Construction of Fe-doped ZIF-8/DOX nanocomposites for ferroptosis strategy in the treatment of breast cancer.

Breast cancer has become one of the top five commonest causes of cancer death. The use of ferroptosis to induce the generation of reactive oxygen species (ROS) in cancer cells presents a promising and potential strategy for cancer treatment. Herein, a series of facile bimetallic nanoparticles (x% Fe-doped ZIF-8) were synthesized and tested, and doxorubicin (DOX), a classic drug for breast cancer therapy, was encapsulated. After comparing the ratios of Fe2+/(Fe2+ + Zn2+), 7% Fe-doped ZIF-8 (7FZ) was found to be the most suitable particle for medical application. The drug loading efficiency of DOX@7FZ was 58.01 ± 0.02%. The pH-sensitive DOX@7FZ was degraded and DOX was released in lysosomes once internalized. Both the intracellular content of iron and ROS increased significantly. Meanwhile, the cell viability declined to 13.98% in 24 h at a concentration of 60 µg mL-1 and the IC50 was 42.68 µg mL-1. Moreover, the expression of Bcl-2 and GPX-4 proteins decreased in a time-dependent manner, indicating that DOX@7FZ was able to enhance the ROS level in cancer cells via a synergistic effect between apoptosis and ferroptosis. The mechanism of action of DOX@7FZ was further verified using hematoxylin and eosin staining and immunohistochemical staining of Bcl-2 and GPX-4. These remarkable characteristics of DOX@7FZ may inspire further advancements in the treatment of breast cancer.

Ligand Modulation on the Various Structures of Three Zinc(II)-Based Coordination Polymers for Antibiotics Degradation.

The efficient removal of organic contaminants from wastewater is, nowadays, a prominent area of study due to its biological as well as environmental significance. Antibiotics are now found in wastewater because of their high use, which has become a source of aquatic pollution. These antibiotics have dangerous implications for people's health. Hence, effective pharmaceutical removal from wastewater and contaminated water bodies, especially the removal of antibiotics, is of major interest to global research organizations. This is why it is necessary to investigate this class of toxic material in wastewater discharge. We synthesized three different coordination polymers (CPs) in the presence of various assistant carboxylate linkers, namely, [Zn(Hbtc)(dip)]n (1), [Zn4(1,2-bdc)4(dip)4]n (2), and [Zn(1,4-bdc)(dip)]n (3) (3,5-di(1H-imidazol-1-yl)pyridine = dip, 1,3,5-benzenetricarboxylic acid = H3btc, 1,2-benzenedicarboxylic acid = 1,2-H2bdc, and 1,4-benzendicarboxylic acid = 1,4-bdc). These CPs were characterized by using different techniques, including single-crystal X-ray diffraction. The structural studies demonstrated that in 2, there are four Zn(II) centers and both centers are in different coordination environments (Zn2 has distorted tetrahedral geometry, whereas Zn1, Zn3, and Zn4 have square pyramidal geometry). Hirshfeld surfaces analysis revealed that different types of intermolecular interactions (C⋯C, H⋯C, H⋯H, O⋯C, N⋯H, and O⋯H) are present in the synthesized CPs. We examined the different antibiotics, such as metronidazole (MDZ), nitrofurazone (NFZ), dimetridazole (DTZ), sulfasalazine(SLA), and oxytetracycline (OXY), degradation behaviors of the synthesized CPs, which showed remarkable degradation efficiency. 1 showed photocatalytic behavior toward the NFZ antibiotic in an aqueous media. This study also showed that these catalysts are stable and reusable under mild conditions.

Mixed-Valent Trinuclear CoIII-CoII-CoIII Complex with 1,3-Bis(5-chlorosalicylideneamino)-2-propanol.

A mixed-valent trinuclear complex with 1,3-bis(5-chlorosalicylideneamino)-2-propanol (H3clsalpr) was synthesized, and the crystal structure was determined by the single-crystal X-ray diffraction method at 90 K. The molecule is a trinuclear CoIII-CoII-CoIII complex with octahedral geometries, having a tetradentate chelate of the Schiff-base ligand, bridging acetate, monodentate acetate coordination to each terminal Co3+ ion and four bridging phenoxido-oxygen of two Schiff-base ligands, and two bridging acetate-oxygen atoms for the central Co2+ ion. The electronic spectral feature is consistent with the mixed valent CoIII-CoII-CoIII. Variable-temperature magnetic susceptibility data could be analyzed by consideration of the axial distortion of the central Co2+ ion with the parameters Δ = -254 cm-1, λ = -58 cm-1, κ = 0.93, tip = 0.00436 cm3 mol-1, θ = -0.469 K, gz = 6.90, and gx = 2.64, in accordance with a large anisotropy. The cyclic voltammogram showed an irreversible reduction wave at approximately -1.2 V·vs. Fc/Fc+, assignable to the reduction of the terminal Co3+ ions.

A multimodal Metal-Organic framework based on unsaturated metal site for enhancing antitumor cytotoxicity through Chemo-Photodynamic therapy.

Chemodynamic therapy when combined with chemotherapy opens up a new avenue for treatment of cancer. However, its development is still restricted by low targeting, high dose and toxic side effects. Herein, rational designing and construction of a new multifunctional platform with the core-shell structure 5-ALA@UiO-66-NH-FAM@CP1 (ALA = 5-aminolevulinic acid, CP1 = zirconium-pemetrexed (Zr-MTA)) has been performed. In this platform, CP1 acting as a shell is encapsulated with the UiO-66-NH2 to engender a core-shell structure that promotes and achieves a high MTA loading rate through high affinity between MTA and unsaturated Zr site of UiO-66-NH2. The 5-ALA and 5-carboxyl fluorescein (5-FAM) was successfully loaded and covalently combined with UiO-66-NH2 due to its high porosity and presence of amino groups. The characterization results indicated that the loading rate of MTA (41.03 wt%) of platform is higher than the reported values. More importantly, the in vitro and in vivo results also demonstrated that it has a good folate targeting ability and realizes high efficient antitumor activity by chemotherapy combied with photodynamic therapy (PDT). This newly developed multifunctional platform could provide a new idea for designing and constructing the carrier with chemotherapy and PDT therapy.

Structures of Dimer-of-Dimers Type Defect Cubane Tetranuclear Copper(II) Complexes with Novel Dinucleating Ligands.

Only a limited number of multinucleating ligands can stably maintain multinuclear metal structures in aqueous solutions. In this study, a water-soluble dinucleating ligand, 2,6-bis{[N-(carboxylatomethyl)-N-methyl-amino]methyl}-4-methylphenolate ((sym-cmp)3-), was prepared and its copper(II) complexes were structurally characterized. Using the single-crystal X-ray diffraction method, their dimer-of-dimers type defect cubane tetranuclear copper(II) structures were characterized for [Cu4(sym-cmp)2Cl2(H2O)2] and [Cu4(sym-cmp)2(CH3O)2(CH3OH)2]. In the complexes, each copper(II) ion has a five-coordinate square-pyramidal coordination geometry. The coordination bond character was confirmed by the density functional theory (DFT) calculation on the basis of the crystal structure, whereby we found the bonding and anti-bonding molecular orbitals. From the cryomagnetic measurement and the magnetic analysis, overall antiferromagnetic interaction was observed, and this magnetic behavior is also explained by the DFT result. Judging from the molar conductance and the electronic spectra, the bridging chlorido ligand dissociates in water, but the dinuclear copper(II) structure was found to be maintained in an aqueous solution. In conclusion, the tetranuclear copper(II) structures were crystallographically characterized, and the dinuclear copper(II) structures were found to be stabilized even in an aqueous solution.

Prediction of Blood-Brain Barrier Penetration (BBBP) Based on Molecular Descriptors of the Free-Form and In-Blood-Form Datasets.

The blood-brain barrier (BBB) controls the entry of chemicals from the blood to the brain. Since brain drugs need to penetrate the BBB, rapid and reliable prediction of BBB penetration (BBBP) is helpful for drug development. In this study, free-form and in-blood-form datasets were prepared by modifying the original BBBP dataset, and the effects of the data modification were investigated. For each dataset, molecular descriptors were generated and used for BBBP prediction by machine learning (ML). For ML, the dataset was split into training, validation, and test data by the scaffold split algorithm MoleculeNet used. This creates an unbalanced split and makes the prediction difficult; however, we decided to use that algorithm to evaluate the predictive performance for unknown compounds dissimilar to existing ones. The highest prediction score was obtained by the random forest model using 212 descriptors from the free-form dataset, and this score was higher than the existing best score using the same split algorithm without using any external database. Furthermore, using a deep neural network, a comparable result was obtained with only 11 descriptors from the free-form dataset, and the resulting descriptors suggested the importance of recognizing the glucose-like characteristics in BBBP prediction.

A new magnetic adsorbent of eggshell-zeolitic imidazolate framework for highly efficient removal of norfloxacin.

Many effluents contain various antibiotics commonly, where the simultaneous removal of them is a big challenge. In this study, the magnetic biocomposite (eggshell-zeolitic imidazolate framework) was designed and synthesized by green and facile method. Zeolitic imidazolate framework-8 (ZIF-8) particles were stabilized on the surface of magnetic eggshell (Fe3O4-ES), generating a new Fe3O4-ES/ZIF-8 adsorbent, which was also fully characterized using FTIR, XRD, SEM and BET techniques. Thereafter, norfloxacin (NOR) adsorption processes were investigated through different influencing factors (dosage, concentration, pH and temperature). The Langmuir adsorption isotherm could confirm a maximum removal efficiency of 80.13% for NOR. Kinetic studies illustrated that the pseudo-first-order model was in line with the experimental data of the simultaneous removal of NOR. Moreover, the magnetic nature of the adsorbent caused an easy separation from the aqueous solution.

Changes in childhood vaccination during the coronavirus disease 2019 pandemic in Japan.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has greatly affected daily life. COVID-19 often causes asymptomatic or mild disease in children; however, delayed routine childhood immunization is a concern, as it could increase the risk of vaccine-preventable disease. No study has evaluated the status of childhood vaccinations in Japan during the COVID-19 pandemic. METHODS: This retrospective observational study evaluated the number of vaccine doses administered to children in 4 Japanese cities (2 cities in the Tokyo metropolitan area and 2 cities far from Tokyo) during the period from 2016 to 2020. Vaccine doses administered between January and September 2020 during the COVID-19 pandemic were compared, by month, with those given during 2016-2019. Age-stratified demographic data were collected to determine whether factors other than change in the child population over time affected vaccination trends. RESULTS: In all cities the decrease in vaccine doses administered was most apparent in March and April 2020, i.e., just before or coincident with the declaration of a nationwide COVID-19 emergency on April 7, 2020. The decrease started as early as February in the Tokyo metropolitan area. As child age increased, the decrease became more apparent. Before the lift of national emergency on May 25, catch-up of the vaccination was observed in all age groups in all cities. Vaccine doses persistently increased in older age groups but not in infants. The overall vaccination trends did not differ significantly among the 4 cities. CONCLUSIONS: The COVID-19 pandemic significantly affected routine childhood immunization in Japan. Thus, a nationwide electronic surveillance system and announcements for guardians to encourage timely routine immunization are warranted.

Structure Controlling Factors of Oxido-Bridged Dinuclear Iron(III) Complexes.

Oxido bridges commonly form between iron(III) ions, but their bond angles and symmetry vary with the circumstances. A large number of oxido-bridged dinuclear iron(III) complexes have been structurally characterized. Some of them belong to the C2 point group, possessing bent Fe-O-Fe bonds, while some others belong to the Ci symmetry, possessing the linear Fe-O-Fe bonds. The question in this study is what determines the structures and symmetry of oxido-bridged dinuclear iron(III) complexes. In order to gain further insights, three oxido-bridged dinuclear iron(III) complexes were newly prepared with 2,2'-bipyridine (bpy) and 1,10-phenanthroline (phen) ligands: [Fe2OCl2(bpy)4][PF6]2 (1), [Fe2O(NO3)2(bpy)4][PF6]2·0.6MeCN·0.2(2-PrOH) (2), and [Fe2OCl2(phen)4][PF6]2·MeCN·0.5H2O (3). The crystal structures of 1, 2, and 3 were determined by the single-crystal X-ray diffraction method, and all of them were found to have the bent Fe-O-Fe bonds. Judging from the crystal structure, some intramolecular interligand hydrogen bonds were found to play an important role in fixing the structures. Additional density functional theory (DFT) calculations were conducted, also for a related oxido-bridged dinuclear iron(III) complex with a linear Fe-O-Fe bond. We conclude that the Fe-O-Fe bridge tends to bend like a water molecule, but is often stretched by interligand steric repulsion, and that the structures are mainly controlled by the intramolecular interligand interactions.

Go-sha-jinki-Gan Alleviates Inflammation in Neurological Disorders via p38-TNF Signaling in the Central Nervous System.

Go-sha-jinki-Gan (GJG) is a traditional Japanese herbal medicine. In clinical practice, GJG is effective against neuropathic pain and hypersensitivity induced by chemotherapy or diabetes. In our previous study using a chronic constriction injury mouse model, we showed that GJG inhibited microglia activation by suppressing the expression of tumor necrosis factor-α (TNF-α) and p38 mitogen-activated protein kinase (p38 MAPK) in the peripheral nervous system. To investigate whether GJG can suppress inflammation in the central nervous system (CNS) in the context of neurological disorders, we examined the effect of GJG on the activation of resident glial cells and on p38-TNF signaling in two mouse models of neurological disorders: the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. GJG administration relieved the severity of clinical EAE symptoms and MPTP-induced inflammation by decreasing the number of microglia and the production of TNF-α in the spinal cord of EAE mice and the substantia nigra of MPTP-treated mice. Accordingly, GJG suppressed the phosphorylation of p38 in glial cells of these two mouse models. We conclude that GJG attenuates inflammation of the CNS by suppressing glial cell activation, followed by a decrease in the production of TNF-α via p38-TNF signaling.

ADSSL1 myopathy is the most common nemaline myopathy in Japan with variable clinical features.

OBJECTIVE: To elucidate the prevalence of Japanese ADSSL1 myopathy and determine the clinicopathologic features of the disease. METHODS: We searched for ADSSL1 variants in myopathic patients from January 1978 to March 2019 in our repository and assessed the clinicopathologic features of patients with variants. RESULTS: We identified 63 patients from 59 families with biallelic variants of ADSSL1. Among the 7 distinct variants identified, c.781G>A and c.919delA accounted for 53.2% and 40.5% of alleles, respectively, suggesting the presence of common founders, while the other 5 were novel. Most of the identified patients displayed more variable muscle symptoms, including symptoms in the proximal and/or distal leg muscles, tongue, masseter, diaphragm, and paraspinal muscles, in adolescence than previously reported patients. Dysphagia with masticatory dysfunction developed in 26 out of 63 patients; hypertrophic cardiomyopathy developed in 12 out of 48 patients; and restrictive ventilatory insufficiency developed in 26 out of 34 patients in later stages. Radiologically, fat infiltration into the periphery of vastus lateralis, gastrocnemius, and soleus muscles was observed in all patients. Pathologically, nemaline bodies in addition to increased lipid droplets and myofibrillar disorganization were commonly observed in all patients, suggesting that the disease may be classified as nemaline myopathy. This finding revealed that ADSSL1 myopathy is the most frequent among all genetically diagnosable nemaline myopathies in our center. CONCLUSIONS: ADSSL1 myopathy is characterized by more variable manifestations than previously reported. It is the most common among all genetically diagnosable nemaline myopathies in our center, although mildly increased lipid droplets are also constantly observed features.

Detailed magnetic analysis and successful deep-neural-network-based conformational prediction for [VO(dmso)5][BPh4]2.

Pentakis(dimethylsulfoxide-κO)oxidovanadium(iv) bis(tetraphenylborate), [VO(dmso)5][BPh4]2 (dmso: dimethylsulfoxide), was synthesized, and its pseudo-C 4 VO6 coordination geometry was revealed by a single-crystal X-ray method. A novel equation set was obtained for magnetic susceptibility and magnetization of the d1 complexes, considering the axial distortion and the spin-orbit coupling for the 2D free-ion term. The equation set enabled magnetic simulation for significantly symmetry-lowered d1 complexes to obtain the anisotropic g-values and also the excitation energies. In addition, conformational prediction was conducted, using the enumeration results on the basis of the group theory. The dominant conformers were predicted on the basis of the density functional theory (DFT) method, and especially, the conformer in the crystal was successfully predicted by a deep neural network method.

Zero-field slow relaxation of magnetization in cobalt(ii) single-ion magnets: suppression of quantum tunneling of magnetization by tailoring the intermolecular magnetic coupling.

The correlation between magnetic relaxation dynamics and the alignment of single-ion magnets (SIMs) in a crystal was investigated using four analogous cobalt(ii) complexes with unique hydrogen-bond networks. The hydrogen-bonding interactions in the crystals resulted in a relatively short intermolecular Co⋯Co distance, which led to non-zero intermolecular magnetic coupling. All the complexes with a Co⋯Co distance shorter than 6.5 Å exhibited zero-field slow magnetic relaxation as weak magnetic interactions split the ground ±Ms levels and suppressed quantum tunneling of magnetization (QTM). In particular, antiferromagnetically coupled one-dimensional chain SIM networks effectively suppressed QTM when the two intrachain Co⋯Co distances were non-equivalent. However, when the two distances in a chain were equivalent and each molecular symmetry axis aligned parallell within the chain, QTM suppression was insufficient because magnetic coupling from the adjacent molecules was virtually cancelled. Partial substitution of the CoII ion with the diamagnetic ZnII ion up to 33% for this complex resulted in complete QTM suppression in the absence of an external field. These results show that the manipulation of intermolecular distances and alignments is effective for suppressing undesired QTM events in SIMs.

Paddlewheel-type diruthenium(iii,iii) tetrakis(2-aminopyridinate) complexes with NIR absorption features: combined experimental and theoretical study.

The reactions of [Ru2(O2CCH3)4Cl] with 2-aminopyridine (Hamp) and 2-amino-4-methylpyridine (Hammp) afforded two novel Ru2 complexes, [Ru2(amp)4Cl2] (1) and [Ru2(ammp)4Cl2] (2), respectively. Single crystal X-ray diffraction analyses revealed that 1 and 2 adopted typical paddlewheel-type structures, where the Ru2 units are coordinated with four aminopyridinate ligands with a cis-2:2 arrangement at the equatorial positions and two chloride ligands at the axial positions. The stabilities of 1 and 2 were supported by unrestricted density functional theory (uDFT) calculations. The zero-point energies of the three structural isomers (trans-2:2, 3:1, and 4:0 arrangements) of 1 and 2 were less stable than those of the respective cis-2:2 arrangements. Temperature-dependences of the magnetic susceptibility measurements and uDFT calculations showed that the oxidation and spin states of the Ru2 units in 1 and 2 were commonly Ru26+ and triplet states, respectively. Cyclic voltammetry showed that 1 and 2 underwent one-electron reduction processes, i.e., 1/1- and 2/2-, at redox potentials (E1/2) of -0.08 and -0.18 V vs. SCE, respectively. These results agreed well with the DFT-calculated E1/2 values of 1 (-0.08 V vs. SCE) and 2 (-0.18 V vs. SCE) and were theoretically attributed to Ru2-centred (δ*(Ru2)) redoxes. Moreover, 1 and 2 showed unique near-infrared absorption bands at approximately 1200-1500 nm, which were theoretically attributed to the ligand-to-metal charge transfer (LMCT) with π(amp or ammp) →δ*(Ru2) transition characteristics.

The crystal structure of [Mg(dmso)6][BPh4]2 and the formation mechanism of the conformer on the basis of conformational analysis.

The crystal structure of a new magnesium(ii) complex, [Mg(dmso)6][BPh4]2 (1) (dmso: dimethylsulfoxide), was determined, and the reason for the observed structure was clarified by conformational analysis. For a dmso-ligand arm, three conformations, α, ß, and γ, are possible. The α-arm is the most energetically favourable and is suitable for reducing the steric repulsion between the arms; the ß-arm is less energetically favourable, but can be stabilized by interaction with surroundings (e.g. CHπ interaction); the γ-arm is not energetically favourable, but is effective in reducing the size of the complex cation. From the conformational analysis, the most stable conformer of the [Mg(dmso)6]2+ complex cation was found to be the α6 conformer, and the complex cation in dmso solution was predicted to exist as a mixture of α6, α5ß, and trans-α4ß2 species. On the contrary, in the crystal structure, the trans-ß2γ4 species, considered to be unstable, was observed. From the conformational analysis in the tetraphenylborate surroundings, the trans-ß2γ4 structure was found to become more stable, due to its small size suitable for crystal packing with bulky tetraphenylborate anions.

Biomimetic Polyelectrolytes Based on Polymer Nanosheet Films and Their Proton Conduction Mechanism.

We report a biomimetic polyelectrolyte based on amphiphilic polymer nanosheet multilayer films. Copolymers of poly( N-dodecylacrylamide- co-vinylphosphonic acid) [p(DDA/VPA)] form a uniform monolayer at the air-water interface. By depositing such monolayers onto solid substrates using the Langmuir-Blodgett (LB) method, multilayer lamellae films with a structure similar to a bilayer membrane were fabricated. The proton conductivity at the hydrophilic interlayer of the lamellar multilayer films was studied by impedance spectroscopy under temperature- and humidity-controlled conditions. At 60 °C and 98% relative humidity (RH), the conductivity increased with increasing mole fraction of VPA ( n) up to 3.2 × 10-2 S cm-1 for n = 0.41. For a film with n = 0.45, the conductivity decreased to 2.2 × 10-2 S cm-1 despite the increase of proton sources. The reason for this decrease was evaluated by studying the effect of the distance between the VPAs ( lVPA) on the proton conductivity as well as their activation energy. We propose that for n = 0.41, lVPA is the optimal distance not only to form an efficient two-dimensional (2D) hydrogen bonding network but also to reorient water and VPA. For n = 0.45, on the other hand, the lVPA was too close for a reorientation. Therefore, we concluded that there should be an optimal distance to obtain high proton conductivity at the hydrophilic interlayer of such multilayer films.

Detection of mutations in the VP7 gene of vaccine-derived strains shed by monovalent rotavirus vaccine recipients.

Strains of Rotarix, a live attenuated monovalent oral rotavirus vaccine, replicate in the intestine and are shed for about one month in immunocompetent recipients. The current study aimed to identify genetic changes of shed strains to reveal any significant mutations and their clinical impact on recipients. Stool samples of recipients of the first dose of Rotarix were sequentially collected for one month from the day of administration. Sequence analyses of the VP7 gene in eight recipients revealed five amino acid substitutions. Among them, two were observed in aa123, which is located in antigenic region 7-1a. Since there were no associated clinical symptoms, the genetic changes were unlikely to have caused reversion of pathogenicity of vaccine strain. Of interest, the virus in one case became closer to wild-type rotavirus via an amino acid change at aa123 occurring 14 days after administration, which might have resulted from multiple replications and long-term shedding of the vaccine strain.