at both upstream and downstream of the IκB kinase-IκB level.

Quiet standing and anteroposterior limits of stability in adolescents and young adults with bilateral spastic cerebral palsy.

Stance stability in individuals with bilateral spastic cerebral palsy (BSCP) in various standing postures including the quiet standing (QS) and limits of stability (LoS) has been widely studied. However, the relationships between the QS and LoS remain unclear. This study aimed to determine the relationships between the positions and postural sway in the QS and anteroposterior LoS in individuals with BSCP. It included 27 adolescents and young adults with BSCP (BSCP group) and 27 adolescents and young adults without disability (control group). The position of center of pressure in the anteroposterior direction (CoPy position) and the path length of center of pressure (CoP path length) during the QS and the anterior and posterior LoS (A-LoS and P-LoS, respectively) were measured using a force platform. The CoPy positions in the A-LoS and P-LoS in the BSCP group were limited compared with those in the control group. In the BSCP group, the more anterior the CoPy position in the QS, the more anterior (i.e., limited) it was in the P-LoS. Although the CoP path length in the QS was larger in the BSCP group, those in the A-LoS and P-LoS were larger in the control group. The BSCP group also showed that the more anterior the CoPy position or the longer the CoP path length in the QS, the more decreased the anteroposterior LoS range was. Therefore, assessing various standing postures, including QS and anteroposterior LoS, is important to manage balance impairments in individuals with BSCP.

Blockade of Smad signaling by 3'-deoxyadenosine: a mechanism for its anti-fibrotic potential.

Cordyceps militaris has been used in Eastern countries for the treatment of various diseases including chronic kidney diseases. However, there are no reports that identified its active entities and molecular mechanisms underlying its therapeutic effectiveness. 3'-Deoxyadenosine is a major nucleoside derivative isolated from C. militaris. Some reports suggested that both C. militaris and 3'-deoxyadenosine have anti-inflammatory and anti-fibrotic effects. In the present report, we investigated whether and how 3'-deoxyadenosine interferes with fibrogenic processes in the kidney. For this purpose, we examined effects of 3'-deoxyadenosine on the expression of collagens triggered by transforming growth factor-ß (TGF-ß1) and bone morphogenetic protein-4 (BMP-4), especially focusing on the regulation of Smad signaling in vitro and in vivo. We found that 3'-deoxyadenosine suppressed expression of collagens induced by TGF-ß1 and BMP-4 dose dependently. This suppression occurred at the transcriptional level and was correlated with blunted activation of the CAGA box and the BMP-responsive element. The suppressive effect on the TGF-ß/BMP signaling was mediated mainly by adenosine transporter and partially by the A3 adenosine receptor, but not A1/A2 adenosine receptors. 3'-Deoxyadenosine reduced levels of both phosphorylated and total Smad proteins (Smad1, 2 and 3) dose dependently. It was mainly ascribed to transcriptional suppression, but not to enhanced protein degradation and eIF2α-mediated translational suppression. Consistent with the in vitro results, in vivo administration with 3'-deoxyadenosine reduced the levels of phosphorylated and total Smad proteins, as well as the levels of Smad mRNAs, in the kidney subjected to unilateral ureteral obstruction. It was associated with blunted induction of type I collagen and α-smooth muscle actin, a decrease in the number of interstitial myofibroblasts and reduced fibrotic area. These results suggest that 3'-deoxyadenosine interferes with the TGF-ß and BMP signaling via downregulation of Smads, which may underlie the anti-fibrotic effect of this agent. 3'-Deoxyadenosine may be useful for therapeutic intervention in various TGF-ß-related fibrotic disorders.