Discovery and structure–activity relationship of plastoquinone analogs as anticancer agents against chronic myelogenous leukemia cells

Two series of amino‐1,4‐benzoquinones ( AQ1–18 ) based on the structural analogs of plastoquinones were synthesized and the structure–activity relationship against chronic myelogenous leukemia activity was examined. All of the synthesized compounds were tested for their cytotoxic effects on different leukemic cell lines. Of interest, AQ15 exhibited a better selectivity than the reference drug imatinib on cancer cells. Owing to this, AQ15 was selected for a further apoptosis/necrosis evaluation where AQ15 ‐treated K562 cells demonstrated similar apoptotic effects like imatinib‐treated cells at their IC₅₀ values. The inhibitory effects of AQ15 and the other three compounds with various activities against eight tyrosine kinases, including ABL1, were investigated. AQ15 showed weak activity against ABL1, and a correlation was observed between the anti‐K562 and anti‐ABL1 activities. The binding mode of AQ15 into the ATP binding pocket of ABL1 kinase was predicted in silico, showing the formation of some key interactions. In addition, AQ15 was shown to suppress the downstream signaling of BCR‐ABL in K562 cells. Finally, AQ15 obviously cleaved DNA in the presence of an iron(II) complex system, indicating that this can be the major mechanism of its antiproliferative action, whereas the mild inhibition of ABL kinase is just in‐part mechanism of its overall outstanding cellular activity.     

Zinc transporter SLC39A10/ZIP10 facilitates antiapoptotic signaling during early B-cell development

The immune system is influenced by the vital zinc (Zn) status, and Zn deficiency triggers lymphopenia; however, the mechanisms underlying Zn-mediated lymphocyte maintenance remain elusive. Here we investigated ZIP10, a Zn transporter expressed in the early B-cell developmental process. Genetic ablation of Zip10 in early B-cell stages resulted in significant reductions in B-cell populations, and the inducible deletion of Zip10 in pro-B cells increased the caspase activity in parallel with a decrease in intracellular Zn levels. Similarly, the depletion of intracellular Zn by a chemical chelator resulted in spontaneous caspase activation leading to cell death. Collectively, these findings indicated that ZIP10-mediated Zn homeostasis is essential for early B-cell survival. Moreover, we found that ZIP10 expression was regulated by JAK-STAT pathways, and its expression was correlated with STAT activation in human B-cell lymphoma, indicating that the JAK-STAT-ZIP10-Zn signaling axis influences the B-cell homeostasis. Our results establish a role of ZIP10 in cell survival during early B-cell development, and underscore the importance of Zn homeostasis in immune system maintenance.Zinc (Zn) has wide-ranging effects on immunity. Zn deficiency has uncovered the importance of Zn homeostasis in immune cell maintenance and function (1). Dramatic effects of Zn on immunity have been observed in several immune and allergy-related cells, including lymphocytes such as B cells (2–6). B cells develop in the bone marrow (BM); the initial commitment to pro-B cells is followed by their differentiation into pre-B cells, and subsequently into immature B cells, which express the B-cell receptor on their surface (7). The immature B cells reach the spleen as transitional B cells, further differentiating into follicular or marginal zone mature B cells (7). Although the perturbation of Zn homeostasis causes splenic atrophy associated with lymphocyte reduction, and compromises cellular and humoral immune responses (6), the mechanisms underlying how Zn controls immune cell function, and in particular, the impact on early B-cell development, have been largely unknown.Zn homeostasis is tightly controlled by Zn transporter family members, Zrt- and Irt-like proteins (ZIPs, Zn importers) and zinc transporters (ZnTs, Zn exporters) (8), and recent studies revealed that alterations in Zn homeostasis mediated by specific Zn transporters play indispensable roles in a variety of cellular events (9). The intestinal Zn transporter ZIP4 is important for the initial absorption of dietary Zn, and patients with mutations in the SLC39A4/ZIP4 gene suffer from the inherited disorder acrodermatitis enteropathica (10, 11). ZIP13 controls the formation of bone, teeth, and connective tissues by modulating BMP/TGF-β signaling (12), and its loss-of-function mutation causes spondylocheiro dysplastic Ehlers-Danlos syndrome in humans (12, 13). ZIP14 controls systemic growth by regulating G protein-coupled receptor (GPCR) signaling (14), and ZIP8 is involved in osteoarthritis (15) and negatively manipulates NF-κB activation (16). In addition, ZnT5 regulates cytokine production by controlling the activation of protein kinase C upon antigen exposure in mast cells (17). Thus, Zn homeostasis mediated by Zn transporters is linked to a wide variety of biological and regulatory functions, and the disruption of a Zn transporter-Zn axis can lead to various symptoms in the absence of redundant machinery (18).Here we demonstrate a definitive role of ZIP10 in early B-cell development. We found that a loss of ZIP10 during an early B-cell stage specifically abrogated cell survival, resulting in the absence of mature B cells, which led to splenoatrophy and reduced Ig levels. The inducible deletion of Zip10 in pro-B cells increased the caspase activity because of the reduced intracellular Zn level, leading to cell death. This phenomenon was mimicked by the intracellular chelation of Zn. These findings indicated that Zn homeostasis via ZIP10 plays an indispensable role in early B-cell survival. We also demonstrated that the ZIP10 expression levels were regulated by STAT3/STAT5 activation, and that ZIP10 was highly expressed in human B-cell lymphoma samples in which both STAT proteins were activated, indicating that the JAK-STAT-ZIP10-Zn signaling axis is important for B-cell maintenance. Our results establish a functional link between ZIP10 and the survival of early stages of B cells, revealing a molecular mechanism underlying the requirement of Zn for maintenance of the immune system.     

Glycated Albumin Predicts the Risk of Mortality in Type 2 Diabetic Patients on Hemodialysis: Evaluation of a Target Level for Improving Survival

Glycated albumin (GA) is considered a more reliable marker than glycated hemoglobin (HbA1c) for monitoring glycemic control, particularly in diabetic hemodialysis patients. We investigated the associations of GA, HbA1c, and random serum glucose levels with survival, and evaluated possible targets for improving survival in diabetic hemodialysis patients. In this prospective, longitudinal, observational study, we enrolled 90 diabetic hemodialysis patients across six dialysis centers in Japan. The median duration of follow‐up was 36.0 months (mean follow‐up, 29.8 months; range, 3–36 months). There were 11 deaths during the observation period. GA was a significant predictor for mortality (hazard ratio, 1.143 per 1% increase in GA; 95% confidence interval, 1.011–1.292; P = 0.033), whereas HbA1c and random glucose levels were not predictors for mortality. Receiver operating characteristics curve analysis showed that the cutoff value of GA for predicting the risk of mortality was 25%. In the Kaplan–Meier analysis, the cumulative survival rate was significantly greater in patients with GA ≤25% than in patients with GA >25%. GA predicted the risk of all‐cause and cardiovascular mortality in diabetic hemodialysis patients. Our results suggest that GA ≤25% is an appropriate target for improving survival in diabetic hemodialysis patients.     

Impacts of Recombinant Human Erythropoietin Treatment During Predialysis Periods on the Progression of Chronic Kidney Disease in a Large‐Scale Cohort Study (Co‐JET study)

The effect of recombinant human erythropoietin (rHuEPO) treatment on the progression of chronic kidney disease (CKD) has not been fully evaluated in Japan. We therefore retrospectively evaluated this in a sub‐cohort of a prospective multicenter study to investigate optimal hemoglobin (Hb) level of CKD patients on hemodialysis (HD) treated with rHuEPO; Japan Erythropoietin Treatment Study for Target Hb and Survival (JET study). Effect of rHuEPO treatment during predialysis period to delay initiation of HD was retrospectively assessed in 2434 patients from the JET study comparing groups with and without rHuEPO treatment. The assessment was done by Cox proportional hazards regression analysis and inverse probability‐weighted (IPW) analysis to adjust for time‐dependent confounders. The weights used in the IPW analysis were calculated using a logistic model that included baseline confounders and time‐dependent variables. During the predialysis period, 71.7% (1746 patients) were treated with rHuEPO (mean Hb level of 8.7 g/dL at initiation of rHuEPO treatment). Covariates significantly associated with initiation of rHuEPO treatment were Hb level, serum creatinine level, age, diabetes, cardiac insufficiency, and hypertension. The adjusted hazard ratio for time until HD initiation under rHuEPO treatment was 0.272 (95% CI, 0.223–0.331; P < 0.001) in the Cox analysis and 0.63 (95% CI, 0.53–0.76; P < 0.0001) in the IPW analysis. This retrospective study suggests that rHuEPO treatment during the predialysis period has preventive effects on the progression of CKD although further prospective investigation on the efficacy is needed.     

Pulmonary involvement: a rare extraintestinal manifestation of ulcerative colitis

Ulcerative colitis (UC) is associated with a number of extraintestinal manifestations (EIMs) that may affect most organ systems. Among the EIMs, those involving the lung are rare. We report a case of pulmonary involvement and pyoderma gangrenosum in a patient with refractory UC. A chest computed tomography showed multiple nodular infiltrates in bilateral lungs. The patient had no respiratory symptoms. No infectious agents were detected. A transbronchial biopsy specimen showed nonspecific features. Prednisolone was initiated with significant improvement in the patient’s abdominal symptoms and pyoderma gangrenosum. Subsequent imaging after steroid therapy showed improvement of the pulmonary infiltrates. The patient’s abdominal symptoms relapsed when prednisolone was tapered. The patient subsequently received a proctocolectomy. Chest radiographs have shown resolution of pulmonary infiltrates. Because pulmonary involvement follows an independent course and a proctocolectomy may not be protective against a recurrence of pulmonary involvement, a careful follow-up should be continued.     

Impact of interocclusal contacts on infrared laser fluorescence in pits of sound first permanent molars in children

International Journal of Paediatric Dentistry 2012; 22: 265–270 Background. A device based on infrared laser fluorescence (IRLF) has become available as an adjunct for the diagnosis of dental caries. Aims. The objective of this study was to clarify the differences of IRLF readings in the mesial, central and distal occlusal pits of first permanent molars. Design. Sixty‐four children (average age 8.0 years) were examined using IRLF. The mesial, central and distal pits of clinically healthy first permanent molars were measured. The instrument provides measurements in arbitrary units on an open‐ended interval scale. Results. Mean (± SE) IRLF values in the mesial pits were 4.9 ± 0.4 (upper) and 6.5 ± 0.4 (lower) and were significantly lower than those in the central (8.8 ± 0.6 and 11.5 ± 0.9) and distal (9.6 ± 0.7 and 10.4 ± 0.8) pits in the maxilla and mandible. There was no significant difference between the right (7.3 ± 0.5, 9.4 ± 0.6) and left (8.2 ± 0.5, 9.5 ± 0.6) dental arches. IRLF measurements in the mesial pits of human first permanent sound molars were lower than the central and distal pits in children whose second molars had not erupted. Conclusions. The inherently higher IRLF values of some sites should not be misinterpreted and trigger early invasive treatment.     

Effective infliximab treatment for a recurrent type of acute intestinal graft-versus-host disease accompanied by steroid-induced depression

A 22-year-old man with chronic active Epstein-Barr virus infection underwent allogeneic bone marrow transplantation (allo-BMT) from an HLA two allele-mismatched unrelated donor. Ten months after allo-BMT, he developed protein-losing enteropathy following a respiratory syncytial virus infection. A diagnosis of a recurrent type of acute graft-versus-host disease (GVHD) was made based on the histopathological findings, such as the infiltration of T lymphocytes into the superficial epithelium and crypts, and apoptotic bodies in crypts. Although methylprednisolone (mPSL: 10 mg/kg) administration for two consecutive days improved gastrointestinal symptoms, acute pancreatitis and severe depression developed in association with corticosteroid treatment. Reduction of mPSL and administration of infliximab (5 mg/kg/dose, 3 times) resulted in rapid improvement of depression and pancreatitis without aggravating intestinal GVHD. Recent studies have demonstrated that tumor-necrosis-factor (TNF)-α is associated with not only GVHD but also depression and acute pancreatitis. In the present case, anti-TNF-α treatment enabled us to reduce corticosteroid dose without aggravating GVHD, which suggests that this approach might be effective for the treatment of depression and acute pancreatitis.