Redox Engineering of Myoglobin by Cofactor Substitution to Enhance Cyclopropanation Reactivity

Kagawa Y., Oohora K., Himiyama T., et al. Redox Engineering of Myoglobin by Cofactor Substitution to Enhance Cyclopropanation Reactivity. Angewandte Chemie - International Edition, (2024); https://doi.org/10.1002/anie.202403485.Design of metal cofactor ligands is essential for controlling the reactivity of metalloenzymes. We investigated a carbene transfer reaction catalyzed by myoglobins containing iron porphyrin cofactors with one and two trifluoromethyl groups at peripheral sites (FePorCF₃ and FePor(CF₃)₂, respectively), native heme and iron porphycene (FePc). These four myoglobins show a wide range of Fe(II)/Fe(III) redox potentials in the protein of +147 mV, +87 mV, +42 mV and −198 mV vs. NHE, respectively. Myoglobin reconstituted with FePor(CF₃)₂ has a more positive potential, which enhances the reactivity of a carbene intermediate with alkenes, and demonstrates superior cyclopropanation of inert alkenes, such as aliphatic and internal alkenes. In contrast, engineered myoglobin reconstituted with FePc has a more negative redox potential, which accelerates the formation of the intermediate, but has low reactivity for inert alkenes. Mechanistic studies indicate that myoglobin with FePor(CF₃)₂ generates an undetectable active intermediate with a radical character. In contrast, this reaction catalyzed by myoglobin with FePc includes a detectable iron–carbene species with electrophilic character. This finding highlights the importance of redox-focused design of the iron porphyrinoid cofactor in hemoproteins to tune the reactivity of the carbene transfer reaction

Longitudinal observation of insulin secretory ability before and after the onset of immune checkpoint inhibitor-induced diabetes mellitus: A report of two cases

Immune checkpoint inhibitor-induced diabetes mellitus is a rare immune-related adverse event. This report illustrates clinical data and insulin secretory ability before and after the onset of immune checkpoint inhibitor-induced diabetes

Perioperative immune responses in cancer patients undergoing digestive surgeries

<p>Abstract</p> <p>Background</p> <p>Th1/Th2 cell balance is thought to be shifted toward a Th2-type immune response not only by malignancy but also by surgical stress. The aim of this study was to estimate perioperative immune responses with respect to the Th1/Th2 balance in patients with gastrointestinal cancer.</p> <p>Methods</p> <p>Ninety-four patients who underwent abdominal surgeries were divided into three groups: gastric resection (n = 40), colorectal resection (n = 34) and hepatic resection (n = 20). Twelve patients undergoing laparoscopic cholecystectomy and 20 healthy subjects were served as control groups. Intracellular cytokine staining in CD4+ T lymphocytes was identified to characterize Th1/Th2 balance. Th1/Th2 balance was evaluated before operation and until postoperative days (POD) 14.</p> <p>Results</p> <p>The preoperative Th1/Th2 ratio was significantly lower in patients with malignancy compared with control. The Th1/Th2 ratio of patients in all groups decreased significantly postoperatively. Th1/Th2 balance on POD 2 in patients with malignancy was significantly decreased compared to patients with laparoscopic cholecystectomy, but there were no significant differences among the four groups on POD 14.</p> <p>Conclusion</p> <p>Patients with malignancy showed an abnormal perioperative Th1/Th2 balance suggesting predominance of a type-2 immune response. Major abdominal surgeries induce a marked shift in Th1/Th2 balance toward Th2 in the early postoperative stage.</p

Prevention of the initial testosterone surge induced by a luteinizing hormone-releasing hormone analogue in prostate cancer patients:the endocrinological effects of pretreatment with chlormadinone acetate

We investigated the endocrinological effects of pretreatment with chlormadinone acetate (CMA) in preventing the initial testosterone surge induced by a luteinizing hormone-releasing hormone (LH-RH) analogue. A total of 25 patients with previously untreated prostate cancer were included in this study. The patients were randomly assigned to 2 treatment groups:Group1;CMA therapy was begun 4 weeks before the initial LH-RH analogue injection. Group 2;CMA therapy was begun 2 weeks before the initial LH-RH analogue injection. After the initial LH-RH analogue injection, CMA was administered during this study. After LH-RH analogue application, the mean values of serum luteinizing hormone (LH) and testosterone increased in both groups on day 3. However, LH and testosterone levels remained beneath pretreatment values in both groups. The mean relative PSA levels did not significantly increased on day 3 and day 7in both groups. Our results indicate that pretreatment with CMA for 2 weeks was sufficient to prevent the initial testosterone surge in the maximal androgen blockade which was associated with CMA

A Novel Combination Cancer Therapy with Iron Chelator Targeting Cancer Stem Cells via Suppressing Stemness

Excess iron causes cancer and is thought to be related to carcinogenesis and cancer progression including stemness, but the details remain unclear. Here, we hypothesized that stemness in cancer is related to iron metabolism and that regulating iron metabolism in cancer stem cells (CSCs) may be a novel therapy. In this study, we used murine induced pluripotent stem cells that expressed specific stem cell genes such as Nanog, Oct3/4, Sox2, Klf4, and c-Myc, and two human cancer cell lines with similar stem cell gene expression. Deferasirox, an orally available iron chelator, suppressed expression of stemness markers and spherogenesis of cells with high stemness status in vitro. Combination therapy had a marked antitumor effect compared with deferasirox or cisplatin alone. Iron metabolism appears important for maintenance of stemness in CSCs. An iron chelator combined with chemotherapy may be a novel approach via suppressing stemness for CSC targeted therapy

ショハツ カンサイボウ ガン ノ ビョウイン ト ヨゴ キテイ インシ ニ カン スル リンショウ テキ ケントウ

目的:初発肝細胞癌の病因と予後規定因子について検討し,2000年の我々の獨協医科大学病院症例を対象とした報告と比較することを目的とした.方法:初発肝細胞癌102例を対象とした.病因はB型肝炎 (HBV),C型肝炎 (HCV),NBNC,アルコールの4つに分類した.Kaplan-Meier法を用いて生存率を求め,Coxの比例ハザードモデルを用いて予後因子の検討を行った.得られた結果を2000年の報告と比較した.結果:病因はHBV 12.8%,HCV 60.7%,NBNC 15.7%,アルコール10.8%であり,HCVは減少し,NBNCとアルコールは増加傾向にあった.治療例の生存率は1年87.5%,2年78.0%,3年71.5%であり,近年の診断と治療の進歩による予後改善が確認された.腫瘍ステージがIII以上であること,およびPIVKA-II 40 mAU/ml以上の2つが独立した予後規定因子であった.結論:肝細胞癌の病因ではHCVが減少し,NBNCとアルコールが増加していた.腫瘍ステージ,PIVKA-IIが独立した生命予後規定因子であった.Purpose:The purpose of this study was to investigate the causes of initial hepatocellular carcinoma and the factors determining prognosis, and to compare the findings with those of our year 2000 report.Method:Subjects comprised 102 patients with initial hepatocellular carcinoma. Causes were divided into four categories: hepatitis B virus (HBV);hepatitis C virus (HCV);non-B, non-C hepatitis (NBNC);and alcohol. Survival rates were obtained using the Kaplan-Meier method and prognostic factors were investigated using Cox\u27s proportional hazards model. The results were compared with the findings of the year 2000 report.Results:The cause was HBV in 12.8 % of cases, HCV in 60.7%, NBNC in 15.7%, and alcohol in 10.8%. Frequency of HCV was decreased and frequencies of NBNC and alcohol showed increasing tendencies. The survival rate of treated patients was 87.5 % at 1 year, 78.0 % at 2 years, and 71.5 % at 3 years. Improved prognosis was confirmed with diagnosis in recent years and treatment advances. Two factors were independently associated with poor prognosis:tumor stage III or IV; and PIVKA-II level>40 mAU/ml.Conclusion:HCV decreased and NBNC and alcohol increased as causes of hepatocellular carcinoma. Factors independently associated with life prognosis were tumor stage and PIVKA-II level

Risk Factors for the Requirement of Antenatal Insulin Treatment in Gestational Diabetes Mellitus

Poor maternal glycemic control increases maternal and fetal risk for adverse outcomes, and strict management of gestational diabetes mellitus (GDM) is recommended to prevent neonatal and maternal complications. However, risk factors for the requirement of antenatal insulin treatment (AIT) are not well-investigated in the pregnant women with GDM. We enrolled 37 pregnant women with GDM and investigated the risk for AIT by comparing the patients with AIT (AIT group; n=10) and without insulin therapy (Diet group; n=27). The 1-h and 2-h plasma glucose levels and the number of abnormal values in 75 g OGTT were significantly higher in AIT group compared with Diet group. By logistic regression analysis, plasma glucose level at 1-h was significant predictor for AIT and the odds ratios were 1.115 (1.004–1.239) using forward selection method and 1.192 (1.006–1.413) using backward elimination method. There were no significant differences in obstetrical outcomes and neonatal complications. 1-h plasma glucose levels in 75 g OGTT are useful parameters in predicting the requirement for AIT in GDM. Both maternal and neonatal complications are comparable in GDM patients with and without insulin therapy