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[Display omitted] • Decrease in the amount of RORα is observed in Purkinje cells of SCA1 and SCA3 model mice. • AAV vectors were used to knock-down RORα specifically in mature Purkinje cells in vivo. • The RORα knock-down caused Purkinje cell dendrite atrophy and disruption of the cell layer. • RORα-knock-down mice showed motor learning deficits and, later, overt cerebellar ataxia. • Decrease in RORα expression in Purkinje cells could be a primary etiology of cerebellar symptoms in SCAs. Retinoid-related orphan receptor α (RORα) is a transcription factor expressed in a variety of tissues throughout the body. Knockout of RORα leads to various impairments, including defects in cerebellar development, circadian rhythm, lipid metabolism, immune function, and bone development. Previous studies have shown significant reduction of RORα expression in Purkinje cells (PCs) of spinocerebellar ataxia (SCA) type 1 and type 3/MJD (Machado–Joseph disease) model mice. However, it remains unclear to what extent the RORα reduction in PCs is involved in the disease pathology. Here, RORα expression was downregulated specifically in mature mouse PCs by intravenous infusion of blood–brain barrier-permeable adeno-associated virus (AAV), expressing a microRNA against RORα (miR-RORα) under the control of the PC-specific L7-6 promoter. The systemic AAV infusion led to extensive transduction of PCs. The RORα knock-down caused degeneration of PCs including disruption of the PC monolayer alignment and dendrite atrophy. In behavioral experiments, mice expressing miR-RORα showed motor learning deficits, and later, overt cerebellar ataxia. Thus, RORα in mature PCs plays pivotal roles in maintenance of PC dendrites and the monolayer alignment, and consequently, motor learning and motor function. Decrease in RORα expression in PCs could be a primary etiology of the cerebellar symptoms in patients with SCA1 and SCA3/MJD. [ABSTRACT FROM AUTHOR]

• A close relationship is found between low serum zinc and severe states of COVID-19. • Hypozincemia critically contributes to the aggravation of COVID-19. • Serum zinc level can be a predictive factor for a critical illness of COVID-19. • We would recommend oral medication of zinc salts to patients with COVID-19. Because most severely ill patients with COVID-19 in our hospital showed zinc deficiency, we aimed to examine the relationship between the patient's serum zinc level and severe cases of COVID-19. Serum zinc <70 μg/dL was defined as the criterion for hypozincemia, and patients continuously with serum zinc <70 μg/dL were classified in the hypozincemia cohort. To evaluate whether hypozincemia could be a predictive factor for a critical illness of COVID-19, we performed a multivariate analysis by employing logistic regression analysis. Prolonged hypozincemia was found to be a risk factor for a severe case of COVID-19. In evaluating the relationship between the serum zinc level and severity of patients with COVID-19 by multivariate logistic regression analysis, critical illness can be predicted through the sensitivity and false specificity of a ROC curve with an error rate of 10.3% and AUC of 94.2% by only two factors: serum zinc value (P = 0.020) and LDH value (P = 0.026). Proper management of the prediction results in this study can contribute to establishing and maintaining a safe medical system, taking the arrival of the second wave, and the spread of COVID-19 in the future into consideration. [ABSTRACT FROM AUTHOR]

Using an in vitro random screening of small-molecule compounds, we discovered cis-diamminedichloroplatinum( II) (cisplatin), an anticancer agent, as a potential inhibitor of collagen fibril-formation. The inhibitory effect was found only when cisplatin was dissolved in dimethylsulphoxide ( DMSO), indicating that the active species were cisplatin derivatives formed in the DMSO solution. The cisplatin derivatives inhibited the formation of collagen fibrils in vitro without affecting the triple-helical conformation of the collagen molecules. Incubation with the cisplatin solution in DMSO also inhibited in situ deposition of collagen fibrils in a human umbilical vein endothelial cell (HUVEC) culture. In addition, the derivatization of cisplatin in DMSO abolished the cytotoxicity of the original compound. The platinum complex was further revealed to interact with specific sites on the collagen triple helix, and the binding sites were suggested to contain His and/or Met residues. Mass spectrometry analysis of the cisplatin solution in DMSO and a structure-activity relationship study strongly suggested that the active compound is [Pt( NH3)2(Cl)( DMSO)]+. This platinum complex will be useful for investigating molecular mechanisms of collagen self-assembly and for drug development for the treatment of fibrotic diseases. [ABSTRACT FROM AUTHOR]

Abstract: Diabetes mellitus (DM) is a considerably diagnosed metabolic disease and a serious problem worldwide. We prepared various zinc complexes and studied their potential for use as new antidiabetic agents. In this study, we synthesized a seleniferous zinc complex, di(2-selenopyridine-N-oxidato)zinc(II) ([ZPS]) that has a Zn(Se2O2) coordination mode. Analyses of structure-activity relationships between its insulin-like activity and the coordination mode of [ZPS]-related complexes showed that it had high insulin-like activity. Hypoglycemic effects of [ZPS] on type 2 diabetic KK-Ay mice were exerted at the lowest dose administered (1.25–2.5mg Zn/kg body weight), unlike previously synthesized zinc complexes. Furthermore, [ZPS] afforded us a new advantage; we were able to investigate the tissue distribution of the ligand by measuring the amount of selenium in the organs of [ZPS]-treated mice. Gastrointestinal absorption and tissue penetration of zinc derived from [ZPS] in ddY mice, which was monitored using an isotope tracer technique, was significantly increased compared to that of ZnCl2. These results suggest that [ZPS] has superior antidiabetic effects compared to previously reported zinc complexes, and is thus a potential novel antidiabetic agent that facilitates the possibility of organoselenium ligands as new metal delivery systems for treating DM. [Copyright &y& Elsevier]

Purpose: In the present study, the time-concentration profile of platinum (Pt) in plasma was compared to that of serum cystatin C (Cys C) in Japanese esophageal cancer patients receiving perioperative cisplatin-based chemotherapy. Methods: Five male and one female patients receiving 2 successive cycles of cisplatin-based chemotherapy combined with 5-fluorouracil, the treatment for esophageal squamous cell carcinoma, participated in this study. The pharmacokinetic parameters in each patient were calculated from the individual plasma Pt concentration-time curve after intravenous infusion of cisplatin using the one-compartment model. Results: Within a week of starting the first cycle of chemotherapy, serum Cys C concentrations increased in all patients from 122.6 to 143.0 %, subsequently returning to baseline levels in approximately 10 days. A similar increase in serum Cys C levels also occurred during the second treatment cycle. However, no increase in serum creatinine levels was observed during either treatment cycle. In addition, the concentration of plasma Pt 2 days after treatment in the first and second cycles did not correlate with those of either serum Cys C or creatinine. Finally, the half-life of Pt in plasma during the first treatment cycle was not significantly different from that in the second cycle. Conclusions: These findings suggest that concentration fluctuations in serum Cys C are unlikely to correlate with Pt elimination from the plasma and that renal function estimates based on serum Cys C concentration might be underestimated during perioperative cisplatin-based chemotherapy for esophageal cancer. [ABSTRACT FROM AUTHOR]

Abstract: We disclose the reductive trifluoromethylation of chemically stable homocystine and cystine to provide corresponding trifluoromethyl ethers by the CF3I/Na/Liq.NH3 system. Both non-protected and protected homocystines can be nicely converted into trifluoromethylated methionines under the same condition. The method described offers a robust synthesis of pharmaceutically important trifluoromethionine, suitable for multigram synthesis. Pentafluoroethylation of homocystine was also achieved by the CF3CF2I/Na/Liq.NH3 system. [Copyright &y& Elsevier]

Abstract: We disclose here a novel electrophilic fluorinating reagent, N-fluoro-(3,5-di-tert-butyl-4-methoxy)benzenesulfonimide (NFBSI) as a sterically demanding analogue of popular fluorinating reagent, N-fluorobenzenesulfonmide (NFSI). NFBSI improves the enantioselectivity of the products as much as 18% for the cinchona alkaloid-catalyzed enantioselective fluorination of silylenol ether compared to the use of NFSI. [Copyright &y& Elsevier]

The temperature dependence of toluene decomposition behavior was investigated with a two-stage discharge and ozone-decomposition-catalyst hybrid reactor. Toluene conversion jumped by four times by adding catalyst to the discharge at ambient temperature. This synergistic effect diminished with an increase in temperature, and no synergy was observed at higher than 200 °C. In the hybrid reactor, COx formation was promoted compared to discharge alone irrespective of temperature, and toluene was completely oxidized to COx at higher than 100 °C. Ozone acts as the precursor of the key oxidants in the toluene decomposition. [ABSTRACT FROM AUTHOR]

The antidiabetic effect of vanadium is a widely accepted phenomenon; some oxovanadium(IV) complexes have been found to normalize high blood glucose levels in both type 1 and type 2 diabetic animals. In light of the future clinical use of these complexes, the relationship among their chemical structures, physicochemical properties, metallokinetics, and antidiabetic activities must be closely investigated. Recently, we found that among bis(3-hydroxypyronato)oxovanadium(IV) [VO(3hp)2] related complexes, bis(allixinato)oxovanadium(IV) [VO(alx)2] exhibits a relatively strong hypoglycemic effect in diabetic animals. Next, we examined its metallokinetics in the blood of rats that received five VO(3hp)2-related complexes by the blood circulation monitoring–electron paramagnetic resonance method. The metallokinetic parameters were obtained from the blood clearance curves based on a two-compartment model; most parameters, such as area under the concentration curve and mean residence time, correlated significantly with the in vitro insulinomimetic activity in terms of 1/IC50 (IC50 is the 50% inhibitory concentration of the complex required for the release of free fatty acids in adipocytes) and the lipophilicity of the complex (log P com). The oxovanadium(IV) concentration was significantly higher and the species resided longer in the blood of rats that received VO(alx)2 than in the blood of rats that received VO(3hp)2 or bis(kojato)oxovanadium(IV); VO(alx)2 also exhibited higher log P com and 1/IC50 values. On the basis of these results, we propose that the introduction of lipophilic groups at the C2 and C6 positions of the 3hp ligand is an effective method to enhance the hypoglycemic effect of the complexes, as supported by the observed in vivo exposure and residence in the blood. [ABSTRACT FROM AUTHOR]

As reactive oxygen species (ROS) are involved in the pathogenesis of various diseases, superoxide dismutase (SOD) and its mimetic complexes have been intensively studied. Recently, we found that Cu2(aspirinate)4 (Cu2(asp)4) has both in vitro and in vivo antioxidative activities. We investigated the suppressive effect of Cu2(asp)4 on ROS generation in the skin of hairless mice that were orally administered Cu2(asp)4 and followed by UVA exposure. The results were compared with those obtained from mice that were orally administered Cu(salicylate)2 (Cu(sal)2) or Cu(acetate)2, (Cu(ace)2) and followed by UVA exposure. After confirming that Cu2(asp)4 suppressed ROS generation in the skin, we measured both SOD activity and metallothionein (MT) and SOD protein levels in the whole proteins extracted from the skin of ICR mice that were orally administered Cu(II) compounds. The Cu2Zn2-SOD activity was enhanced by the administration of Cu(II) compounds; however, no alterations in the protein levels of MT and SOD were observed. Metallokinetics of the paramagnetic Cu(II) species in the circulating blood of rats, as estimated by electron spin resonance (ESR), revealed that among the Cu(II) compounds, the residence time of the Cu(II) species from Cu2(asp)4 was the longest. On the basis of these results, we conclude that Cu2(asp)4 is an orally potent antioxidative compound that suppresses ROS generation in the skin. The residence time of Cu(II) in the blood and the enhanced SOD activity in the skin following the oral administration of Cu2(asp)4 support this conclusion. Here, we propose that Cu2(asp)4 may be used to protect the skin against ROS generation. [ABSTRACT FROM AUTHOR]

Enantioselective electrophilic fluorination of β-keto �esters with Selectfluor� catalyzed by DNA and a nonchiral ligand-Cu(II) complex is presented. The chirality transfer from DNA to the substrate appears to be caused by the intercalation or groove binding of the substrate-ligand-Cu(II) complex to DNA. [ABSTRACT FROM AUTHOR]

Although the formation of reactive oxygen species (ROS) in the skin induced by the ultraviolet (UV) light has been shown to lead to many cutaneous disorders, skin cancer and photoageing, the mechanism and distribution of ROS generation has not yet been definitively determined. In the present study, we examined the distribution of UVA-induced ROS in the skin of live hairless mice, using our proposed in vivo imaging chemiluminescent (CL) method to detect ROS combined with a CL probe ( cypridina hilgendorfii luciferin analogue; CLA) and tape stripping (TS) technique. The CL intensities in the skin of live hairless mice were confirmed to significantly increase by UVA exposure. When TS was conducted five times in a maximum level after CL measurement following UVA exposure and subsequent CLA application, CL intensities due to UVA-induced ROS generation in the residual skin decreased to 10% of the original levels; and those in the stripped skin on each tape decreased in the stripped order such as 52%, 16%, 11%, 6% and 5%. Next, CLA was applied and then CL intensities were measured in the residual skin after advance 1, 3 and 5 tape strippings, and CL intensities due to ROS were detected primarily in the outer layer of the skin. On the basis of these results, we concluded that ROS induced by UVA exposure occurs and distributes in the outermost layer of the stratum corneum. [ABSTRACT FROM AUTHOR]

Abstract: The objective of this study is to image and detect reactive oxygen species (ROS) generated in the UVB-exposed three-dimensional human skin equivalent model (HSEM), EpiDerm™ 200, because the alternative system needs to be urgently established as a replacement for the skin of experimental animals. Evidence that the ROS generation is enhanced in the skin of live animals after the UVB exposure was already obtained, by using the real-time chemiluminescent (RT-CL) method consisting of a sensitive CL probe (CLA) and an ultra-low light imaging apparatus. In this study, CL emission due to the reaction of CLA with endogenously generated ROS increased significantly in the UVB-treated HSEM compared with that in the intact HSEM, the maximum level being observed at a dose of 27mJ/cm2. ROS under UVB exposure was identified to be and 1O2 as observed by suppressive effects of SOD and β-carotene topically applied on sample surface before the UVB exposure. The results for UVB-induced ROS generation in HSEM were consistent with those observed in the skin of live animals. HSEM combined with the RT-CL method was shown to be useful system not only to predict UVB-induced ROS-related skin responses in human but also to find protective agents against UVB-stimulated oxidative stress in place of animals and ex vivo human skin. [Copyright &y& Elsevier]

Abstract: CYP2E1 is known to be induced in streptozotocin (STZ)-treated diabetic rats (STZ rats), and its induction is improved by insulin. We have examined the age-dependent changes of CYP2E1 in the liver microsomes of type 1 diabetic STZ rats, the effects of VOSO4 on the contents of total P450 and CYP2E1, and the activities of CYP2E1 in terms of p-nitrophenol hydroxylation. The contents of P450 and CYP2E1 and CYP2E1 activity were enhanced with the development of diabetes. When the hyperglycemia of STZ rats was improved by daily intraperitoneal injections of VOSO4 for 10 days at the doses of 7 mg/kg body weight for 5 days, 5 mg/kg for the following 3 days, and then 2.5 mg/kg for 2 days, the P450 and CYP2E1 levels and CYP2E1 activity were lowered than those in the untreated STZ rats. To understand the mechanism underlying CYP2E1-dependent hydroxylation activity, the production of reactive oxygen species was examined in the NADPH-liver microsomal systems by ESR spin-trapping. Singlet oxygen (1O2) was detected in all microsomal systems, while superoxide anion radical( O2 −) and hydroxyl radical ( OH) were not. On the basis of these results, we conclude that (1) CYP2E1 level and activity are enhanced in the diabetic state, however, they are improved by VOSO4 treatment, and (2) 1O2 is generated during CYP2E1-dependent substrate oxygenation. [Copyright &y& Elsevier]

The total syntheses of (+)-mycoepoxydiene and (-)-1893A have been completed. The present synthetic strategy features the use of one-pot ring-opening/cross metathesis (ROM/CM) followed by a ring-closing metathesis (RCM) reaction, allowing for the concise construction of the 9-oxabicyclo[4.2.1]nona-2,4-diene framework from a 7-oxabicyclo[2.2.1]hept-2-ene derivative and 1,3-butadiene. The sequential metathesis product was converted into (+)-mycoepoxydiene through the oxidative rearrangement of a furfuryl alcohol to a pyranone, thereby establishing its absolute stereochemistry. From the common intermediate, a structurally related natural product (-)-1893A was also synthesized via the vinylogous aldol reaction. [ABSTRACT FROM AUTHOR]

Abstract: Recently, aluminum (Al) in drinking water has been proposed to be a risk factor for development of Alzheimer’s disease (AD). Because the physiological role of Al in humans is not yet known, we previously examined this role using an experimental animal model. Our results revealed a greater accumulation of Al in the brain, liver, kidney and spleen of mice who received long-term (90 days) administration of an Al complex, aluminum–maltolate (ALM), than in untreated controls. This observation prompted us to examine the degree of injury in the organs of mice in terms of lipid peroxidation evaluated by thiobarbituric acid reactive substances (TBARS) and NOx levels in order to determine the effects of Al accumulation. Six-week-old mice were given drinking water containing AlCl3 or ALM for 120 days. TBARS and NOx levels were found to change depending on the organs and chemical forms of Al. In particular, TBARS and NOx levels in the brain of mice given ALM for 30, 60 and 120 days were significantly increased compared with those of the control group. In addition, nervous degeneration was detected in the brain of the ALM-treated group. These results indicate that the chemical form of Al alters the distribution and oxidative stress in the brain. In addition, we propose a more precise method of determining Al levels in biological systems using neutron activation analysis. When the biological samples are irradiated with a neutron flux, both 27Al and 31P can be counted to 28Al by the reactions, 27Al(n,γ)28Al and 31P(n,α)28Al, respectively. The level of Al in the organs can then be determined by subtraction of the radioactivity due to 28Al originated in 31P from the total radioactivity of the samples. [Copyright &y& Elsevier]

Nitric oxide (NO) is well known to have a wide variety of biological and physiological functions in animals. On the basis of the fact that Fe(II)-dithiocarbamates react with NO, a Fe(II)- N -(dithiocarboxy)sarcosine complex (Fe(II)-DTCS) was proposed as a trapping agent for endogenous NO. However, quantitative pharmacokinetic investigation for NO-Fe(II)-dithiocarbamate complexes in experimental animals has been quite limited. This paper describes the results on the quantitative pharmacokinetic features of a NO-Fe(II)- N -DTCS in both the blood and bile of rats following intravenous (i.v.) administration of the complex. For this purpose, we applied two in vivo methods, i.e. (1) in vivo blood circulation monitoring-electron spin resonance (BCM-ESR) which previously developed, and (2) in vivo biliary excretion monitoring-electron spin resonance (BEM-ESR). We monitored real-time ESR signals due to nitrosyl-iron species in the circulating blood and bile flow. The ESR signal due to NO-Fe(II)-DTCS was stable in biological systems such as the fresh blood and bile. In in vivo BCM- and BEM-ESR, the pharmacokinetic parameters were calculated on the basis of the two-compartment and hepatobiliary transport models. The studies also revealed that the compound is widely distributed in the peripheral organs and partially excreted into the bile. We named a kinetic method to follow spin concentrations as spinnokinetics and this method will be useful for detecting and quantifying the endogenously generated NO in Fe(II)-DTCS administered animals. [ABSTRACT FROM AUTHOR]

In vivo ESR spectroscopy using a low frequency microwave of approximately 1 GHz has been developed to measure non-invasive ESR spectra in animals given paramagnetic compounds, in which a loop-gap-type resonator was used and ESR spectra were measured at the animal's head or abdomen. Therefore, the concentrations of paramagnetic species in both the blood and organs were compositely contributed to the spectra. When we understand the kinetics of paramagnetic species in detail, it is essentially important to know how these kinetics are expressed in each organ. For this purpose, a surface-coil-type resonator, which enabled local ESR measurement in specific organs, has been developed. By using this method, we studied the real-time pharmacokinetics of spin clearance curves detected in the organs of mice given 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (4-hydroxy-TEMPO) intravenously (i.v.), by monitoring the inferior vena cava, liver and kidney. Quantified clearance curves in the organs were analyzed on the basis of a two-compartment model, and pharmacokinetic parameters were estimated based on the curve-fitting. The obtained pharmacokinetic parameters were found to depend on the measurement site, and the distribution and elimination processes of the spin probe were successfully separated between the blood and organs of mice. [ABSTRACT FROM AUTHOR]

The insulinomimetic effect of vanadium is the most remarkable and important among its several biological actions. Vanadyl ion (+4 oxidation state of vanadium) and its complexes have been found to normalize the blood glucose levels of both type 1 and 2 diabetic animals. We have developed insulinomimetic vanadyl complexes having different coordination modes, emphasizing the possible usefulness of vanadyl-picolinate [VO(pa)2] and its related complexes with the VO(N2O2) coordination mode. In order to apply these complexes clinically in the future, the relationship between the chemical structure, insulinomimetic action, organ distribution of vanadium, and blood disposition of vanadyl species must be closely investigated. In the present investigation, we studied the blood disposition of the vanadyl-picolinate complexes in healthy rats, and tried to understand comprehensively the relationship between the structures, insulinomimetic activity, and metallokinetic parameters of the complexes, which had been recently prepared and specifically synthesized for the present study, by using an in vivo blood circulation monitoring – electron spin resonance (BCM-ESR) method for analyzing ESR signals due to paramagnetic metal ions and complexes in the blood in real time. Metallokinetic parameters were estimated based on the blood clearance curves in terms of a two-compartment pharmacokinetic model, and vanadyl species were indicated to be distributed in peripheral tissues and gradually eliminated from the circulating blood, depending on their chemical structures. Vanadyl concentrations in the blood of rats given bis(5-iodopicolinato)oxovanadium(IV) [VO(5ipa)2] and bis(3-methylpicolinato)oxovanadium(IV) [VO(3mpa)2] with electron-withdrawing and donating groups, respectively, remained significantly higher and longer, due to their slower clearance rates from the blood, than in rats given other complexes, suggesting that the high exposure and long residence of vanadyl species bring about the high normoglyceric effect in diabetic animals. We then examined the relationship between insulinomimetic activity and metallokinetic parameters in the family of VO(pa)2 for further development of insulinomimetic vanadyl complexes. IC50, the 50% inhibitory concentration of the complexes on the free fatty acid release from isolated rat adipocytes treated with epinephrine, was found to be sufficiently correlated with metallokinetic parameters such as area under the concentration curve, mean residence time, total clearance, and distribution volume at steady-state. Furthermore, the in vivo antidiabetic activity of the complexes was enhanced with increasing exposure and residence of vanadyl species in the blood of animals. On the basis of these results, we concluded that in vitro insulinomimetic activity, metallokinetic character, and in vivo antidiabetic action of vanadyl-picolinate complexes are closely related to their chemical structures. [Copyright &y& Elsevier]

The article presents a distinct screening strategy for protection against UV-induced skin damage with the combination of human skin equivalent model (HSEM) and 8-OHdG immunohistochemistry. It discuses the real-time chemiluminescent imaging to detect reactive oxygen species in HSEM after UVB exposure. It describes the method as an alternative to animal experiments and focuses on emerging concepts in fragile genomic sites for oxidative stress and UV-specific DNA base modifications.

Understanding the homeostatic interactions among essential trace metals is important for explaining their roles in cellular systems. Recent studies in vertebrates suggest that cellular Mn metabolism is related to Zn metabolism in multifarious cellular processes. However, the underlying mechanism remains unclear. In this study, we examined the changes in the expression of proteins involved in cellular Zn and/or Mn homeostatic control and measured the Mn as well as Zn contents and Zn enzyme activities to elucidate the effects of Mn and Zn homeostasis on each other. Mn treatment decreased the expression of the Zn homeostatic proteins metallothionein (MT) and ZNT1 and reduced Zn enzyme activities, which were attributed to the decreased Zn content. Moreover, loss of Mn efflux transport protein decreased MT and ZNT1 expression and Zn enzyme activity without changing extracellular Mn content. This reduction was not observed when supplementing with the same Cu concentrations and in cells lacking Cu efflux proteins. Furthermore, cellular Zn homeostasis was oppositely regulated in cells expressing Zn and Mn importer ZIP8, depending on whether Zn or Mn concentration was elevated in the extracellular milieu. Our results provide novel insights into the intricate interactions between Mn and Zn homeostasis in mammalian cells and facilitate our understanding of the physiopathology of Mn, which may lead to the development of treatment strategies for Mn‐related diseases in the future. [ABSTRACT FROM AUTHOR]

Purpose: We previously reported that T2 dark bands and placental bulges observed in magnetic resonance imaging (MRI) can predict adverse maternal outcomes in patients with placenta accreta spectrum (PAS) and placenta previa undergoing prophylactic balloon occlusion of the internal iliac artery. On the other hand, the risk factors associated with the use of prophylactic aortic balloon occlusion (PABO) have not been sufficiently investigated. This retrospective study aimed to identify MRI-based risk factors associated with adverse maternal outcomes in the context of PABO during a cesarean section (CS) for PAS and placenta previa. Materials and Methods: Ethical approval was obtained for a data analysis of 40 patients diagnosed with PAS and placenta previa undergoing PABO during a CS. Clinical records, MRI features, and procedural details were examined. The inclusion criteria for the massive bleeding group were as follows: an estimated blood loss (EBL) > 2500 mL, packed red blood cell (pRBC) transfusion (>4 units), and the need for a hysterectomy or transcatheter arterial embolization after delivery. The massive and nonmassive bleeding groups were compared. Results: Among the 22 patients, those in the massive bleeding group showed significantly longer operative durations, a higher EBL (p < 0.001), an increased number of pRBC transfusions (p < 0.001), and prolonged postoperative hospital stays (p < 0.05). T2 dark bands on MRI were significant predictors of adverse outcomes (p < 0.05). Conclusion: T2 dark bands on MRI were crucial predictors of adverse maternal outcomes in patients undergoing PABO for PAS or placenta previa during a CS. Recognizing these MRI features proactively indicates the need for effective management strategies during childbirth and emphasizes the importance of further prospective studies to validate and enhance these findings. [ABSTRACT FROM AUTHOR]

This methodology demonstrates the ability to sequentially regulate copper-mediated radioiododeboronation and an azide–alkyne cycloaddition reaction, which facilitates the continuous incorporation of reagents into the reaction system and mediates the integration of the purification steps into the final process. Additionally, this reaction is suited to be conducted under mild conditions and yields target compounds through potent radiochemical conversions. [ABSTRACT FROM AUTHOR]

Japan has many unexcavated tumuli, most of which were buried along with artifacts of precious cultural heritage. For such a tumulus, it is essential to understand how changes in its exterior environment affect its interior environment, and how those interior changes affect the deterioration of the relics buried in the stone chamber. In this study, an underground space was constructed in the forest of the Katsura Campus of Kyoto University to simulate the environment of an unexcavated tumulus, and long-term monitoring was implemented in the simulated stone chamber, including the temperature, humidity, water potential, wetness, and oxygen and carbon dioxide concentrations, along with metal corrosion tests. This article is focused on environmental monitoring, and the results demonstrate that the simulated tumulus has the general characteristics of the hygrothermal environments of an unexcavated tumulus that has small temperature fluctuation and near-saturation humidity. The ceiling of the simulated chamber condensed significantly from October to April, which is related to the variations of the ceiling and floor temperatures. Also, the wetness of the walls in the simulated chamber was affected by rainfall. The oxygen concentration in the simulated stone chamber varied in the range of 13%–19% in 2015, and the variation of carbon dioxide concentration in the simulated stone chamber was contrary to the oxygen concentration and varied in the range of 3%–9% in 2016. The oxygen concentration in the stone chamber was similar to that in the surrounding soil that decreased at times of rainfall, contrary to the fluctuations in the soil water content. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) is a serious problem worldwide and is becoming increasingly prevalent. Previously, we reported the use of various zinc (Zn) complexes as new anti-diabetic agents. In this study, we synthesized novel organo‑selenium (Se) Zn complexes with hydroxy-pyrone derivatives that have a Zn(Se 2 O 2 ) coordination mode. The results of in vitro insulin-mimetic analyses showed that the compound bis(3-hydroxy-2-methyl-4(H)-pyran-4-seleno)Zn ([Zn(hmps) 2 ]) exhibited the strongest activity among all the complexes. In the in vivo studies of Zn complexes with 3-hydroxy-2-methyl-4(H)-pyran-4-one, maltol, (hmpo) derivatives, [Zn(hmps) 2 ] exhibited a stronger anti-diabetic effect than bis(3-hydroxy-2-methyl-4(H)-pyran-4-one)Zn ([Zn(hmpo) 2 ]), which had a Zn(O 4 ) coordination mode. Additionally, we investigated the organ distribution of both Zn and Se by determining the amounts of these elements in the organs of [Zn(hmps) 2 ]-administered mice. We then evaluated the effect of treatment with Zn complexes on hepatic lipid accumulation and pancreatic islet hypertrophy by hematoxylin and eosin (HE) histological staining. Zn complexes were found to improve the hypertrophy in the pancreas. There were some reports that Se-containing Zn complexes such as di(2-selenopyridine- N -oxidato)Zn(II) ([ZPS]) were effective for treating diabetes mellitus, so in this study, we examined different types of zinc complexes with organo‑selenium ligands. [ABSTRACT FROM AUTHOR]

Reaction products of astaxanthin and its acetate with hydroxy radical, superoxide anion radical, and singlet oxygen were analyzed by LC/PDA ESI-MS and ESR spectrometry. Astaxanthin epoxides were found to be major reaction products of astaxanthin with superoxide anion radical and hydroxyl radical. On the other hand, astaxanthin endoperoxides were identified as major reaction products of astaxanthin with singlet oxygen. The same results were obtained in the case of astaxanthin acetate. The ESR study revealed that astaxanthin and its acetate take up superoxide anion radical by the formation of their epoxide through peroxide and oxide radicals. [ABSTRACT FROM AUTHOR]

Introduction: Only a few reports are available on the population pharmacokinetic (PK) analysis of linezolid and its main metabolites. Therefore, we investigated the population PK of linezolid and its metabolites in adult patients treated with intravenous linezolid to identify the causative factors affecting pharmacokinetics, and evaluated the relationship between the parent compound and major metabolites PNU‐142300 and PNU‐142586. Methods: Population PK analysis was performed using medical data collected from patients who were treated with intravenous linezolid (600 mg twice daily). We examined the impact of covariate candidates such as demographic characteristics and laboratory parameters. Simulations using the final model were investigated and used to estimate the plasma concentrations, trough concentrations (Cmin), and area under the curve (AUC) of linezolid and its metabolites, and the metabolite‐to‐parent ratios for Cmin and AUC were used to assess the accumulation of metabolites over linezolid. Results: A total of 82 plasma concentrations from 23 patients were analyzed. The volume of distribution was estimated to be 47.1 L, assuming that linezolid and its metabolites were the same. The total clearance (CL) of linezolid, and CLs of PNU‐142300 and PNU‐142586 were influenced by creatinine clearance (CLcr), with population mean CLs of 3.86, 7.27, and 13.54 L/h, respectively. The Cmin and AUCs of linezolid and its metabolites and the ratios of metabolites per linezolid were predicted to increase exponentially with decreasing renal function. Conclusion: We developed the first population PK model in which CLcr was incorporated as a covariate in the CL of linezolid and its metabolites. Using the final model, it was possible to predict the plasma concentration, Cmin, and AUC appropriately. The model was found to be a potentially useful tool for future studies on optimal dosing and toxicity analysis. [ABSTRACT FROM AUTHOR]

The zinc homeostatic proteins Zn transporter 1 (ZNT1) and metallothionein (MT) function in dampening increases in cytosolic zinc concentrations. Conversely, the expression of ZNT1 and MT is expected to be suppressed during decreases in cytosolic zinc concentrations. Thus, ZNT1/MT homeostatic responses are considered to be essential for maintaining cellular zinc homeostasis because cellular zinc concentrations are readily altered by changes in the expression of several Zrt-/Irt-like proteins (ZIPs) under both physiological and pathological conditions. However, this notion remains to be tested experimentally. Here, we investigated the aforementioned homeostatic process by analyzing ZNT1 and MT protein expression in response to ZIP expression. Overexpression of cell-surface-localized ZIPs, such as ZIP4 and ZIP5, increased the cellular zinc content, which caused an increase in the expression of cell-surface ZNT1 and cytosolic MT in the absence of zinc supplementation in the culture medium. By contrast, elimination of the overexpressed ZIP4 and ZIP5 resulted in decreased expression of ZNT1 but not MT, which suggests that differential regulation of ZNT1 and MT expression at the protein level underlies the homeostatic responses necessary for zinc metabolism under certain conditions. Moreover, increased expression of apically localized ZIP4 facilitated basolateral ZNT1 expression in polarized cells, which indicates that such a coordinated expression mechanism is crucial for vectorial transcellular transport. Our results provide novel insights into the physiological maintenance of cellular zinc homeostasis in response to alterations in cytosolic zinc concentrations caused by changes in the expression of ZIPs. [ABSTRACT FROM AUTHOR]

Abstract: Human myoglobin (hMb) possesses a cysteine (Cys) residue which is rare among mammalian Mbs. To investigate the effects of this unique Cys residue at the amino acid position 110 (Cys110) on hMb reactions, we studied the reactions of wild type (WT) methMb and its alanine mutant at Cys110 (C110A) with H2O2, particularly in the presence of reduced glutathione (GSH) which is well known as a reducing agent. The formation rates of the ferryloxo (Fe(IV)=O) species by H2O2 under air were about the same for WT and C110A methMbs, whereas the protein decomposed more in the case of WT than C110A hMb. With the addition of GSH, hMb consumed H2O2 faster and decomposition of the protein decreased, where the effects were more prominent in WT than C110A hMb. The radicals produced by the reaction with H2O2 decreased significantly due to the addition of 1mM GSH in the case of WT hMb, but not in the case of C110A hMb. These results show that GSH reduces H2O2-induced protein decomposition due to reduction of the C110-thiyl radical in WT hMb by electron transfer. [Copyright &y& Elsevier]

Abstract: Amoebiasis, caused by infection with the enteric protist Entamoeba histolytica, is one of the major parasitic diseases. Although metronidazole and its derivatives are currently employed in therapy, the paucity of effective drugs and potential clinical resistance necessitate the development of a novel drug. Trifluoromethionine (TFM) is a promising lead compound for antiamoebic drugs. To potentiate the antiamoebic effect of TFM, we synthesised various amide derivatives of TFM and evaluated their cytotoxicity. The amide derivatives of TFM were observed to have a superior cytotoxic effect compared with TFM and metronidazole against E. histolytica in vitro. Although TFM showed cytotoxicity following degradation by methionine γ-lyase, the derivatives were degraded by the enzyme less efficiently compared with TFM. We further demonstrated that a representative derivative was hydrolysed by the amoebic cell lysate to first yield TFM, followed by degradation similar to TFM. Hydrolysis was partially inhibited by protease inhibitors. A single subcutaneous or oral administration of TFM and its amide derivatives also effectively prevented the formation of amoebic liver abscess in a rodent model. These data demonstrate the improved effectiveness of TFM derivatives against E. histolytica infection and elucidate the mechanisms underlining the mode of action of these compounds. [Copyright &y& Elsevier]

Abstract: Macromolecular nitric oxide (NO) donors possessing the ability to target a specific type of liver cells were developed for delivering NO to the liver. Six NO molecules were covalently bound to mannosylated (Man) or galactosylated (Gal) bovine serum albumin (BSA) through an S-nitrosothiol linkage to obtain Man-poly SNO-BSA and Gal-poly SNO-BSA, respectively. The carrier parts of Man-poly SNO-BSA and Gal-poly SNO-BSA predominantly accumulated in the liver after intravenous injection in mice. In an ischemia/reperfusion injury mouse model, in which hepatic injury was induced by occluding the portal vein for 15 min followed by a 6 h reperfusion, the elevation of plasma alanine aminotransferase and aspartate aminotransferase levels was significantly inhibited by a bolus intravenous injection of Man-poly SNO-BSA or Gal-poly SNO-BSA, just before the start of reperfusion. In marked contrast, S-nitroso-N-acetyl penicillamine and NO-conjugated BSA, two classical S-nitrosothiols, had no statistically significant effects on the serum levels of the markers. The released NO in mouse liver was detected by electron spin resonance spectrometry only in the liver of mice receiving Man-poly SNO-BSA or Gal-poly-SNO-BSA. These findings indicate that Man-poly SNO-BSA and Gal-poly SNO-BSA are promising compounds for preventing hepatic ischemia/reperfusion injury by delivering pharmacologically active NO to the liver. [Copyright &y& Elsevier]

A copper‐mediated radioiodination using aryl boronic precursors is attracting attention as a solution to oxidative iododestannylation and nickel‐mediated radioiodination drawbacks. The copper‐mediated radiolabeling method allows radioiodination at room temperature with stable aryl boronic precursors without preparing complex starting materials or reagents and can be performed in a reaction vessel exposed to air. This method has good potential in radiochemistry; however, studies on the scope of copper‐mediated radioiodination through boronic precursors are insufficient. In particular, few reports have demonstrated the effect of protecting groups on radiolabeling efficiency. Therefore, the effect of the protecting group of aryl boronic acids on the copper‐mediated radioiodination was investigated. In addition, this method, which does not require heating, is expected to be useful for direct radiolabeling of peptides. Thus, we attempted direct radioiodination of c(RGDyk) as an example. The resulting radioiodination method was well tolerated in various substrates and was unaffected by the pinacol ester‐type protecting group. Also, c(RGDyk) was labeled with 125I via copper‐mediated radioiodination using an aryl boronic acid precursor. The reaction time and yield were improved, compared with the indirect method. Furthermore, the large difference in polarity between the boronic acid precursor and the radiolabeled compound facilitated purification. [ABSTRACT FROM AUTHOR]

[Display omitted] We previously reported that our sugar-conjugated platinum complex (cis -dichloro [(2-fluoro-α- d -glucopylanosidyl) propane-1,3-diamine] platinum: FGC-Pt) has low toxicity and tumor growth inhibitory effect comparable to that of cisplatin. We focused on radioactive Pt isotopes in order to analyze the kinetics of FGC-Pt using gamma-ray imaging techniques, assuming that FGC-Pt could be used for chemotherapy in the future. Therefore, in this study, we aimed to develop a non-invasive method to analyze the biodistribution of FGC-Pt using 191Pt-labeled FGC-Pt ([191Pt]FGC-Pt). 191Pt was produced via the (n,2n) reaction induced by accelerator neutrons. [191Pt]FGC-Pt was prepared using two different methods. In the first method, [191Pt]FGC-Pt (method A) was obtained through the accelerator neutron irradiation of FGC-Pt. In the second method, [191Pt]FGC-Pt (method B) was synthesized using [191Pt]K 2 PtCl 4 , which was obtained by the accelerator neutron irradiation of K 2 PtCl 4. Highly purified [191Pt]FGC-Pt was obtained using the latter method, which suggests that the synthetic method using a 191Pt-labeled platinum reagent is suitable for the radioactivation of platinum complexes. We also aimed to investigate whether a significant correlation existed between the biodistribution of FGC-Pt and [191Pt]FGC-Pt in healthy mice 24 h after tail vein administration. FGC-Pt and [191Pt]FGC-Pt were similarly distributed in healthy mice, with a higher accumulation in the liver and kidney 24 h post injection. In addition, a significant correlation (p < 0.05, r = 0.92) between the 191Pt radioactivity concentration (%ID/g (gamma counter)) and platinum concentration (%ID/g (ICP-MS)) was observed in 13 organs. These results suggest that 191Pt-labeled compounds, synthesized using radioactive platinum reagents, can be used to confirm the biodistribution of platinum compounds. Our study on the biodistribution of [191Pt]FGC-Pt is expected to contribute to the development of novel platinum-based drugs in the future. [ABSTRACT FROM AUTHOR]

The binding of zinc(II) ions onto γ-pga was studied in aqueous solution as a function of contact time, solution pH, initial concentration of metal ion, and solution temperature, respectively. IR and 13C NMR spectra of γ-pga and Zn(γ-pga) complex revealed binding of zinc(II) with carboxylate and amide groups on γ-pga. The strong interaction between zinc(II) ions and γ-pga occurred at pH 5. The binding kinetic data followed a pseudo-second-order kinetic model. The equilibrium binding data were fitted well by Langmuir isotherm model. The maximum amount of zinc(II) ions bound to γ-pga was estimated to be 13.97 mmol/g at 30 °C and 20.58 mmol/g at 45 °C. The values of activation energy (Ea 18.23 kJ/mol), changes in free energy (∆G°), enthalpy (∆H°), and entropy (∆S°) indicate that the formation of Zn(γ-pga) complex is an endothermic spontaneous physisorption process. The antimicrobial activity of Zn(γ-pga) complex was examined against a gram-negative bacteria (i.e., Escherichia coli) and a gram-positive bacteria (i.e., Bacillus subtilis). The IC50 values of Zn(γ-pga) complex were estimated to be (0.76 ± 0.03) mmol/L for E. coli and (0.94 ± 0.02) mmol/L for B. subtilis, respectively. Therefore, Zn(γ-pga) complex can be used as an antimicrobial agent against gram-positive and gram-negative microorganisms. [ABSTRACT FROM AUTHOR]

Abstract: We found alpha-glucosidase inhibitory (α-GI) effect of metal ions and their complexes which showed the high blood glucose lowering effect in diabetic model animals. The Cu(II) ion and its complexes showed strong α-GI activity greater than clinically used acarbose in in vitro studies. Furthermore, in in vivo experiments, α-GI action was newly discovered in normal ddy mice. These results suggested that one of action mechanisms of the anti-diabetic metal ions and complexes is related to the α-GI effects. [Copyright &y& Elsevier]

Copper(II) ion-bound CysGly dipeptides linked by an azobenzene derivative were photoisomerized between the trans and cis forms. The two copper(II) ion centers were positioned close to each other in the cis form, whereas they were far away from each other in the trans form. The copper complex in the cis form exhibited DNA cleavage activity, whereas the activity in the trans form was negligible. The DNA cleavage activity of the cis form is attributed to the cooperation of the closely located copper(II) centers. The present results show the photocontrol of the cooperation of metal ions for DNA cleavage. [ABSTRACT FROM AUTHOR]

We observed a novel type of airflow produced by an atmospheric rf discharge between asymmetric parallel rod electrodes. The electrodes were a bare metal rod 1 mm in diameter and a glass-coated metal rod 3.2 mm in diameter. The thrust, measured by a pendulum, increased with discharge input power. [ABSTRACT FROM AUTHOR]

Zn(II) complexes with 2-ethyl-3-hydroxy-4H-pyran-4-thione, [Zn(ehpt)2], and 2-ethyl-3-hydroxy-4H-pyran-4-selenone, [Zn(ehps)2], were synthesized and characterized by single crystal X-ray diffraction. Complexes are isostructural, crystallize in sp. gr. P21/n with Z = 4. The Zn2+ ion has a distorted tetrahedral coordination with two S or Se atoms and two O atoms from ehpt or ehps, respectively. In vitro, insulin-mimetic activities of [Zn(ehpt)2] and [Zn(ehps)2] are much higher than that of Zn complex with maltol, 3-hydroxy-2-methyl-4H-pyran-4-one, [Zn(hmpo)2]}, where Zn coordination is completed by H2O molecules. It suggests that Zn complexes with distorted tetrahedral coordination might exhibit higher insulin-mimetic activities than those with octahedral or square pyramidal coordination. [ABSTRACT FROM AUTHOR]

• New 5-oxo-2-thioxopyrrolidines were synthesized through a novel reaction. • Zinc(II) complexes with the new ligands showed marked antidiabetic activity. • Lipophilicity of complexes is important to control the antidiabetic activities. We have developed a synthetic route to novel ethyl 1-arylmethyl-5-oxo-2-thioxopyrrolidine-3-carboxylates (1a – e) via an unprecedented reaction of ethyl 1-arylmethyl-4-acetoxy-5-oxo-2,5-dihydro-1 H -pyrrole-3carboxylates with potassium thioacetate. Synthesized products 1a – e were further converted into their zinc(II) complexes (10a – e), having an S 2 O 2 -type coordination mode, that showed improved insulin-mimetic activities compared to ZnSO 4 , a positive standard, and also the previously reported zinc(II) complexes of ethyl 1-benzyl-4-hydroxy-5-oxo-2,5-dihydro-1 H -pyrrole-3-carboxylates with O 4 -type coordination mode. [ABSTRACT FROM AUTHOR]

Elevated oxidative stress (OS) is widely accepted to be involved in the pathogenesis of Down syndrome (DS). However, the mechanisms underlying the elevation of OS in DS are poorly understood. Biometals, in particular copper and iron, play roles in OS. We therefore focused on biometals in the brain with DS. In this study, we analyzed the profile of elements, including biometals, in the brain of Ts1Cje mice, a widely used genetic model of DS. An inductively coupled plasma-mass spectrometry (ICP-MS)-based comparative metallomic/elementomic analysis of Ts1Cje mouse brain revealed a higher level of copper in the hippocampus and cerebral cortex, but not in the striatum, in comparison to wild-type littermates. The expression of the copper transporter CTR1, which is involved in the transport of copper into cells, was decreased in the ependymal cells of Ts1Cje mice, suggesting a decrease in the CTR1-mediated transport of copper into the ependymal cells, which excrete copper into the cerebrospinal fluid. To evaluate the pathological significance of the accumulation of copper in the brain of Ts1Cje mice, we examined the effects of a diet with a low copper content (LoCD) on the elevated lipid peroxidation, the accumulation of hyperphosphorylated tau, and some behavioral anomalies. Reducing the copper concentration in the brain by an LoCD restored the enhanced lipid peroxidation and phosphorylation of tau in the brain and reduced anxiety-like behavior, but not hyperactivity or impaired spatial leaning, in Ts1Cje mice. The findings highlight the reduction of accumulation of copper in the brain may be a novel therapeutic strategy for DS. fx1 • Copper accumulates in the brain of Ts1Cje mice, a Down syndrome model. • The expression of CTR1 decreases in the ependymal cells of Ts1Cje mice. • Reducing the copper accumulation restored the lipid peroxidation in the Ts1Cje brain. • The copper accumulation deposited hyperphosphorylated tau in the Ts1Cje brain. • Reducing the copper accumulation reduced less anxious behavior of Ts1Cje mice. [ABSTRACT FROM AUTHOR]

Abstract Carotenoids are phytochemicals with strong antioxidant activity against reactive oxygen species that are widely distributed in fruits and vegetables. The beneficial effects of carotenoids on human health have attracted considerable attention. The plasma carotenoid profile in humans is generally recognized to reflect the dietary carotenoid composition. Although carotenoid profile in plasma is believed to correlate well with that in other tissues, the data for tissue accumulation of carotenoids in humans is very limited and poorly understood. In order to test the hypothesis that blood carotenoids reflect tissue accumulation of dietary carotenoids, the cynomolgus monkey was used as a model to determine it's suitable for extrapolation of data on tissue accumulation of carotenoids to humans. Herein, plasma carotenoids were measured in cynomolgus monkeys given a dietary mixture of carotenoids. The findings indicate that cynomolgus monkeys and humans are similar with regard to preferential accumulation of β-cryptoxanthin in the blood and brain. These results suggested that cynomolgus monkeys could be used to collect data on tissue accumulation of carotenoids for extrapolation to humans. The tissue accumulation of carotenoids in other tissues of cynomolgus monkeys that have not yet been evaluated in humans were also investigated, revealing marked differences in carotenoid levels and composition among plasma and various monkey tissues. These results suggest that accumulation of carotenoids in plasma does not reflect necessarily that in tissues, so that predicting the tissue accumulation of carotenoids from plasma carotenoid levels and profiles alone could lead to errors. [ABSTRACT FROM AUTHOR]

Exposure to asbestos fiber is central to mesothelial carcinogenesis, for which iron overload in or near mesothelial cells is a key pathogenic mechanism. Alternatively, iron chelation therapy with deferasirox or regular phlebotomy was significantly preventive against crocidolite-induced mesothelial carcinogenesis in rats. However, the role of iron transporters during asbestos-induced carcinogenesis remains elusive. Here, we studied the role of divalent metal transporter 1 (DMT1; Slc11a2), which is a Fe(II) transporter, that is present not only on the apical plasma membrane of duodenal cells but also on the lysosomal membrane of every cell, in crocidolite-induced mesothelial carcinogenesis using DMT1 transgenic (DMT1Tg) mice. DMT1Tg mice show mucosal block of iron absorption without cancer susceptibility under normal diet. We unexpectedly found that superoxide production was significantly decreased upon stimulation with crocidolite both in neutrophils and macrophages of DMT1Tg mice, and the macrophage surface revealed higher iron content 1 h after contact with crocidolite. Intraperitoneal injection of 3 mg crocidolite ultimately induced malignant mesothelioma in ∼50% of both wild-type and DMT1Tg mice (23/47 and 14/28, respectively); this effect was marginally (p = 0.069) delayed in DMT1Tg mice, promoting survival. The promotional effect of nitrilotriacetic acid was limited, and the liver showed significantly higher iron content both in DMT1Tg mice and after crocidolite exposure. The results indicate that global DMT1 overexpression causes decreased superoxide generation upon stimulation in inflammatory cells, which presumably delayed the promotional stage of crocidolite-induced mesothelial carcinogenesis. DMT1Tg mice with low-stamina inflammatory cells may be helpful to evaluate the involvement of inflammation in various pathologies. [ABSTRACT FROM AUTHOR]

Vanadium(v) compounds with 3,5-difluoropicolinic acid (HpicFF) and 3-hydroxypicolinic acid (H2hypic) and zinc(ii) compounds with HpicFF, H2hypic and 4-methylhydroxypicolinic acid (HpicCH2OH) in the presence or absence of pyridine (py), 4-(dimethylamino)pyridine (DMAP), and 1,10-phenanthroline (phen) have been synthesized and characterized. The crystal structures of NH4[VO2(picFF)2]·1.6H2O (3·1.6H2O), NH4[VO2(hypic)2]·H2O (4·H2O), [Zn(picFF)2(H2O)2] (5), [Zn(picFF)2(py)2]·py (6·py), [Zn(picFF)2(DMAP)2]·UGRAPHIC DISPLAY="INLINE" ID="UGT1" SRC="UGT1"/H2O (7·UGRAPHIC DISPLAY="INLINE" ID="UGT2" SRC="UGT2"/H2O), [Zn(picFF)2(phen)]·2CHCl3 (8·2CHCl3), [Zn(Hhypic)2(MeOH)2] (10), [Zn(Hhypic)2(DMAP)(H2O)] (11) and [Zn(Hhypic)2(phen)] (12) were determined by X-ray crystallography. The spatial arrangement of the vanadium(v) complex 3 possesses carboxylate oxygen atoms in a mutual trans orientation while crystal structure 4 represents the first crystallographic evidence for the formation of an isomer with two picolinato nitrogen atoms in a mutual trans position. Two different spatial arrangements were found in the zinc(ii) complexes with trans (5, 10 and 11) and cis (6, 7, 8 and 12) octahedral geometry. Insulin-mimetic activity of the selected VIVO, VVO2 and ZnII complexes was studied by in vitro inhibition of the free fatty acid (FFA) release from isolated rat adipocytes treated with epinephrine. All the studied metal complexes showed insulin-mimetic activity. Vanadium complexes 1–4 exhibit activities similar to VOSO4 with the Hhypic complexes being more active than the picFF ones. The zinc complexes also exhibited some insulin-mimetic activity, with the Hhypic complex (9) being more active than the other two, however, the insulin-mimetic activity of these complexes did not show more potent activity than ZnSO4. [ABSTRACT FROM AUTHOR]

The newly designed 1-(arylmethyl)-2,5-dihydro-4-hydroxy-5-oxo-1H-pyrrole-3-carboxamides (1a–e) were synthesized by using N-tritylated acrylamide as a starting material, and their zinc(ii) complexes (10a–e) were readily prepared by simply mixing 1a–e and ZnSO4 in the presence of LiOH. The aldose reductase (AR) inhibitory activity of 1a–e was evaluated to reveal important structural features for 2,5-dihydro-5-oxo-1H-pyrrole derivatives to exhibit high AR inhibitory activity. The in vitro insulin–mimetic activity of these complexes was evaluated from 50% inhibitory concentrations (IC50) on free fatty acid (FFA) release from isolated rat adipocytes treated with epinephrine. Four out of the five newly synthesized complexes exhibited higher in vitro insulin-mimetic activities than ZnSO4, a positive control. This study proved that the newly synthesized N2O2-coordination-type zinc(ii) complexes based on pyrrole-3-carboxamide derivatives (1a–d) are potential hypoglycemic agents. [ABSTRACT FROM AUTHOR]

Vanadium(v) compounds with 5-cyanopicolinato acid (HpicCN), pyrazine-2-carboxylic acid (Hprz) and 3-aminopyrazine-2-carboxylic acid (HprzNH2) and zinc compounds with HpicCN in the presence of 4-aminopyridine (4apy), pyridine (py) and 1,10-phenanthroline (phen) have been synthesized and characterized. The crystal structures of NH4[VO2(picCN)2] (3), NH4[VO2(prz)2] (4), NH4[VO2(przNH2)2]·H2O (5·H2O), [Zn(picCN)2(H2O)2] (6), [Zn(picCN)2(4apy)2]·C7H8 (7·C7H8), [Zn(picCN)2(4apy)] (8), [Zn(picCN)2(py)2] (9) and [Zn(picCN)2(phen)]·C7H8·2MeOH (10·C7H8·2MeOH) were determined by X-ray crystallography. The spatial arrangements of all the vanadium(v) complexes are similar, having carboxylate oxygen atoms in a mutual trans orientation. In the zinc bis(5-cyanopicolinato) complexes three different arrangements were found with trans (6) and a cis (7, 9 and 10) octahedral and square-pyramidal (8) geometries. The insulino-mimetic activity of selected VO(iv), VO2(v) and Zn(ii) complexes was studied by in vitro inhibition of the free fatty acid (FFA) release from isolated rat adipocytes treated with epinephrine. All metal complexes showed insulino-mimetic activity and among them the VO(iv)–prz complex 2 was found to have higher insulino-mimetic activity than the positive control. The other vanadium compounds have activities similar to VOSO4. The Zn complexes also exhibited some insulino-mimetic activity. Introduction of the N-donor 4apy to the zinc picCN complex 8 significantly increased inhibition of FFA release compared to 6. [ABSTRACT FROM AUTHOR]

Iron is an essential nutrient for every type of life on earth. However, excess iron is cytotoxic and can lead to an increased cancer risk in humans. Catalytic ferrous iron [Fe(II)] is an initiator of the Fenton reaction, which causes oxidative stress by generating hydroxyl radicals. Recently, it became possible to localize catalytic Fe(II) in situ with a turn-on fluorescent probe, RhoNox-1. Here, we screened each organ/cell of rats to globally evaluate the distribution of catalytic Fe(II) and found that eosinophils showed the highest abundance. In various cells, lysosomes were the major organelle, sharing ∼40–80% of RhoNox-1 fluorescence. We then used an ovalbumin-induced allergic peritonitis model to study the dynamics of catalytic Fe(II). Peritoneal lavage revealed that the total iron contents per cell were significantly decreased, whereas an increase in the number of inflammatory cells (macrophages, neutrophils, eosinophils and lymphocytes) resulted in an increased total iron content of the peritoneal inflammatory cells. Notably, macrophages, eosinophils and neutrophils exhibited significantly increased catalytic Fe(II) with increased DMT1 expression and decreased ferritin expression, though catalytic Fe(II) was significantly decreased in the peritoneal lavage fluid. In conclusion, catalytic Fe(II) in situ more directly reflects cellular activity and the accompanying pathology than total iron does. [ABSTRACT FROM AUTHOR]