Understanding and Improving Platinum Anticancer Drugs - Phenanthriplatin

Approximately half of all patients who receive anticancer chemotherapy are treated with a platinum drug. Despite the widespread use of these drugs, the only cure that can be claimed is that of testicular cancer following cisplatin treatment. This article reviews some of our recent work on phenanthriplatin, a cisplatin derivative in which a chloride ion is replaced by phenanthridine, and on one of its analogues, the previously reported pyriplatin. These cationic complexes form monofunctional adducts on DNA that do not significantly distort the duplex, yet efficiently block transcription. Cell-based assays reveal altered cellular uptake properties and a cancer cell-killing profile different from those of established platinum drugs. Mechanistic work, including a crystal structure analysis of platinum-modified DNA in the active site of RNA polymerase II, is discussed herein.National Cancer Institute (U.S.) (Grant CA034992)Misrock Foundation (Postdoctoral Fellowship

Crocin Suppresses LPS-Stimulated Expression of Inducible Nitric Oxide Synthase by Upregulation of Heme Oxygenase-1 via Calcium/Calmodulin-Dependent Protein Kinase 4

Crocin is a water-soluble carotenoid pigment that is primarily used in various cuisines as a seasoning and coloring agent, as well as in traditional medicines for the treatment of edema, fever, and hepatic disorder. In this study, we demonstrated that crocin markedly induces the expression of heme oxygenase-1 (HO-1) which leads to an anti-inflammatory response. Crocin inhibited inducible nitric oxide synthase (iNOS) expression and nitric oxide production via downregulation of nuclear factor kappa B activity in lipopolysaccharide- (LPS-) stimulated RAW 264.7 macrophages. These effects were abrogated by blocking of HO-1 expression or activity. Crocin also induced Ca2+ mobilization from intracellular pools and phosphorylation of Ca2+/calmodulin-dependent protein kinase 4 (CAMK4). CAMK4 knockdown and kinase-dead mutant inhibited crocin-mediated HO-1 expression, Nrf2 activation, and phosphorylation of Akt, indicating that HO-1 expression is mediated by CAMK4 and that Akt is a downstream mediator of CAMK4 in crocin signaling. Moreover, crocin-mediated suppression of iNOS expression was blocked by CAMK4 inhibition. Overall, these results suggest that crocin suppresses LPS-stimulated expression of iNOS by inducing HO-1 expression via Ca2+/calmodulin-CAMK4-PI3K/Akt-Nrf2 signaling cascades. Our findings provide a novel molecular mechanism for the inhibitory effects of crocin against endotoxin-mediated inflammation

1,3-Bis[(6-methyl-2-pyrid­yl)meth­yl]imidazolium bromide

The title compound, C17H19N4 +·Br−, is built up from 1,3-bis­[(6-methyl-2-pyridin­yl)meth­yl]imidazolium cations and bromide anions. Each of two 6-methyl-2-pyridyl rings is rotated out of the imidazole plane, making dihedral angles of 79.90 (9) and 86.40 (9)°. The packing is consolidated by aromatic π–π inter­actions between the pyridine rings of neighbouring mol­ecules [centroid–centroid distance = 3.554 (2) Å] and by weak C—H⋯N and C—H⋯Br hydrogen bonds

Similarities and differences among Internet gaming disorder, gambling disorder and alcohol use disorder: A focus on impulsivity and compulsivity

Background and aims: The aim of the present study was to test the impulsivities and compulsivities of behavioral addictions, including Internet gaming disorder (IGD) and gambling disorder (GD), by directly comparing them with alcohol use disorder (AUD) and a healthy control (HC) group. Methods: We enrolled male patients who were diagnosed with IGD, GD or AUD, with 15 patients per group, as well as 15 HCs. Trait impulsivity was measured using the Barratt Impulsiveness Scale version 11 (BIS-11). The stop-signal test (SST) from the Cambridge Neuro-psychological Test Automated Battery (CANTAB) was used to assess the patients’ abilities to inhibit prepotent responses. Compulsivity was measured using the intra–extra dimensional set shift (IED) test from the CANTAB. The Trail Making Test (TMT) was also used in this study. Results: The IGD and AUD groups scored significantly higher on the BIS-11 as a whole than did the HC group (p = 0.001 and p = 0.001, respectively). The IGD and AUD groups also scored significantly higher on the BIS-11 as a whole than did the GD group (p = 0.006 and p = 0.001, respectively). In addition, the GD group made significantly more errors (p = 0.017 and p = 0.022, respectively) and more individuals failed to achieve criterion on the IED test compared with the IGD and HC groups (p = 0.018 and p = 0.017, respectively). Discussion: These findings may aid in the understanding of not only the differences in categorical aspects between individuals with IGD and GD but also in impulsivity–compulsivity dimensional domains. Conclusion: Additional studies are needed to elucidate the neurocognitive characteristics of behavioral addictive disorders in terms of impulsivity and compulsivity

Canine adipose tissue-derived MSCs engineered with mRNA to overexpress TSG-6 and enhance the anti-inflammatory effects in canine macrophages

BackgroundMesenchymal stem cells (MSCs) are useful agents in the treatment of various inflammatory diseases. The immunomodulatory effects of MSCs are largely related to their secretory properties. mRNA engineering emerged as a safe alternative to enhance the secretory function of MSCs. Optimization of the untranslated region (UTR) sequence is important for enhancing the translational efficiency of exogenous mRNAs. However, research on the optimization of UTR in canine MSCs has not yet been conducted.ObjectivesWe aimed to identify the UTR sequence related to the expression efficiency of in vitro transcription (IVT) mRNA in canine MSCs and investigate whether mRNA-engineered MSCs that overexpress TSG-6 exhibit enhanced anti-inflammatory effects.MethodsCanine adipose tissue-derived (cAT)-MSCs were transfected with green fluorescence protein (GFP) mRNA with three different UTRs: canine hemoglobin subunit alpha-like 1 (HBA1), HBA2, and hemoglobin subunit beta-like (HBB). The translation efficacy of each mRNA was evaluated using relative fluorescence. TSG-6 mRNA was produced with the UTR optimized according to relative fluorescence results. cAT-MSCs were transfected with TSG-6 mRNA (MSCTSG-6), and TSG-6 expression was analyzed using real-time quantitative PCR, ELISA, and western blotting. To evaluate the anti-inflammatory effects of MSCsTSG-6, DH82 cells were co-cultured with MSCsTSG-6 or treated with dexamethasone, and changes in the expression of inflammatory cytokines were analyzed using qPCR.ResultsThe highest fluorescence level was observed in the HBA1 UTR at 24 h post-transfection. TSG-6 mRNA transfection yielded high levels of TSG-6 in the cAT-MSCs. In DH82 cells co-cultured with MSCsTSG-6, the expression of inflammatory cytokines decreased compared to that in co-culturing with naïve MSCs and dexamethasone treatment.ConclusionsOptimization of the HBA1 UTR improved the translation efficiency of IVT mRNA in canine MSCs. cAT-MSCs engineered with TSG-6 mRNA effectively enhanced the anti-inflammatory effects of the MSCs when co-cultured with LPS-activated DH82 cells

Accuracy of Administrative Claim Data for Gastric Adenoma After Endoscopic Resection

BACKGROUND/AIMS: Administrative databases provide valuable information for large-cohort studies. This study aimed to evaluate the diagnostic accuracy of an administrative database for resected gastric adenomas. METHODS: Data of patients who underwent endoscopic resection for benign gastric lesions were collected from three hospitals. Gastric adenoma cases were identified in the hospital database using International Classification of Diseases (ICD) 10-codes. The non-adenoma group included patients without gastric adenoma codes. The diagnostic accuracy for gastric adenoma was analyzed based on the pathological reports of the resected specimen. RESULTS: Among 5,095 endoscopic resections with codes for benign gastric lesions, 3,909 patients were included in the analysis. Among them, 2,831 and 1,078 patients were allocated to the adenoma and non-adenoma groups, respectively. Regarding the overall diagnosis of gastric adenoma with ICD-10 codes, the sensitivity, specificity, positive predictive value, and negative predictive value were 98.7%, 88.5%, 95.2%, and 96.8%, respectively. There were no significant differences in these parameters between the tertiary and secondary centers. CONCLUSION: Administrative codes of gastric adenoma, according to ICD-10 codes, showed good accuracy and can serve as a useful tool to study prognosis of these patients in real-world data studies in the future

EFFECT OF LOW DOSE RADIATION ON DIFFERENTIATION OF BONE MARROW CELLS INTO DENDRITIC CELLS

Low dose radiation has been shown to be beneficial to living organisms using several biological systems, including immune and hematopoietic systems. Chronic low dose radiation was shown to stimulate immune systems, resulting in controlling the proliferation of cancer cells, maintain immune balance and induce hematopoietic hormesis. Since dendritic cells are differentiated from bone marrow cells and are key players in maintaining the balance between immune activation and tolerance, it may be important to further characterize whether low dose radiation can influence the capacity of bone marrow cells to differentiate into dendritic cells. We have shown that bone marrow cells from low dose- irradiated (γ-radiation, 0.2Gy, 15.44mGy/h) mice can differentiate into dendritic cells that have several different characteristics, such as expression of surface molecules, cytokine secretion and antigen uptake capacity, when compared to dentritic cells differentiated from the control bone marrow cells. These differences observed in the low dose radiation group can be beneficial to living organisms either by activation of immune responses to foreign antigens or tumors, or maintenance of self-tolerance. To the best of our knowledge, this is the first report showing that total-body low dose radiation can modulate the capacity of bone marrow cells to differentiate into dendritic cells