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Chung Hyun Nahm,1 Moon Hee Lee,2 Noriyoshi Fujii,3 Tatsuyoshi Fujii,4 Jong Weon Choi1 1Department of Laboratory Medicine, College of Medicine, Inha University, Incheon, Republic of Korea; 2Department of Internal Medicine, College of Medicine, Inha University, Incheon, Republic of Korea; 3Department of Dermatology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan; 4Department of Internal Medicine, Teikyo University Chiba Medical Center, Chiba, JapanCorrespondence: Jong Weon Choi, Department of Laboratory Medicine, College of Medicine, Inha University, Inhang-ro 27, Jung-gu, Incheon, Republic of Korea, Tel +82-32-890-2503, Fax +82-32-890-2529, Email jwchoi@inha.ac.krBackground: Nitric oxide (NO) is a bioactive signaling molecule that mediates various physiological and biological processes. Type 2 diabetes mellitus (T2DM) can be categorized into several subgroups according to fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) levels. Few studies have closely examined the effect of NO and lipocalin-2 on albuminuria and insulin resistance in T2DM subgroups. This study investigated the role of NO, lipocalin-2, and proinflammatory cytokines on the development of proteinuria and insulin resistance in patients with T2DM subgroups.Methods: A total of 256 subjects, including 191 patients with T2DM and 65 non-diabetic healthy individuals, were evaluated. NO metabolites (NOx), lipocalin-2, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) levels were measured. Patients with T2DM were classified into three subgroups: patients with FPG-defined diabetes (PG-DM), those with HbA1c-defined diabetes (HA-DM), and those who met the criteria for both FPG and HbA1c (PG/HA-DM). The albumin-to-creatinine ratio (ACR) and the homeostasis model assessment of β-cell function (HOMA-B) and insulin resistance (HOMA-IR) were calculated.Results: NOx, lipocalin-2, and TNF-α levels were significantly higher in patients with T2DM than in healthy individuals. Patients with PG/HA-DM had significantly higher NOx levels than those with PG-DM or HA-DM. Of the patients with high NOx levels, patients with lipocalin-2 elevation exhibited higher ACR and HOMA-IR than those without lipocalin-2 elevation. NOx was positively correlated with lipocalin-2, ACR, HOMA-IR, and TNF-α but not with HOMA-B and IL-6. The upper quartile of NOx levels led to a 1.2-fold increase in the risk of albuminuria (odds ratio: 1.215; 95% CI: 1.012– 2.418; p < 0.001).Conclusion: NO plays a crucial role in proteinuria and insulin resistance by collaborating with lipocalin-2 and TNF-α, showing significantly higher levels in patients with PG/HA-DM than in those with PG-DM or HA-DM.Keywords: nitric oxide, lipocalin-2, proteinuria, insulin resistance, diabetes subgroups

Chung Hyun Nahm,1 Moon Hee Lee,2 Tatsuyoshi Fujii,3 Noriyoshi Fujii,4 Jong Weon Choi1 1Department of Laboratory Medicine, College of Medicine, Inha University, Incheon, Republic of Korea; 2Department of Internal Medicine, College of Medicine, Inha University, Incheon, Republic of Korea; 3Department of Internal Medicine, Teikyo University Chiba Medical Center, Chiba, Japan; 4Department of Internal Medicine, Tsuchiura Kyodo General Hospital, Ibaraki, JapanCorrespondence: Jong Weon Choi, Department of Laboratory Medicine, College of Medicine, Inha University, Inhang-ro 27, Jung-gu, Incheon, 22332, Republic of Korea, Tel +82-32-890-2503, Fax +82-32-890-2529, Email jwchoi@inha.ac.krBackground: Mild renal dysfunction (MRD) is a common condition often associated with diabetes or inflammation and regarded as a risk factor for cardiovascular disease in patients with hypertension. Few studies have examined the role of lipocalin-2 (LCN2) as a regulator of iron and a contributor to anemia in MRD. The aim of this study was to investigate the relationship between LCN2, soluble transferrin receptor (sTfR), erythropoietin (EPO), reticulocyte production, and the prevalence of anemia in MRD.Methods: A total of 235 subjects with MRD were evaluated. LCN2, sTfR, EPO, and iron levels were measured. Reticulocyte maturity index (RMI) and corrected LCN2 (cLCN2) values were calculated using reticulocyte subpopulations and the inflammation index, respectively.Results: Subjects with LCN2 elevation had significantly higher sTfR and significantly lower RMI levels than those without LCN2 elevation. Compared to subjects without LCN2 elevation, those with LCN2 elevation exhibited significantly lower hemoglobin (12.9 ± 1.6 g/dL vs 14.0 ± 1.7 g/dL, p < 0.001) and more prevalent anemia (27.7% vs 13.3%, p = 0.008). Patients with anemia had significantly higher LCN2 and cLCN2 than those without anemia. LCN2 was positively correlated with sTfR and negatively correlated with RMI but not EPO. Elevated LCN2 led to a 1.3-fold increase in the prevalence of anemia (odds ratio: 1.302; 95% CI: 1.012– 2.527; p < 0.001).Conclusion: LCN2 elevation may contribute to the development of anemia in MRD, particularly in conjunction with restricted iron availability and suppressed reticulocyte production.Keywords: lipocalin-2, transferrin receptor, erythropoietin, renal dysfunction, anemia

Targeted inhibition of Hedgehog signaling at the cell membrane has been associated with anticancer activity in preclinical and early clinical studies. Hedgehog signaling involves activation of Gli transcription factors that can also be induced by alternative pathways. In this study, we identified an interaction between Gli proteins and a transcription coactivator TBP-associated factor 9 (TAF9), and validated its functional relevance in regulating Gli transactivation. We also describe a novel, synthetic small molecule, FN1-8, that efficiently interferes with Gli/TAF9 interaction and downregulate Gli/TAF9-dependent transcriptional activity. More importantly, FN1-8 suppresses cancer cell proliferation in vitro and inhibits tumor growth in vivo. Our results suggest that blocking Gli transactivation, an important control point of multiple oncogenic pathways, may be an effective anticancer strategy.