Reversible Ligand-Centered Reduction in Low-Coordinate Iron Formazanate Complexes.

Coordination of redox-active ligands to metals is a compelling strategy for making reduced complexes more accessible. In this work, we explore the use of redox-active formazanate ligands in low-coordinate iron chemistry. Reduction of an iron(II) precursor occurs at milder potentials than analogous non-redox-active ß-diketiminate complexes, and the reduced three-coordinate formazanate-iron compound is characterized in detail. Structural, spectroscopic, and computational analysis show that the formazanate ligand undergoes reversible ligand-centered reduction to form a formazanate radical dianion in the reduced species. The less negative reduction potential of the reduced low-coordinate iron formazanate complex leads to distinctive reactivity with formation of a new N-I bond that is not seen with the ß-diketiminate analogue. Thus, the storage of an electron on the supporting ligand changes the redox potential and enhances certain reactivity.

Preparation of Halogenated Fluorescent Diaminophenazine Building Blocks.

A short, convenient, and scalable protocol for the one-pot synthesis of a series of fluorescent 7,8-dihalo-2,3-diaminophenazines is introduced. The synthetic route is based on the oxidative condensation of 4,5-dihalo-1,2-diaminobenzenes in aqueous conditions. The resulting diaminophenazines could be attractive intermediates for the preparation of polyfunctional phenazines and extended polyheteroacenes. We find that the undesired hydroxylation byproducts, typically obtained in aqueous conditions, are completely suppressed by addition of a stoichiometric amount of acetone during the oxidation step allowing for selective formation of 7,8-dihalo-2,2-dimethyl-2,3-dihydro-1H-imidazo[4,5-b]phenazine derivatives with good to excellent yields. Under reductive conditions, the imidazolidine ring can be hydrolyzed into the desired 7,8-dihalo-2,3-diaminophenazines. Furthermore, we report a selective route under highly reducing conditions to monohydrodeaminate the 2,3-di(methylamino) phenazine derivatives, which allows for further structural variations of these phenazine building blocks. All of these derivatives are luminescent, with measured fluorescence quantum-yields of up to 80% in ethanol for the more rigid structures, highlighting the potential of such materials to provide new fluorophores.

Diagnosis and management of acute colonic diverticulitis: results of a survey among Korean gastroenterologists.

BACKGROUND/AIMS: Some management strategies for acute colonic diverticulitis remain controversial in Korean real-world practice because their clinical features differ from those in the West. This study aimed to investigate the opinions of Korean physicians regarding the diagnosis and treatment of acute diverticulitis. METHODS: A web-based survey was conducted among gastroenterologists specializing on treating lower gastrointestinal disorders. The questionnaires concerned overall management strategies for colonic diverticulitis, including diagnosis, treatment, and follow-up. RESULTS: In total, 209 gastroenterologists responded to the survey. Less than one-fourth of the respondents (23.6%) answered that left-sided colonic diverticulitis is more likely to be complicated than right-sided colonic diverticulitis. Most respondents agreed that immunocompromised patients with diverticulitis have worse clinical outcomes than immunocompetent patients (71.3%). Computed tomography was the most preferred tool for diagnosing diverticulitis (93.9%). Approximately 89% of the respondents answered that they believed antibiotic treatment is necessary to treat acute uncomplicated diverticulitis. Most respondents (92.6%) agreed that emergency surgery is not required for diverticulitis with an abscess or microperforation without panperitonitis. Further, 94.7% of the respondents agreed that colon cancer screening is necessary in patients aged ≥ 50 years with diverticulitis after they have recovered from acute illness. Many respondents (71.4%) agreed that surgery for recurrent diverticulitis should be individualized. CONCLUSION: Opinions regarding management strategies for colonic diverticulitis among Korean gastroenterologists were well agreed upon in some areas but did not agree well in other areas. Evidence-based guidelines that meet the practical needs of the Korean population should be developed.

Comparative outcomes of acute colonic diverticulitis in immunocompromised versus immunocompetent patients: a systematic review and meta-analysis.

BACKGROUND/AIMS: Immunocompromised patients with acute colonic diverticulitis are at high risk for complications and failure of non-surgical treatment. However, evidence on the comparative outcomes of immunocompromised and immunocompetent patients with diverticulitis is lacking. This systematic review and meta-analysis investigated the outcomes of medical treatment in immunocompromised and immunocompetent patients with diverticulitis. METHODS: A comprehensive literature search was conducted in PubMed, Embase, and the Cochrane Library. Studies comparing the clinical outcomes of immunocompromised and immunocompetent patients with diverticulitis were included. RESULTS: A total of 10 studies with 1,946,461 subjects were included in the quantitative synthesis. The risk of emergency surgery and postoperative mortality after emergency surgery was significantly higher in immunocompromised patients than in immunocompetent patients with diverticulitis (risk ratio [RR], 1.76; 95% confidence interval [CI], 1.31-2.38 and RR, 3.05; 95% CI, 1.70-5.45, respectively). Overall risk of complications associated with diverticulitis was non-significantly higher in immunocompromised than in immunocompetent patients (RR, 1.24; 95% CI, 0.95-1.63). Overall mortality irrespective of surgery was significantly higher in immunocompromised than in immunocompetent patients with diverticulitis (RR, 3.65; 95% CI, 1.73-7.69). By contrast, postoperative mortality after elective surgery was not significantly different between immunocompromised and immunocompetent patients with diverticulitis. In subgroup analysis, the risk of emergency surgery and recurrence was significantly higher in immunocompromised patients with complicated diverticulitis, whereas no significant difference was shown in mild disease. CONCLUSIONS: Immunocompromised patients with diverticulitis should be given the best medical treatment with multidisciplinary approach because they had increased risks of surgery, postoperative morbidity, and mortality than immunocompetent patients.

Use of device-assisted enteroscopy in small bowel disease: an expert consensus statement by the Korean Association for the Study of Intestinal Diseases.

The introduction of device-assisted enteroscopy (DAE) in the beginning of 21st century has revolutionized the diagnosis and treatment of diseases of the small intestine. In contrast to capsule endoscopy, the other main diagnostic modality of the small bowel diseases, DAE has the unique advantages of observing the region of interest in detail and enabling tissue acquisition and therapeutic intervention. As DAE becomes an essential procedure in daily clinical practice, there is an increasing need for correct guidelines on when and how to perform it and what technical factors should be considered. In response to these needs, the Korean Association for the Study of Intestinal Diseases developed an expert consensus statement on the performance of DAE by reviewing the current evidence. This expert consensus statement particularly focuses on the indications, choice of insertion route, therapeutic intervention, complications, and relevant technical points.

[Use of Device-Assisted Enteroscopy in Small Bowel Disease: An Expert Consensus Statement by the Korean Association for the Study of Intestinal Diseases].

The introduction of device-assisted enteroscopy (DAE) in the beginning of the 21st century has revolutionized the diagnosis and treatment of diseases of the small intestine. In contrast to capsule endoscopy, the other main diagnostic modality of small bowel diseases, DAE has the unique advantages of allowing the observation of the region of interest in detail and enabling tissue acquisition and therapeutic intervention. As DAE becomes an essential procedure in daily clinical practice, there is an increasing need for correct guidelines on when and how it is to be performed and what technical factors should be taken into consideration. In response to these needs, the Korean Association for the Study of Intestinal Diseases has developed an expert consensus statement on the performance of DAE by reviewing current evidence. This expert consensus statement particularly focuses on the indications, choice of insertion route, therapeutic intervention, complications, and relevant technical points.

Effects of nitric oxide-releasing nonsteroidal anti-inflammatory drugs (NONO-NSAIDs) on melanoma cell adhesion.

A new class of nitric oxide (NO•)-releasing nonsteroidal anti-inflammatory drugs (NONO-NSAIDs) were developed in recent years and have shown promising potential as NSAID substitutes due to their gentle nature on cardiovascular and gastrointestinal systems. Since nitric oxide plays a role in regulation of cell adhesion, we assessed the potential use of NONO-NSAIDs as anti-metastasis drugs. In this regard, we compared the effects of NONO-aspirin and a novel NONO-naproxen to those exerted by their respective parent NSAIDs on avidities of human melanoma M624 cells. Both NONO-NSAIDs, but not the corresponding parent NSAIDs, reduced M624 adhesion on vascular cellular adhesion molecule-1 (VCAM-1) by 20-30% and fibronectin by 25-44% under fluid flow conditions and static conditions, respectively. Only NONO-naproxen reduced (~56%) the activity of ß1 integrin, which binds to α4 integrin to form very late antigen-4 (VLA-4), the ligand of VCAM-1. These results indicate that the diazeniumdiolate (NO•)-donor moiety is critical for reducing the adhesion between VLA-4 and its ligands, while the NSAID moiety can impact the regulation mechanism of melanoma cell adhesion.

Psychological Effects and Medication Adherence among Korean Patients with Inflammatory Bowel Disease during the Coronavirus Disease 2019 Pandemic: A Single-Center Survey.

BACKGROUND AND AIM: This study evaluated the impact of coronavirus disease 2019 (COVID-19) on the mental health of inflammatory bowel disease (IBD) patients. We quantified anxiety, depression, and medication adherence among IBD patients through a single-center survey in South Korea during the COVID-19 pandemic. METHODS: An electronic survey was made available to patients at the IBD clinic in Daejeon St. Mary's hospital from July 2021 to September 2021. The validated Hospital Anxiety and Depression Scale (HADS) was used to assess depression and anxiety. The Korean version of the Medication Adherence Rating Scale (KMARS) questionnaire was used to assess medication adherence. RESULTS: In total, 407 patients (56.5%; ulcerative colitis, 43.5%; Crohn's disease) participated in the survey. Among the respondents, 14.5% showed significant anxiety and 26.3% showed significant depression. Female sex, presence of mental disease, unvaccinated status, and the presence of Crohn's disease were associated with greater risks of anxiety and depression. Among medications, immunomodulators were associated with a greater risk of anxiety. In terms of KMARS, patients reported favorable medication adherence despite the psychological burden of the pandemic. The KMARS score was 7.3 ± 1.5 (mean ± SD) of 10.0 points. High anxiety and depression were associated with a slight decrease in medication adherence. CONCLUSIONS: COVID-19 has increased anxiety and depression among IBD patients, whose medication adherence has nevertheless remained good. Furthermore, anxiety and depression were found to have a negative correlation with adherence. Our results provide insights concerning psychological response and medication adherence among IBD patients in South Korea during the COVID-19 pandemic.

Percutaneous endoscopic necrosectomy in a patient with emphysematous pancreatitis: A case report.

RATIONALE: Emphysematous pancreatitis, a rare complication of acute necrotizing pancreatitis with a high mortality rate, is associated with gas-forming bacteria. When using the step-up approach for treating emphysematous pancreatitis, it is preferable to delay drainage interventions for 4 weeks. However, percutaneous drainage may be necessary, even in the early phase of acute pancreatitis, for a patient whose sepsis deteriorates despite optimal medical management. Percutaneous drainage can then be followed by endoscopic necrosectomy through the percutaneous tract. PATIENT CONCERNS: A 52-year-old man was transferred to our hospital for treatment of sepsis and multiorgan failure associated with emphysematous pancreatitis. DIAGNOSIS: An abdominal computed tomography scan had shown pancreatic and peripancreatic necrosis, along with extensive gas bubbles. INTERVENTIONS: Despite optimal medical management, the patient's condition continued to deteriorate, and it became necessary to insert 2 percutaneous catheter drainages (PCDs), even though the patient was still in the early phase of pancreatitis. Each PCD was upsized and irrigated with sterile saline by an interventional radiologist twice a week. The infected necrosis around the tail of the pancreas was completely resolved after PCD. However, PCD through the transperitoneal route did not resolve necrosis around the pancreatic head. Following the PCDs, percutaneous pancreatic necrosectomy using an ultra-slim upper endoscope was performed, after which the patient recovered quickly and was discharged. OUTCOMES: Follow-up computed tomography was performed 12 weeks after the patient was discharged, and it showed complete resolution of the walled-off necrosis. The patient's condition improved without any fluid collection or complications. LESSONS: PCD can be used in the early phase of emphysematous pancreatitis for patients who continue to deteriorate due to sepsis. This can easily be followed, if necessary, by percutaneous pancreatic necrosectomy using an ultra-slim endoscope.

E2F1-directed activation of Bcl-2 is correlated with lactoferrin-induced apoptosis in Jurkat leukemia T lymphocytes.

Lactoferrin (Lf) has been shown to control the proliferation of a variety of mammalian cells. Recently, we reported that human Lf induces apoptosis via a c-Jun N-terminal kinases (JNK)-associated Bcl-2 pathway that stimulates programmed cell death. In order to gain insight into the mechanism underlying Lf-triggered apoptotic features, we attempted to determine the mechanisms whereby the Lf-induced Bcl-2 family proteins exert their pro- or anti-apoptotic effects in Jurkat leukemia T lymphocytes. Treatment of the cells with high concentrations of Lf resulted in a significant reduction in in vitro growth and cell viability. As the levels of Lf increased, greater quantities of CDK6 and hyper-phosphorylated retinoblastoma protein were produced, resulting in the induction of E2F1-dependent apoptosis. Simultaneously, PARP and caspases were efficiently cleaved during Lf-induced apoptosis. The E2F1-induced apoptotic process occurred preferentially in p53-deficient Jurkat leukemia cells. Therefore, we attempted to determine whether E2F1-regulated Bcl-2 family proteins involved in the apoptotic process were relevant to Lf-induced apoptosis. We found that Lf increased the interaction of Bcl-2 with the pro-apoptotic protein Bad, whereas the total protein levels did not change significantly. Our results, collectively, suggest that Lf exploits the control mechanism of E2F1-regulated target genes or Bcl-2 family gene networks involved in the apoptotic process in Jurkat human leukemia T lymphocytes.

Strongly Coupled Phenazine-Porphyrin Dyads: Light-Harvesting Molecular Assemblies with Broad Absorption Coverage.

The development of light-harvesting architectures with broad absorption coverage in the visible region continues to be an important research area in the field of artificial photosynthesis. Here, we introduce a new class of ethynyl-linked panchromatic dyads composed of dibenzophenazines coupled ortho and meta to tetrapyrroles with an anchoring group that can be grafted onto metal oxide surfaces. Quantum chemical calculations and photophysical measurements of the synthesized materials reveal that both of the dibenzophenazine dyads absorb broadly from 300 to 636 nm and exhibit absorption bands different from those of the constituent chromophore units. Moreover, the different points of attachment of dibenzophenazines to tetrapyrroles give different absorption profiles which computations suggest result from differences in the planarity of the two dyads. Applicability of the dyads in artificial photosynthesis systems was assessed by their incorporation and characterization of their performance in dye-sensitized solar cells.

Oxidative stress induces PKR-dependent apoptosis via IFN-gamma activation signaling in Jurkat T cells.

The dsRNA-dependent protein kinase, PKR, is a central component in antiviral defense. The biological importance of PKR is further remarked by its critical role in apoptosis induced by a variety of stresses. Here, we analyzed the implication of oxidative stress in the induction of PKR-dependent apoptosis in Jurkat cells. Our results revealed that reactive oxygen species (ROS) induced endogenous pkr gene expression at the transcriptional level by activating the interferon (IFN)-gamma gene. However, IFN-gamma siRNA expression abrogated the H(2)O(2)-mediated pkr induction. The radical scavenger N-acetyl-l-cysteine profoundly inhibited pkr induction via the reduction of IFN-gamma expression. The treatment of cells with the specific JAK-STAT inhibitor, AG490, reduced the PKR expression, and suppressed PKR-dependent cell death. Finally, siRNA-mediated depletion of IFN-gamma or pkr efficiently downregulated H(2)O(2)-mediated apoptotic cell death. These results indicated that oxidative stress induces PKR expression essentially via the IFN-gamma activation signal, and causes apoptosis in Jurkat T cells.

Preparation, swelling and electro-mechano-chemical behaviors of a gelatin-chitosan blend membrane.

Swelling, states of water, morphology, stability in the aqueous solution, and electro-mechano-chemical bending behaviors of the gelatin-chitosan blend system were studied in order to clarify the potential use of this blend system as an actuator. The gelatin-chitosan blend system was prepared in order to avoid dissolution of the pure chitosan in an aqueous medium and the rigidity and easy degradation of the pure gelatin in the swollen state. The blend systems showed improved material properties: the vacuum-dried blend sample at the G75/C25 (w/w, gelatin-chitosan) ratio showed ∼6 times swelling (in distilled water, at neutral pH and room temperature), ∼5 times stability (in distilled water), and ∼6 times bending (at 6 V/53 mm and in a 0.02 M NaCl aqueous solution) as compared to pure gelatin. These enhanced properties could be explained by the introduction of free -OH, -NH2, and -NHOCOCH3 groups of the amorphous chitosan in the blend and the network structure through the electrostatic interactions between the ammonium (-NH3+) ions of the chitosan and the carboxylate (-COO-) ions of the gelatin. The scanning electron microscopy (SEM) micrographs of the surfaces of the blend films showed homogeneous and smooth surfaces due to the good miscibility between gelatin and chitosan. However, a different morphology from the fractured surface was found between the pure gelatin and blend systems which showed condensed and foliaceous morphologies, respectively. The leafy morphology indicates a large and homogeneous pore structure, which would cause increased ion diffusion into the gel and might lead to increased bending.

A Case Report of Recurrent Metastatic Sebaceous Carcinoma Which Showed Favorable Response Tt Non-Fluorouracil Based Chemotherapy.

BACKGROUND Sebaceous carcinoma is a rare malignant tumor of the skin adnexa. While surgical resection is a treatment of choice in localized disease, frequent recurrence and distant metastasis make treatment difficult. Moreover, due to its rarity, optimal systemic treatment has not been determined. CASE REPORT A 59-year-old female presented with disseminated subcutaneous nodules. Past history indicated she received repeated surgery, radiation therapy, and fluorouracil-based systemic chemotherapy for recurrent sebaceous carcinoma. Following a subcutaneous nodule biopsy, histopathologic examination confirmed recurrent metastasis of sebaceous carcinoma. Because there was no established regimen as salvage chemotherapy, we decided to administer paclitaxel plus Adriamycin as a combination regimen after a thorough search of previous reports on PubMed. After the patient received 6 cycles of chemotherapy, all masses dramatically regressed. Unfortunately, several new lesions appeared 3 months after cessation of chemotherapy. Therefore, she was treated with anti-HGF antibody through a clinical trial. After that, she received nivolumab. But treatment with all the new agents did not show any response. Furthermore, her disease progressed rapidly. We re-challenged with the paclitaxel and Adriamycin regimen, 2 cycles of chemotherapy, and the follow-up positron emission tomography - computed tomography revealed marked decrement of multiple metastatic nodules. CONCLUSIONS Although several clinical reports have shown the effectiveness of fluorouracil, especially 5-fluorouracil-based chemotherapy, there has been a paucity of reports on other chemotherapeutic agents. We report a case of metastatic sebaceous carcinoma which showed favorable response to non-fluorouracil-based chemotherapy.

Selective CO Production by Photoelectrochemical Methane Oxidation on TiO2.

The inertness of the C-H bond in CH4 poses significant challenges to selective CH4 oxidation, which often proceeds all the way to CO2 once activated. Selective oxidation of CH4 to high-value industrial chemicals such as CO or CH3OH remains a challenge. Presently, the main methods to activate CH4 oxidation include thermochemical, electrochemical, and photocatalytic reactions. Of them, photocatalytic reactions hold great promise for practical applications but have been poorly studied. Existing demonstrations of photocatalytic CH4 oxidation exhibit limited control over the product selectivity, with CO2 as the most common product. The yield of CO or other hydrocarbons is too low to be of any practical value. In this work, we show that highly selective production of CO by CH4 oxidation can be achieved by a photoelectrochemical (PEC) approach. Under our experimental conditions, the highest yield for CO production was 81.9%. The substrate we used was TiO2 grown by atomic layer deposition (ALD), which features high concentrations of Ti3+ species. The selectivity toward CO was found to be highly sensitive to the substrate types, with significantly lower yield on P25 or commercial anatase TiO2 substrates. Moreover, our results revealed that the selectivity toward CO also depends on the applied potentials. Based on the experimental results, we proposed a reaction mechanism that involves synergistic effects by adjacent Ti sites on TiO2. Spectroscopic characterization and computational studies provide critical evidence to support the mechanism. Furthermore, the synergistic effect was found to parallel heterogeneous CO2 reduction mechanisms. Our results not only present a new route to selective CH4 oxidation, but also highlight the importance of mechanistic understandings in advancing heterogeneous catalysis.

Reactive oxygen species formation and bystander effects in gradient irradiation on human breast cancer cells.

Ionizing radiation (IR) in cancer radiotherapy can induce damage to neighboring cells via non-targeted effects by irradiated cells. These so-called bystander effects remain an area of interest as it may provide enhanced efficacy in killing carcinomas with minimal radiation. It is well known that reactive oxygen species (ROS) are ubiquitous among most biological activities. However, the role of ROS in bystander effects has not been thoroughly elucidated. We hypothesized that gradient irradiation (GI) has enhanced therapeutic effects via the ROS-mediated bystander pathways as compared to uniform irradiation (UI). We evaluated ROS generation, viability, and apoptosis in breast cancer cells (MCF-7) exposed to UI (5 Gy) or GI (8-2 Gy) in radiation fields at 2, 24 and 48 h after IR. We found that extracellular ROS release induced by GI was higher than that by UI at both 24 h (p < 0.001) and 48 h (p < 0.001). More apoptosis and less viability were observed in GI when compared to UI at either 24 h or 48 h after irradiation. The mean effective doses (ED) of GI were ~130% (24 h) and ~48% (48 h) higher than that of UI, respectively. Our results suggest that GI is superior to UI regarding redox mechanisms, ED, and toxic dosage to surrounding tissues.

Phosphorylation of peptides derived from isolated soybean protein: effects on calcium binding, solubility and influx into Caco-2 cells.

Calcium homeostasis in the human body is maintained primarily via the absorption of calcium through the intestine. In order to maintain an efficient absorption of calcium with minimal calcium loss due to the formation of calcium phosphate precipitates in the small intestinal lumen, we developed a calcium-binding mediator using peptides derived from isolated soybean protein (ISP). ISP was modified via tryptic digestion and chemical phosphorylation using sodium trimetaphosphate, thereby generating soybean phosphopeptides (SPP), and this was followed by conducting a binding reaction with calcium chloride. We have established an optimized procedure and reaction conditions for maximal phosphorylation and calcium binding. Consequently, the phosphorylation of soybean peptides resulted in considerable improvement in their calcium binding activities. Next, we demonstrated that SPP was able to render calcium ions resistant to precipitate formation with inorganic phosphates, which suggested the enhancement of calcium bioavailability. Finally, we noted that the addition of calcium-bound SPP induced an increase in cytosolic calcium concentration in the intestinal Caco-2 cells, due to an influx of calcium. These findings provide a new basis by which we may assess the possibility that SPP, as a potent calcium carrier, can be utilized in the prevention of poor absorption of dietary calcium in animals.

Quantification of 4-methylimidazole in carbonated beverages by ultra-performance liquid chromatography-tandem mass spectrometry.

2- and 4-methylimidazoles (2-MI and 4-MI) are undesired byproducts produced during the manufacture of caramel color used to darken food products such as carbonated beverages. The Office of Environmental Health Hazard Assessment in California listed 4-MI as carcinogen in January 2011 with a proposed no significant risk level at 29 µg per person per day. Thus, a quantitative analytical measurement for 2-MI and 4-MI is desired for reliable risk assessments for exposure. An ultra-performance liquid chromatography (UPLC) coupled tandem mass spectrometric (MS/MS) method was developed for the quantification of 4-MI in beverage samples. Chromatographic separation of 2-MI and 4-MI were achieved by using a PFP reversed-phase column and a stepwise gradient of methanol and distilled water containing 0.1 % formic acid. Identification and quantification of 2-MI and 4-MI were performed using electrospray ionization-tandem mass monitoring the precursor to product ion transitions for 2-MI at m/z 83.1 → 42.2 and 4-MI at m/z 83.1 → 56.1 with melamine at m/z 127.1 → 85.1 as the internal standard. The performance of the method was evaluated against validation parameters such as specificity, carryover, linearity and calibration, correlation of determination (r(2)), detection limit, precision, accuracy, and recovery. Calibration curves at 10-400 ng/mL were constructed by plotting concentration versus peak-area ratio (analyte/internal standard) and fitting the data with a weighted 1/x. The accuracy of the assay ranged from 93.58 to 110.53 % for all analytes. Intra-assay precision for 2-MI and 4-MI were below 7.28 (relative standard deviation/RSD %) at QC samples. Here we present a new and improved method using UPLC-MS/MS to significantly simplify sample preparation and decrease chromatographic run time. This method allows accurate and reproducible quantification of 4-MI in carbonated beverages as low as sub ng/mL (ppb) levels.