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Titanium complexes bearing 2-(arylideneamino)phenolates and 2-((arylimino)methyl)phenolates were synthesized, and their catalytic activities in the polymerization of ε-caprolactone and L-lactide were studied. Among five-membered ring Ti complexes bearing 2-(arylideneamino)phenolates, FCl-Ti exhibited the highest level of catalytic activity ([CL] : [FCl-Ti] = 100 : 1, where [CL] = 2 M, and conv. = 86% at 60 °C after 9 h). For six-membered ring Ti complexes bearing 2-((arylimino)methyl)phenolates, SCl-Ti exhibited the highest level of catalytic activity ([CL] : [SCl-Ti] = 100 : 1, where [CL] = 2 M, and conv. = 88% at 60 °C after 118 h). The five-membered ring Ti complexes bearing 2-(arylideneamino)phenolates exhibited a higher level of catalytic activity (6.1-12.8 fold for the polymerization of ε-caprolactone and 6.2-23.0 fold for the polymerization of L-lactide) than the six-membered ring Ti complexes bearing 2-((arylimino)methyl)phenolates. The density functional theory (DFT) results revealed that the free energy of the first transition state FH-Ti-TS1 is 36.49 kcal mol -1 which is lower than that of SH-Ti-TS1 (46.58 kcal mol -1 ), which was ascribed to the fact that the Ti-N im bond (2.742 Å) of FH-Ti-TS1 is longer than that of SH-Ti-TS1 (2.229 Å) and reduces the repulsion between ligands.

This study developed a dual-readout system utilizing fluorescence and colorimetry based on iron oxide quantum dots (IO-QDs) for detecting tetracycline (TCy). IO-QDs were synthesized within 6 h using L-leucine as a surface modifier, achieving a more efficient route. Upon interaction with TCy, IO-QDs exhibited a significant decrease in fluorescence response and observable color changes, while fluorescence lifetime remained consistent regardless of TCy presence. Moreover, IO-QDs' fluorescence response remained stable across various temperatures. The Förster resonance energy transfer distance of less than 2 nm and a quenching constant of 2.90 × 10 12  M -1 s -1 indicated static quenching in the presence of TCy. Additionally, significant changes in observed and corrected fluorescence efficiency suggested the involvement of the inner filter effect in the fluorescence quenching of IO-QDs. The synthesized IO-QDs were then utilized for selective and rapid fluorescence-based TCy detection, showing a linear range of 0.5 to 80 μM. Simultaneously, a colorimetric method for TCy detection was established, demonstrating a good linear relationship within the range of 0.5 to 20 μM. The detection limits for TCy were determined as 0.539 and 0.329 μM using fluorescence and colorimetric approaches, respectively. Furthermore, IO-QDs were applied to detect real samples, and the dual-readout probe exhibited satisfactory recoveries, confirming the practical reliability of the developed method for analyzing milk and drinking water samples., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Muscle contusion is an injury to muscle fibers and connective tissues. It commonly happens in impact events, and could result in pain, swelling, and limited range of motion. Diclofenac is one of commonly used nonsteroidal anti-inflammatory drugs to alleviate pain and inflammation after injury. However, it can potentially cause some side effects including gastrointestinal complications and allergy. Betulin is a lupine-type pentacyclic triterpenoid. It is showed to have valuable pharmacological effects, but the physiological effect of betulin on muscle contusion has not been reported. This study aimed to explore the therapeutic effects of betulin on muscle contusion that produced by the drop-mass method in mice. C57BL/6 mice were randomly assigned to control (no injury), only drop-mass injury (Injury), diclofenac treatment (Injury+diclofenac), and betulin treatment (Injury+betulin) groups. Injury was executed on the gastrocnemius of the right hind limb, and then phosphate-buffered saline (PBS), diclofenac, or betulin were oral gavage administrated respectively for 7 days. Results revealed that betulin significantly restored motor functions based on locomotor activity assessments, rota-rod test, and footprints analysis. Betulin also attenuated serum creatine kinase (CK) and lactate dehydrogenase (LDH) levels after muscle injury. Neutrophil infiltration was alleviated and desmin levels were increased after betulin treatment. Our data demonstrated that betulin attenuated muscle damage, alleviated inflammatory response, improved muscle regeneration, and restored motor functions after muscle contusion. Altogether, betulin may be a potential compound to accelerate the repair of injured muscle., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

In this study, a series of Al complexes bearing amidates, thioamidates, ureidates, and thioureidates were synthesized and their catalytic activity for ε-caprolactone (CL) polymerization was evaluated. SPr-Al exhibited a higher catalytic activity than OPr-Al (3.2 times as high for CL polymerization; [CL] : [SPr-Al] : [BnOH] = 100 : 0.5 : 2; [SPr-Al] = 10 mM, conv. = 93% after 14 min at 25 °C), and USCl-Al exhibited a higher catalytic activity than UCl-Al (4.6 times as high for CL polymerization; [CL] : [USCl-Al] : [BnOH] = 100 : 0.5 : 2; [USCl-Al] = 10 mM, conv. = 90% after 15 min at 25 °C). Regardless of whether aluminum amidates or ureidates were present, thioligands improved the polymerization rate of aluminum catalysts. Density functional theory calculations revealed that the eight-membered ring [SPr-AlOMe2]2 decomposed into the four-membered ring SPr-AlOMe2. However, [OPr-AlOMe2]2 did not decompose because of its strong bridging Al-O bond. The overall activation energy required for CL polymerization was lower when using [SPr-AlOMe2]2 (18.1 kcal mol -1 ) as a catalyst than when using [OPr-AlOMe2]2 (23.9 kcal mol -1 ). This is because the TS2a transition state of SPr-AlOMe2 had a more open coordination geometry with a small N-Al-S angle (72.91°) than did TS3c of [OPr-AlOMe2]2, the crowded highest-energy transition state of [OPr-AlOMe2]2 with a larger N-Al-O angle (99.63°).

Polyphyllin G, a pennogenyl saponin extracted from Paris polyphylla, has been shown to possess antitumor effects. In this study, we demonstrated that doxycycline, an antibiotic medicine, could significantly enhance the sensitivities of osteosarcoma cell lines to polyphyllin G. As the cells were pretreated with doxycycline at non-toxic concentrations and then co-exposed to polyphyllin G, this combination could induce a rapid cell death distinct from apoptosis. The non-apoptotic cell death was characterized by a loss of integrity of plasma membrane without externalization of phosphatidyl serine. Furthermore, this combined treatment resulted in suppression of cell viability and colony-forming ability, and increased the level of γ-H2A.X, a critical marker for DNA damage, in osteosarcoma cell lines. When examining the underlying mechanism, it was revealed combination of polyphyllin G and doxycycline triggered an enhanced generation of reactive oxygen species (ROS), and up-regulated mitochondrial oxidative stress within 0.5 h. Co-administration of the ROS inhibitor NAC reversed the suppressed cell viability and colony-forming ability, and abolished the increased level of γ-H2A.X in the cells with the combined treatment, indicating that the enhanced ROS was involved in the anti-proliferative effect of the combined treatment. Overall, the results demonstrated that doxycycline may function as chemosensitizers by inducing an acute and lethal ROS production to enhance cytotoxic of polyphyllin G in osteosarcoma cell lines, and the combined use of drugs may provide an alternative thinking for the development of new therapeutic agents., (© 2023 Wiley Periodicals LLC.)

Carvacrol is a monoterpenoid phenol that has excellent antimicrobial, antiviral, and anti-inflammatory activities. It can also improve wound healing. However, few studies have explored its antitumor effect on osteosarcoma. In this report, we tried to determine the potential efficacy of carvacrol against osteosarcoma cell lines. Our data revealed that carvacrol exposure inhibited the proliferation of osteosarcoma HOS and U-2 OS cells. In addition, carvacrol exposure enhanced the levels of cleaved PARP and caspase 3 and increased annexin V-positive cells, indicating that carvacrol exposure triggers apoptosis in osteosarcoma cell lines. Furthermore, the levels of reactive oxygen species (ROS) were enhanced after carvacrol exposure and cotreatment with NAC, the ROS scavenger, decreased the levels of cleaved PARP and caspase 3, suggesting the involvement of ROS in carvacrol-induced apoptosis. Importantly, we found that carvacrol exposure triggered several protein expressions related to endoplasmic reticulum (ER) stress, including GRP78/Bip, IRE1a, PERK, and CHOP, in HOS and U-2 OS cells, indicating that carvacrol exposure could result in ER stress in these cell lines. Cotreatment with the ER stress inhibitor 4-PBA increased the levels of cleaved PARP and caspase 3 and further suppressed cellular proliferation in carvacrol-exposed osteosarcoma cell lines. Overall, the results indicate that induced ER stress can protect cells from apoptosis, but increased ROS contributes to apoptosis in carvacrol-treated cells. In this report, we first demonstrate the role of ER stress in carvacrol-induced apoptosis and suggest that ER stress could be targeted to enhance the antitumor activity of carvacrol in osteosarcoma cell lines.

Bayer color filter array (CFA) images are captured by a single-chip image sensor covered with a Bayer CFA pattern which has been widely used in modern digital cameras. In the past two decades, many compression methods have been proposed to compress Bayer CFA images. These compression methods can be roughly divided into the compression-first-based (CF-based) scheme and the demosaicing-first-based (DF-based) scheme. However, in the literature, no review article for the two compression schemes and their compression performance is reported. In this article, the related CF-based and DF-based compression works are reviewed first. Then, the testing Bayer CFA images created from the Kodak, IMAX, screen content images, videos, and classical image datasets are compressed on the Joint Photographic Experts Group-2000 (JPEG-2000) and the newly released Versatile Video Coding (VVC) platform VTM-16.2. In terms of the commonly used objective quality, perceptual quality metrics, the perceptual effect, and the quality-bitrate tradeoff metric, the compression performance comparison of the CF-based compression methods, in particular the reversible color transform-based compression methods and the DF-based compression methods, is reported and discussed.

In this study, aluminum complexes bearing ferrocene-based and arylthiomethylphenolate ligands were synthesized, and their catalytic activity for ε-caprolactone (CL) polymerization was investigated. The catalytic activity of the reduced form of Al complexes was higher than that of the oxidized form. The CL polymerization rate of the reduced form fcO 2 AlMe (75 min, conversion = 100%) was higher than that of the oxidized form fc ox O 2 AlMe (4320 min, conversion = 45%), and the CL polymerization rate of fc(OAlMe 2 ) 2 (40 min, conversion = 100%) was higher than that of fc ox (OAlMe 2 ) 2 (60 min, conversion = 97%). Electron deficiency substituents on phenolate decreased the catalytic activity of Al complexes bearing arylthiomethylphenolate ligands. Density functional theory calculations revealed that thioether coordination stabilized the transition state ( TS1 ) and that the oxidized form fc ox (OAlMe 2 ) 2 exhibited weaker thioether coordination and higher activation energy in TS1 compared with those of the reduced form fcO 2 AlMe . In addition, our study determined that the thioether group is a suitable chelating group for Al catalysts in CL polymerization due to its labile nature.

Background: Systemic inflammation is a potent contributor to increased seizure susceptibility. However, information regarding the effects of systemic inflammation on cerebral vascular integrity that influence neuron excitability is scarce. Necroptosis is closely associated with inflammation in various neurological diseases. In this study, necroptosis was hypothesized to be involved in the mechanism underlying sepsis-associated neuronal excitability in the cerebrovascular components (e.g., endothelia cells)., Methods: Lipopolysaccharide (LPS) was used to induce systemic inflammation. Kainic acid intraperitoneal injection was used to measure the susceptibility of the mice to seizure. The pharmacological inhibitors C87 and GSK872 were used to block the signaling of TNFα receptors and necroptosis. In order to determine the features of the sepsis-associated response in the cerebral vasculature and CNS, brain tissues of mice were obtained for assays of the necroptosis-related protein expression, and for immunofluorescence staining to identify morphological changes in the endothelia and glia. In addition, microdialysis assay was used to assess the changes in extracellular potassium and glutamate levels in the brain., Results: Some noteworthy findings, such as increased seizure susceptibility and brain endothelial necroptosis, Kir4.1 dysfunction, and microglia activation were observed in mice following LPS injection. C87 treatment, a TNFα receptor inhibitor, showed considerable attenuation of increased kainic acid-induced seizure susceptibility, endothelial cell necroptosis, microglia activation and restoration of Kir4.1 protein expression in LPS-treated mice. Treatment with GSK872, a RIP3 inhibitor, such as C87, showed similar effects on these changes following LPS injection., Conclusions: The findings of this study showed that TNFα-mediated necroptosis induced cerebrovascular endothelial damage, neuroinflammation and astrocyte Kir4.1 dysregulation, which may coalesce to contribute to the increased seizure susceptibility in LPS-treated mice. Pharmacologic inhibition targeting this necroptosis pathway may provide a promising therapeutic approach to the reduction of sepsis-associated brain endothelia cell injury, astrocyte ion channel dysfunction, and subsequent neuronal excitability., (© 2022. The Author(s).)

Hinokitiol is a tropolone-related compound isolated from the heartwood of cupressaceous plants. It is known to exhibit various biological functions including antibacterial, antifungal, and antioxidant activities. In the study, we investigated the antitumor activities of hinokitiol against human osteosarcoma cells. The results revealed that hinokitiol treatment inhibited cell viability of human osteosarcoma U-2 OS and MG-63 cells in the MTT assay. Further study revealed that hinokitiol exposure caused cell cycle arrest at the S phase and a DNA damage response with the induction of γ-H2AX foci in both osteosarcoma cell lines. In U-2 OS cells with wild-type tumor suppressor p53, we found that hinokitiol exposure induced p53 expression and cellular senescence, and knockdown of p53 suppressed the senescence. However, in MG-63 cells with mutated p53, a high percentage of cells underwent apoptosis with cleaved-PARP expression and Annexin V staining after hinokitiol treatment. In addition, up-regulated autophagy was observed both in hinokitiol-exposed U-2 OS and MG-63 cells. As the autophagy was suppressed through the autophagy inhibitor chloroquine, hinokitiol-induced senescence in U-2 OS cells was significantly enhanced accompanying more abundant p53 expression. In MG-63 cells, co-treatment of chloroquine increased hinokitiol-induced apoptosis and decreased cell viability of the treated cells. Our data revealed that hinokitiol treatment could result in different cell responses, senescence or apoptosis in osteosarcoma cell lines, and suppression of autophagy could promote these effects. We hypothesize that the analysis of p53 status and co-administration of autophagy inhibitors might provide more precise and efficacious therapies in hinokitiol-related trials for treating osteosarcoma.

Purpose: Evidence for optimizing the first-line chemotherapy for patients with metastatic triple-negative breast cancer (mTNBC) is lacking. This study assessed the utilization patterns of chemotherapy and associated survival outcomes in de novo mTNBC patients., Methods: Taiwan's cancer registry was utilized to extract study patients with newly-diagnosed breast cancer during 2011-2015 and confirmed metastatic triple-negative status. The patients' medical records (e.g., diseases, treatments) and death status were obtained from the National Health Insurance Research Database. Utilization of first-line chemotherapy regimens was analyzed and associated survival outcomes were assessed using Cox models., Results: 93.60% of the mTNBC patients (n = 297) received chemotherapy, where combination regimens (75.54%) were more common than single-agent regimens (24.46%) in the first-line setting. A non-statistically lower all-cause death associated with combination versus single-agent chemotherapy (hazard ratio: 0.830 [0.589, 1.168]) was observed. Age was identified as a significant effect-modifier in treatment-associated survival outcomes (p = 0.008); younger patients (aged < 40 and 40-59 years) versus older patients (aged ≥ 60 years) had a lower all-cause mortality when receiving combination versus single-agent chemotherapy. A lower all-cause mortality associated with taxane- versus non-taxane-based therapy was revealed among those on single-agent chemotherapy (hazard ratio: 0.557 [0.311, 0.999])., Conclusion: Generally, single-agent and combination chemotherapies yielded comparable survival outcomes as the first-line treatment for de novo mTNBC. Younger patients may benefit more from combination regimens, in terms of better survival outcomes. Single-agent chemotherapy may be preferable as the first-line choice for elderly patients who are vulnerable to the toxicity of multiple chemotherapy agents., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2021 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Background: Involvement in cervical ligamentum flavum is a rare manifestation of the calcium pyrophosphate dihydrate deposition disease. Only few cases of this condition have been reported. We revealed eighteen cases of CPPD in cervical ligamentum flavum that diagnosed at a single medical center. In our case series, clinical characteristics and magnetic resonance imaging findings of patients are described., Methods: We retrospectively reviewed the medical charts and imaging studies of the eighteen patients with pseudogout attack of the cervical ligamentum flavum. In addition, we discussed the differences between this disease and ossification of ligamentum flavum in image manifestations., Results: There were fourteen men and four women aged between 59 and 87 years. Diabetes mellitus and hypertension were the most common comorbidities. Myelopathy and neck pain were presented in most patients. C4-5 and C5-6 were attacked most frequently, and multiple- rather than single-level involvement could be observed in our series. "Acute on chronic phenomenon" was a specific magnetic resonance image finding in patients whose symptom durations were between 2 to 5 months. Compared to ossification of ligamentum flavum, calcium pyrophosphate dihydrate crystal deposition had different image signs, including morphology, side of the involved ligament, no continuity with the lamina, acute on chronic phenomenon, and presence of retro-odontoid mass., Conclusions: Nodular calcifications in cervical ligamentum flavum raise highly suspicion for calcium pyrophosphate dihydrate deposition and must be diagnosed by histological examination and polarized light microscopy. This disease is different from ossification of ligamentum flavum, and it could be recognized by specific image features., (© 2021. The Author(s).)

Objective: To assess the healthcare utilization, economic burden, and long-term neurological complications and mortality of an adult population with Japanese encephalitis (JE)., Methods: This study utilized two nationwide datasets in Taiwan: the Notifiable Disease Dataset of confirmed cases from the Centers for Disease Control to identify JE patients, and the National Health Insurance Research Database to obtain patients' healthcare utilization. Survival analyses were performed to identify prognostic factors associated with the all-cause mortality of patients., Results: This study included 352 adult cases with JE (aged≥20 years). The mean age of JE patients was 45 years. Stroke (event rate: 3.49/100 person-years) was the most common neurological complication, followed by epilepsy/convulsions (3.13/100 person-years), encephalopathy/delirium (2.20/100 person-years), and parkinsonism (1.97/100 person-years). Among the 336 hospitalized patients at JE diagnosis, 58.33% required intensive care. Among 79 patients who died following JE diagnosis, 48.84% of death events occurred within the year of diagnosis. The medical costs increased considerably at JE diagnosis and subsequent-year costs remained significantly higher than the costs before diagnosis (p<0.05). Having a four-dose JE vaccination (i.e., born after 1976) versus no JE vaccination history (i.e., born before 1963) was significantly associated with lower all-cause mortality (hazard ratio: 0.221 [95% confidence interval: 0.067, 0.725]). Comorbid diabetes and incident epilepsy/convulsion events significantly increased the mortality risk by 2.47- and 1.85-fold, respectively (p<0.05)., Conclusion: A considerable medical burden associated with JE was observed in affected adults, even in the years following JE diagnosis. Vaccination should be considered to prevent this sporadic, but lethal, viral infection., Competing Interests: All authors of this manuscript have read the journal’s policy and have the following competing interests: Chung-Chih Lai and Rebecca Claire Harris are the employees of Sanofi Pasteur and may hold shares and/or stock options in the company. The other authors have no competing interests to declare.

Aims/introduction: To estimate preference-based measures of health-related quality of life associated with sociodemographic and clinical characteristics in type 2 diabetes patients., Materials and Methods: Individuals with EuroQol-5 dimensions-3 levels data were identified from Taiwan's National Health Interview Survey in 2009 and 2013. Status of diabetes, comorbidities, complications and treatments were ascertained through data linkage to Taiwan's National Health Insurance Research Database. Multivariable ordinary least squares, Tobit and median regression analyses were used to estimate the coefficients that represented independent impacts of patients' characteristics on health-related quality of life., Results: The mean health utility score for 2,104 participants was 0.838. Being female, aging, divorced/widowed, never worked or underweight, or having a lower monthly household income, injectable glucose-lowering therapy, comorbid connective tissue disease or depression were associated with lower health utilities. Having an amputation led to the largest reduction by 0.288 in health utilities, followed by debilitating stroke (0.266), heart failure (0.237), other coronary heart disease (0.185), kidney dialysis/transplant (0.148), coronary revascularizations (0.093), transient ischemic attack/stroke (0.078), diabetic neuropathy (0.062), polyneuropathy (0.055) and other neuropathy (0.043)., Conclusions: Major vascular complications, connective tissue disease and depression are associated with considerably worse health-related quality of life. These health utility estimates can facilitate health economic evaluations to determine cost-effective strategies for diabetes management., (© 2021 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Carbodicarbene (CDC), unique carbenic entities bearing two lone pairs of electrons are well-known for their strong Lewis basicity. We demonstrate herein, upon introducing a weak Brønsted acid benzyl alcohol (BnOH) as a co-modulator, CDC is remolded into a Frustrated Lewis Pair (FLP)-like reactivity. DFT calculation and experimental evidence show BnOH loosely interacting with the binding pocket of CDC via H-bonding and π-π stacking. Four distinct reactions in nature were deployed to demonstrate the viability of proof-of-concept as synergistic FLP/Modulator (CDC/BnOH), demonstrating enhanced catalytic reactivity in cyclotrimerization of isocyanate, polymerization process for L-lactide (LA), methyl methacrylate (MMA) and dehydrosilylation of alcohols. Importantly, the catalytic reactivity of carbodicarbene is uniquely distinct from conventional NHC which relies on only single chemical feature of nucleophilicity. This finding also provides a new spin in diversifying FLP reactivity with co-modulator or co-catalyst., (© 2021 Wiley-VCH GmbH.)

Trinuclear aluminum complexes bearing bipyrazoles were synthesized, and their catalytic activity for ε-caprolactone (CL) polymerization was investigated. D Bu 2 Al 3 Me 5 exhibited higher catalytic activity than did the dinuclear aluminum complex L Bu 2 Al 2 Me 4 (16 times as high for CL polymerization; [CL]:[ D Bu 2 Al 3 Me 5 ]:[BnOH] = 100:0.5:5, [ D Bu 2 Al 3 Me 5 ] = 10 mM, conversion 93% after 18 min at room temperature). Density functional theory calculations revealed a polymerization mechanism in which CL first approached the central Al atom and then moved to an external Al. The coordinated CL ring was opened because the repulsion of two tert -butyl groups on the ligands pushed an alkoxide initiator on an external Al to initiate CL. In these trinuclear Al catalysts, the central Al plays a role in monomer capture and then collaborates with the external Al to activate CL, accelerating polymerization.

Understanding the water state in Nafion is not only crucial for operating a proton-exchange membrane (PEM)-based fuel cell, but also intimately related to the elucidation of the proton transport mechanism in a PEM. Although many studies have been published on this subject, some controversies and ambiguities remain unresolved. In this work, we design three different types of Nafion samples by substituting protons with lithium or sodium cations. We also pay special attention to the preparation of samples for carrying out broad-range variable temperature solid state NMR experiments so that no membrane dehydration occurs during the long experimental time at low temperatures. With these precautions and improvements, clear and largely straightforward information could be obtained to ensure minimal ambiguity and complexity in the interpretation of the experimental data. Our results show that about 40-60% of water remains unfrozen at -70 °C, depending on the type of the substituting cation. Both the 1 H and 2 H spectral and relaxation results indicate that water freezing starts from the center of the nanopores inside Nafion and increases gradually as the temperature decreases. The protons remain dissociated with sulfonate groups even at the lowest temperature we reached (-70 °C), whereas both lithium and sodium are associated with sulfonate groups at most temperatures below 0 °C. The experimental data also suggest that besides frozen and unfrozen water, there is broad distribution of water state and dynamics in Nafion as the temperature is lowered from above zero down to -70 °C. The effect of the size of the substituting cation significantly affects the properties of supercooled water by modifying the cation-water interaction and impeding the rotation of sulfonate groups. These novel results not only help us in establishing a better understanding of the water state in Nafion and its performance as a proton exchange mebrane, but also provide insights into water freezing, antifreeze and supercooling in other nanoscopic environments.

Butein is a flavonoid isolated from various medicinal plants. It is known to have different biological activities including anti-inflammation, anti-adipogenesis, and anti-angiogenesis. In the study, we demonstrated the anti-proliferative effect of butein in human osteosarcoma U-2 OS cells. Our data showed that butein significantly suppressed the viability and colony formation ability of U-2 OS cells. Further experiments revealed butein exposure resulted in a cell cycle arrest at S and G2/M phase in U-2 OS cells. Importantly, we found that butein activated the tumor suppressor p53, and trigged a p53-dependent senescence in U-2 OS cells. Knockdown of p53 suppressed the senescence and rescued the viability in butein-treated U-2 OS cells. Furthermore, we observed that butein exposure significantly enhanced reactive oxygen species (ROS) levels in U-2 OS cells. Co-administration of the ROS inhibitor NAC largely abolished the up-regulated p53 protein level, and rescued the suppressed viability and colony formation ability in butein-exposed U-2 OS cells. Taken together, our data proposed the increased ROS by butein exposure activated p53, and the activated p53 was involved in the anti-proliferative effect of butein via inducing senescence in U-2 OS cells. This report suggests that butein is a promising candidate for cancer therapy against osteosarcoma., (© 2020 Wiley Periodicals LLC.)

Molecular imaging based on magnetic resonance imaging (MRI) requires a contrast agent with high relaxivity and specificity. Much effort has been devoted to this goal over the past decades. In this work, we continue this endeavor by synthesizing an MRI contrast agent that can penetrate the cellular membrane and bind with specific proteins. It was characterized with one- and two-dimensional NMR spectroscopy, NMR micro-imaging, and mass spectroscopy. The target specificity has been further confirmed by both molecular dynamics simulation and micro-imaging on a living biological system. It is one of the largest of peptide-based bioactivated MRI contrast agents, and its relaxivity enhancement factor is among the highest of MRI contrast agents hitherto published. We envision interesting applications and extension of this smart MRI contrast agent with bio-specificity and high contrast for molecular imaging.

Combining dual drugs in one vehicle to cancer cells offers spatiotemporal localization of drug at the site of action, leading to synergistic therapeutic effects and reduced side effects. To improve pH/redox responsiveness to the tumor microenvironments for cancer therapy, a pH/redox-responsive micelle based on poly(ε-caprolactone)-SS-poly(methacrylic acid) (PCL-SS-PMAA) diblock copolymer was fabricated for dual drug delivery. The PCL-SS-PMAA was formulated into a core-shell micelle (PSPm) in an aqueous solution. The critical micelle concentration (CMC) values of PSPm were 7.94 × 10 -3 mg mL -1 at pH 5.0 and 1.00 × 10 -2 mg mL -1 at pH 7.4. The hydrodynamic diameters of PSPm were within 210-270 nm, depending on pH values. Changes in morphology and size of PSPm were clearly observed before and after exposure to a reducing agent. Paclitaxel (PTX) was encapsulated into the core and cisplatin (CDDP) was chelated on the shell of PSPm, with both PTX and CDDP being efficiently released from PSPm in the presence of a reducing agent in an acid condition. MTT and annexin V/propidium iodide dual staining results demonstrated that co-loading of CDDP and PTX into PSPm had a synergistic effect in killing lung cancer cells and exerted superior antitumor activity over the combination of single drug-loaded PSPm or the combination of free-CDDP and free-PTX at equivalent drug amounts. Hence, encapsulating the dual drugs into PSPm exhibits a synergistic effect for potential lung cancer therapy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Using TiO i Pr 4 with a pyrazole ligand for one-pot LA polymerization improved catalytic activity compared with using TiO i Pr 4 only. At 60 °C, TiO i Pr 4 with fur Pz exhibited a higher catalytic activity (approximately 3-fold) than TiO i Pr 4 . At room temperature, TiO i Pr 4 with Bu Pz exhibited a higher catalytic activity (approximately 17-fold) than TiO i Pr 4 . High molecular mass PLA ( M n GPC = 51 100, and Đ = 1.10) could be produced by using TiO i Pr 4 with fur Pz in melt polymerization ([TiO i Pr 4 ] : [ fur Pz] = 1000 : 1 : 1 at 100 °C, 240 min). The crystal structure of Me Pz 2 Ti 2 O i Pr 7 revealed the cooperative activation between two Ti atoms during LA polymerization., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Objectives: We conduct a cost-utility analysis of inotuzumab ozogamicin (INO) versus chemotherapy as the standard of care (SOC) for adults with relapsed or refractory B cell acute lymphoblastic leukemia., Methods: A Markov model incorporating transition probabilities between health states was applied to simulate disease progression. The model inputs, including overall survival, progression-free survival, and utility parameters, were obtained from the INO-VATE ALL trial and literatures. The Taiwan Cancer Registry Database and the Health and Welfare Database were utilized to identify the patient cohort and medical costs from the perspective of National Health Insurance Administration. The lifetime medical costs (in 2017 US dollars), quality-adjusted life years (QALYs) gained, and associated incremental cost-effectiveness ratio (ICER) were the main study outcomes., Results: The lifetime medical costs for INO and SOC were $176,795 and $69,496, and the QALYs gained were 2.25 and 0.84, respectively. The ICER for INO versus SOC was $76,044 per QALY gained, which is slightly more than three times Taiwan's gross domestic product per capita (i.e., $73,224). Favorable economic results for INO versus SOC were found with an increased time horizon for model simulation, less discounting for the future benefit, and higher stem cell transplantation (SCT) rate after INO treatment; and among patients aged less than 55 years, with no SCT history, or in the first salvage treatment., Conclusions: INO versus SOC has higher costs but is more effective. The use of INO is favorable for patients in the early treatment course and when more future benefit associated with INO is considered.

Objective: Developing country-specific unit-cost catalogs is a key area for advancing economic research to improve medical and policy decisions. However, little is known about how health care costs vary by type 2 diabetes (T2D) complications across time in Asian countries. We sought to quantify the economic burden of various T2D complications in Taiwan., Research Design and Methods: A nationwide, population-based, longitudinal study was conducted to analyze 802,429 adults with newly diagnosed T2D identified during 1999-2010 and followed up until death or 31 December 2013. Annual health care costs associated with T2D complications were estimated, with multivariable generalized estimating equation models adjusted for individual characteristics., Results: The mean annual health care cost was $281 and $298 (2017 U.S. dollars) for a male and female, respectively, diagnosed with T2D at age <50 years, with diabetes duration of <5 years, and without comorbidities, antidiabetic treatments, and complications. Depression was the costliest comorbidity, increasing costs by 64-82%. Antidiabetic treatments increased costs by 72-126%. For nonfatal complications, costs increased from 36% (retinopathy) to 202% (stroke) in the event year and from 13% (retinopathy or neuropathy) to 49% (heart failure) in subsequent years. Costs for the five leading costly nonfatal subtype complications increased by 201-599% (end-stage renal disease with dialysis), 37-376% (hemorrhagic/ischemic stroke), and 13-279% (upper-/lower-extremity amputation). For fatal complications, costs increased by 1,784-2,001% and 1,285-1,584% for cardiovascular and other-cause deaths, respectively., Conclusions: The cost estimates from this study are crucial for parameterizing diabetes economic simulation models to quantify the economic impact of clinical outcomes and determine cost-effective interventions., (© 2020 by the American Diabetes Association.)

Betulin is a lupane type pentacyclic triterpenoid, and commonly found in the bark of birch trees. It displays various pharmacological properties, such as antibacterial, anti-inflammation, antitumor, and antiviral. In this report, we attempted to investigate the anti-proliferative and pro-apoptotic effects of betulin on osteosarcoma cell lines. Our results revealed that betulin significantly decreased cell viability and colony formation in osteosarcoma cell lines. Dose-dependent induction of Annexin V positive cells, activated caspase 8, activated caspase 9, activated caspase 3, and the cleavage of poly (ADP-ribose) polymerase were observed after the treatment with betulin, indicating betulin induces apoptosis in osteosarcoma cell lines. mTOR has been identified as a key modulator of autophagy in response to different stresses. In this study, we found that the treatment with betulin suppressed the activation of mTOR, and increased the level of LC 3-II, the autophagy marker, in osteosarcoma cell lines. Co-administration of the autophagy inhibitor chloroquine significantly rescued the cell viability and the clonogenic activity in betulin-treated osteosarcoma cell lines. Our data showed that betulin induced autophagy, and the up-regulated autophagy positively contributed to the apoptosis. Taken together, our findings suggested that betulin may serve as a promising anti-proliferative agent for treating osteosarcoma., (© 2020 Wiley Periodicals, Inc.)

Background: Research indicates that sepsis increases the risk of developing cognitive impairment. After systemic inflammation, a corresponding activation of microglia is rapidly induced in the brain, and multiple neurotoxic factors, including inflammatory mediators (e.g., cytokines) and reactive oxygen species (e.g., superoxide), are also released that contribute to neuronal injury. NADPH oxidase (NOX) enzymes play a vital role in microglial activation through the generation of superoxide anions. We hypothesized that NOX isoforms, particularly NOX2, could exhibit remarkable abilities in developing cognitive deficits induced by systemic inflammation., Methods: Mice with deficits of NOX2 organizer p47phox (p47 phox -/- ) and wild-type (WT) mice treated with the NOX inhibitor diphenyleneiodonium (DPI) were used in this study. Intraperitoneal lipopolysaccharide (LPS) injection was used to induce systemic inflammation. Spatial learning and memory were compared among treatment groups using the radial arm maze task. Brain tissues were collected for evaluating the transcript levels of proinflammatory cytokines, whereas immunofluorescence staining and immunoblotting were conducted to determine the percentage of activated glia (microglia and astroglia) and damaged neurons and the expression of synaptic proteins and BDNF., Results: Cognitive impairment induced by systemic inflammation was significantly attenuated in the p47 phox -/- mice compared to that in the WT mice. The p47 phox -/- mice exhibited reduced microglial and astroglial activation and neuronal damage and attenuated the induction of multiple proinflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and CCL2. Similar to that observed in the p47 phox -/- mice, the administration of DPI significantly attenuated the cognitive impairment, reduced the glial activation and brain cytokine concentrations, and restored the expression of postsynaptic proteins (PSD-95) and BDNF in neurons and astrocytes, compared to those in the vehicle-treated controls within 10 days after LPS injection., Conclusions: This study clearly demonstrates that NOX2 contributes to glial activation with subsequent reduction in the expression of BDNF, synaptic dysfunction, and cognitive deficits after systemic inflammation in an LPS-injected mouse model. Our results provide evidence that NOX2 might be a promising pharmacological target that could be used to protect against synaptic dysregulation and cognitive impairment following systemic inflammation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Licochalcone A, a flavonoid extracted from licorice root, has been shown to exhibit broad anti-inflammatory, anti-bacterial, anticancer, and antioxidative bioactivity. In this study, we investigated the antitumor activity of Licochalcone A against human osteosarcoma cell lines. The data showed that Licochalcone A significantly suppressed cell viability in MTT assay and colony formation assay in osteosarcoma cell lines. Exposure to Licochalcone A blocked cell cycle progression at the G2/M transition and induced extrinsic apoptotic pathway in osteosarcoma cell lines. Furthermore, we found the Licochalcone A exposure resulted in rapid ATM and Chk2 activation, and high levels of nuclear foci of phosphorylated Chk2 at Thr 68 site in osteosarcoma cell lines. In addition, Licochalcone A exposure significantly induced autophagy in osteosarcoma cell lines. When Licochalcone A-induced autophagy was blocked by the autophagy inhibitor chloroquine, the expression of activated caspase-3 and Annexin V positive cells were reduced, and cell viability was rescued in Licochalcone A-treated osteosarcoma cell lines. These data indicate that the activation of ATM-Chk2 checkpoint pathway and autophagy may contribute to Licochalcone A-induced anti-proliferating effect in osteosarcoma cell lines. Our findings display the possibility that Licochalcone A may serve as a potential therapeutic agent against osteosarcoma.

Background: Exercise is an effective therapy for the management of diabetes because it helps regulate glucose and magnesium homeostasis. Nevertheless, the mechanisms by which exercise exerts effects on magnesium transport remain unclear. This study investigated the expression of genes encoding magnesium transporters (GMTs) after a three-month exercise program in diabetic patients., Methods: This study was conducted with a within-subject pre-post design. A total of 15 adult patients with type 2 diabetes mellitus (T2DM) were recruited and underwent a three-month indoor bicycle exercise program. The expression of five GMTs (CNNM2, TRPM6, TRPM7, SLC41A1, and SLC41A3) was determined in blood samples. Relevant anthropometric values and biochemical parameters were also determined., Results: Although the body weight and body mass index decreased after three months exercise, there were no significant differences. Fasting blood glucose, glycated hemoglobin (HbA1c), waist circumference, and magnesium levels decreased after the exercise program (p < 0.05). The expression of SLC41A1 and SLC41A3 were downregulated after exercise, but only CNNM2, TRPM6, and TRPM7 showed significantly decreased expression levels compared with those before the exercise program (p < 0.05)., Conclusion: The three-month exercise program ameliorated blood glucose levels and downregulated the expression of magnesium-responsive genes in patients with T2DM.

Previous, we found that the small molecules capable of inhibiting the expression and the pro-adipogenic activity of ZNF521 might improve the osteogenic performance of aging human bone marrow MSCs (bmMSCs), and that fatty acid synthase (FASN) was a critical effector of ZNF521's pro-adipogenic activity. Here, by characterizing the netoglitazone (MCC-555), one of the thiazolidinediones known as adipogenic enhancers, as an inhibitor of ZNF521 expression, we found that MCC-555 indeed also harbored pro-osteoblastic effect. Investigation revealed that MCC-555 might function as a GSK3β inhibitor to promote osteoblastogenesis and bone formation. Importantly, combination of MCC-555 with FASN knockdown, but not with GW9662 (a PPARγ2 antagonist), blocked the pro-adipogenic but retained the pro-osteoblastic effect of MCC-555. Using a 3-dimentional culture system, we showed that MCC-555 facilitated the FASN-knockdown of aging human bmMSCs to form cell clusters in scaffolds, and to promote osteoblastic differentiation and biomineralization in cell clusters. These data indicated that MCC-555 promoted bmMSCs to produce bone-like tissues. Our data narrate a thiazolidinedione-based novel strategy to improve the osteogenic performance of aging bmMSCs to support the application of autologous aging bmMSCs in cell therapy and in producing bone-like tissues for repairing bone injury in the elderly.

A series of aminophenolate ligands with various pendant groups and associated ethyl Zn complexes were synthesized and studied as catalysts for the ring-opening polymerization (ROP) of lactides (LAs). The thiophenylmethyl group ( L 4 ZnEt ) increased the catalytic activity more than the benzyl group ( L 1 ZnEt ) did, and 2-fluorobenzyl ( L 3 ZnEt ) and 2-methoxybenzyl ( L 2 ZnEt ) groups had the opposite effect. In addition, the LA polymerization mechanism proved by Nuclear Magnetic Resonance and Density Function Theory was that LA was attracted by H···O bond of an α-hydrogen of the LA molecule and the phenoxyl oxygen of the catalyst. After the dissociation of amino group from the Zn atom, the benzyl alcohol initiated LA without replacing the ethyl group of Zn complex. It is the first case where the ethyl group is regarded as a ligand and cannot be replaced by benzyl alcohol, and this information is very important for the mechanism study of ROP.

This study investigated the incidence, rationales, and associated factors of inappropriate urinary catheter use among hospitalized older patients by gender. A longitudinal study of 321 patients with urinary catheter was conducted. Demographic factors, present health factors, urinary catheter factors, and indications of catheter use were collected. A total of 53.7% of urinary catheter-days were inappropriate. For both men and women, there was no significant difference in the incidence and common rationales of inappropriate use. Women, however, have another associated factor with inappropriate use. More tailored alternatives are needed for women to increase comfort to avoid inappropriate catheter use.

A series of five-membered ring aluminum complexes bearing thiol-Schiff base ligands were synthesized, and their application in the ring-opening polymerization of ε-caprolactone (CL) was investigated. The complexes exhibited dramatically higher catalytic activity than the six-membered ring S 2 AlMe 2 complex (approximately 4- to 10-fold higher) and the five-membered ring L 5-Ph AlMe 2 complex (approximately 7- to 19-fold higher). Moreover, a shorter induction period was observed when the five-membered ring aluminum complexes bearing thiol-Schiff base ligands were used compared with the other types of aluminum complexes bearing Schiff base ligands. The electron-withdrawing groups enhanced the catalytic activity of the Al complexes compared with the electron donating groups. The thiol-Schiff base ligand and the five-membered ring aluminum catalysis had a synergistic effect that was stronger than the combination of their individual effects.

POU-homeodomain transcription factor POU3F2 is a critical transcription factor that participates in neuronal differentiation. However, little is known about its downstream mediators. Here genome-wide analyses of a human neuronal differentiation cell model, NT2D1, suggested neurotrophin-3 (NTF3), a key mediator of neuronal development during the early neurogenic period, as a putative regulatory target of POU3F2. Western blot, cDNA microarray, and real-time quantitative PCR analyses showed that POU3F2 and NTF3 were upregulated during neuronal differentiation. Next-generation-sequence-based POU3F2 chromatin immunoprecipitation-sequencing and genome-wide in silico prediction demonstrated that POU3F2 binds to the NTF3 promoter during neuronal differentiation. Furthermore, unidirectional deletion or mutation of the binding site of POU3F2 in the NTF3 promoter decreased promoter-driven luciferase activity, indicating that POU3F2 is a positive regulator of NTF3 promoter activity. While NTF3 knockdown resulted in decreased viability and differentiation of NT2D1 cells, and POU3F2 knockdown downregulated NTF3 expression, recombinant NTF3 significantly rescued viable neuronal cells from NTF3- or POU3F2-knockdown cell cultures. Moreover, immunostaining showed colocalization of POU3F2 and NTF3 in developing mouse neurons. Thus, our data suggest that NTF3 is a novel target gene of POU3F2 and that the POU3F2/NTF3 pathway plays a role in the process of neuronal differentiation.

Background: Systemic inflammation associated with sepsis can induce neuronal hyperexcitability, leading to enhanced seizure predisposition and occurrence. Brain microglia are rapidly activated in response to systemic inflammation and, in this activated state, release multiple cytokines and signaling factors that amplify the inflammatory response and increase neuronal excitability. NADPH oxidase (NOX) enzymes promote microglial activation through the generation of reactive oxygen species (ROS), such as superoxide anion. We hypothesized that NOX isoforms, particularly NOX2, are potential targets for prevention of sepsis-associated seizures., Methods: To reduce NADPH oxidase 2-derived ROS production, mice with deficits of NOX regulatory subunit/NOX2 organizer p47 phox (p47 phox-/- ) or NOX2 major subunit gp91 phox (gp91 phox-/- ) were used or the NOX2-selective inhibitor diphenyleneiodonium (DPI) was used to treat wild-type (WT) mice. Systemic inflammation was induced by intraperitoneal injection of lipopolysaccharide (LPS). Seizure susceptibility was compared among mouse groups in response to intraperitoneal injection of pentylenetetrazole (PTZ). Brain tissues were assayed for proinflammatory gene and protein expression, and immunofluorescence staining was used to estimate the proportion of activated microglia., Results: Increased susceptibility to PTZ-induced seizures following sepsis was significantly attenuated in gp91 phox-/- and p47 phox-/- mice compared with WT mice. Both gp91 phox-/- and p47 phox-/- mice exhibited reduced microglia activation and lower brain induction of multiple proconvulsive cytokines, including TNFα, IL-1β, IL-6, and CCL2, compared with WT mice. Administration of DPI following LPS injection significantly attenuated the increased susceptibility to PTZ-induced seizures and reduced both microglia activation and brain proconvulsive cytokine concentrations compared with vehicle-treated controls. DPI also inhibited the upregulation of gp91 phox transcripts following LPS injection., Conclusions: Our results indicate that NADPH oxidases contribute to the development of increased seizure susceptibility in mice after sepsis. Pharmacologic inhibition of NOX may be a promising therapeutic approach to reducing sepsis-associated neuroinflammation, neuronal hyperexcitability, and seizures.

Novel comb-shaped amphiphilic copolymers based on methoxy poly(ethylene glycol)-b-[poly(ε-caprolactone)-g-poly(methacrylic acid)] (MPCL-g-pMAA), were synthesized via ring opening polymerization (ROP) and atom transfer radical polymerization (ATRP) for drug delivery systems. MPCL-g-pMAAs with various MAA repeating units self-assemble into a core-shell structure in an aqueous solution. Critical aggregation concentrations range within 5.6×10 -3 -7.0×10 -2 mg/mL in double deionized water and 8.9×10 -3 -7.0×10 -2 mg/mL in phosphate buffered saline of pH 7.4, decreasing with increase in pMAA length. The carboxylic groups of MPCL-g-pMAAs were utilized to coordinate cisplatin, forming polymer-metal complexes for chemotherapy. The average hydrodynamic diameters of particles are within 220-246nm, slightly dependent on pMAA length. However, the cisplatin-loaded MPCL-g-pMAAs particles have average hydrodynamic diameters of 263-412nm owing to increasing drug loading efficiency with increase in pMAA length. Nevertheless, the MPCL-g-pMAA with the least number of MAA repeating unit shows the fastest drug release rate as well as the highest cytotoxicity against CRL-5802 cells. The cellular uptake of MPCL-g-pMAA particles, involving mainly clathrin-mediated endocytosis, increases with incubation time. MPCL-g-pMAA particles are non-cytotoxic to CRL-5802 cells but the cisplatin-loaded MPCL-g-pMAA particles show profound cell-killing ability. The MPCL-g-pMAA is a potential carrier for drug delivery systems., (Copyright © 2017 Elsevier B.V. All rights reserved.)

A series of dinuclear aluminum (Al 2 Pyr 2 ) complexes bridged by two pyrazole ligands were synthesized, and their catalytic activity toward ring-opening polymerization of ε-caprolactone (CL) was investigated. Different types of the Al-N-N-Al-N-N skeletal ring were found among these Al 2 Pyr 2 complexes. The butterfly form, L Thio 2 Al 2 Me 4 , exerted the highest catalytic activity for CL polymerization. κ 2 -CL coordination with both Al centers within the butterfly form L Thio 2 Al 2 Me 4 facilitates the initiation process. Generally speaking, the Al 2 Pyr 2 complexes exhibited substantially higher catalytic activity for CL polymerization than literature examples such as β-diketiminate- or traiaza-bearing aluminum complexes. In fact, the Al 2 Pyr 2 complexes can even carry out CL polymerization at room temperature.

β-Diketiminato copper(I) complexes play important roles in bioinspired catalytic chemistry and in applications to the materials industry. However, it has been observed that these complexes are very susceptible to disproportionation. Coordinating solvents or Lewis bases are typically used to prevent disproportionation and to block the coordination sites of the copper(I) center from further decomposition. Here, we incorporate this coordination protection directly into the molecule in order to increase the stability and reactivity of these complexes and to discover new copper(I) binding motifs. Here we describe the synthesis, structural characterization, and reactivity of a series of unsymmetrical N-aryl-N'-alkylpyridyl β-diketiminato copper(I) complexes and discuss the structures and reactivity of these complexes with respect to the length of the pyridyl arm. All of the aforementioned unsymmetrical ß-diketiminato copper(I) complexes bind CO reversibly and are stable to disproportionation. The binding ability of CO and the rate of pyridyl ligand decoordination of these copper(I) complexes are directly related to the competition between the degree of puckering of the chelate system and the steric demands of the N-aryl substituent.

A series of sodium complexes bearing NNO-tridentate Schiff base ligands with an N-pendant arm were synthesized and used as catalysts for the ring-opening polymerization of L-lactide (L-LA). Electronic effects of ancillary ligands coordinated by sodium complexes substantially influence the catalysis, and ligands with electron-donating groups increase the catalytic activity of the sodium complexes for catalyzing L-LA polymerization. In particular, a sodium complex bearing a 4-methoxy group has the highest activity with conversion up to 95% within 30 s at 0 °C and a low polydispersity index of 1.13, whereas the 4-bromo group showed the poorest performance with regard to the catalytic rate of L-LA polymerization in the presence of benzyl alcohol (BnOH). (1)H NMR pulsed-gradient spin-echo diffusion experiments and single-crystal X-ray analyses showed that sodium complexes [L(H)Na(THF)]2 and [L(4-Cl)Na(THF)]2 were dinuclear species in both solution and the solid state. The kinetic results indicated a first-order dependence on each of [[L(4-Cl)Na]2], [l-LA], and [BnOH].

A series of titanium (Ti) complexes bearing hydrazine-bridging Schiff base ligands were synthesized and investigated as catalysts for the ring-opening polymerization (ROP) of L-lactide (LA). Complexes with electron withdrawing or steric bulky groups reduced the catalytic activity. In addition, the steric bulky substituent on the imine groups reduced the space around the Ti atom and then reduced LA coordination with Ti atom, thereby reducing catalytic activity. All the dinuclear Ti complexes exhibited higher catalytic activity (approximately 10-60-fold) than mononuclear L(Cl-H)-TiOPr2 did. The strategy of bridging dinuclear Ti complexes with isopropoxide groups in the ROP of LA was successful, and adjusting the crowded heptacoordinated transition state by the bridging isopropoxide groups may be the key to our successful strategy.

A series of Al complexes bearing Schiff base and thio-Schiff base ligands were synthesized, and their application for the ring-opening polymerization of ε-caprolactone (CL) and l-lactide (LA) was studied. It was found that steric effects of the ligands caused higher polymerization rate and most importantly the Al complexes with N,S-Schiff base showed significantly higher polymerization rate than Al complexes with N,O-Schiff base (5-12-fold for CL polymerization and 2-7-fold for LA polymerization). The reaction mechanism of CL polymerization was investigated by density functional theory (DFT). The calculations predicted a lower activation energy for a process involved with an Al complex bearing an N,S-Schiff base ligand (17.6 kcal/mol) than for that of an Al complex bearing an N,O-Schiff base ligand (19.0 kcal/mol), and this magnitude of activation energy reduction is comparable to the magnitude of rate enhancement observed in the experiment. The reduction of activation energy was attributed to the catalyst-substrate destabilization effect. Using a sulfur-containing ligand to decrease the activation energy in the ring-opening polymerization process may be a new strategy to design a new Al complex with high catalytic activity.

Background: Strategies combining anti-vascular therapy and vascular imaging may facilitate the prediction of early response and outcome in cancer treatment., Objective: The aim of this study was to investigate the relationship between the tumor-associated vasculature in melanoma and to develop an approach for melanoma treatment by utilizing the free form and micelle form of the photosensitizer (PS) chlorin e6 in photodynamic therapy (PDT)., Methods: Green fluorescence protein (GFP) expressing B16-F10 melanoma cells were implanted into the mouse ear dermis. Ce6 in free form or in micelle form was administered via the tail vein. An OV100 imaging system was used to record the red fluorescence of Ce6 to obtain real-time vascular images in the GFP tumor., Results: Compared to free Ce6, Ce6 linked to the micelle-nanocarrier depicted a much clearer vascular image and had an effective vascular destruction by PDT. Micelle Ce6 was localized in lysosomes and in the endoplasmic reticulum of cultured endothelial cells, implying an active endocytosis of the nano-carrier., Conclusion: Micelle Ce6 can serve as a bifunctional PS for vascular imaging and PDT, which facilitates its delivery in the tumor microenvironment., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Previous studies on the ring-opening polymerization of ε-caprolactone using structurally related aluminum complexes as pre-catalysts showed inconsistent trends in the total conversion time. We propose that an induction period for Al complexes for conversion to real catalytic species, Al alkoxide, should be considered because the total conversion time consists of both an induction period and polymer propagation time. Herein, the polymerization rate of a series of Al complexes bearing ketimine ligands was investigated. The catalytic results indicated complexes with more steric hindrance with an electron-withdrawing group on the ligands, or the fact that less chelating ligands demonstrated greater propagation activity. The opposite trend for these structural effects was observed on the measurement of induction periods. These features on ligands of aluminum complexes are responsible for facilitating the conversion process to Al alkoxides. The overall catalytic performance should consider both the induction period and the propagation time.

Serum magnesium (Mg) levels are closely controlled through a variety of Mg transporters and ionic channels during physiological conditions. These levels have been shown to increase during exercise. However, the effect of Mg transporter expression during exercise remains to be determined. The purpose of this study was to examine the gene expression of SLC41A1, a Na + /Mg 2+ exchanger, during exercise. In the present study, male C57BL/6JNarl mice (n=16, 8 weeks old) were subjected to 3 h forced exercise on a treadmill. The mice in the control and Mg groups were injected with saline and Mg (MgSO 4 , 90 mg/kg, intraperitoneal), respectively. Blood samples were obtained at three time points: prior to, following and 24 h after exercise. The gene expression levels of SLC41A1 were significantly downregulated to 23.6±4.6 and 12.6±10.2% following exercise in the control and Mg groups, respectively. The expression levels returned to the basal levels 24 h after exercise in the two groups and there was no significant difference found between the two groups. The downregulated role of SLC41A1 expression and its interaction with the Mg status in exercise requires further investigation.

Chondroitin sulfate-g-poly(ε-caprolactone) (CP) copolymers were synthesized via atom transfer radical addition (ATRA). The CP copolymers self-assembled into micelles in water, and the micelles could be used to encapsulate a hydrophobic anticancer drug, camptothecin (CPT), in the core for tumor targeting delivery. The physicochemical properties of the micelles and CPT-loaded micelles were thoroughly characterized. For the in vitro test, the CPT release, the protection of the lactone ring of CPT from hydrolysis and the cellular uptake of CPT were studied. The cell-killing and apoptosis-inducing effects using the CPT-loaded micelles were significantly better than using free CPT against CRL-5802 cells. The micellar internalization into CRL-5802 cells was primarily via CD44 and clathrin dual-mediated endocytosis. For the in vivo test, the therapeutic efficacy of the CPT-loaded micelles was studied in a non-small-cell lung cancer xenograft animal model. The CPT-loaded micelles showed good inhibition in tumor growth as compared with a commercial product, CPT-11, in CRL-5802 tumor-bearing mice. The in vitro and in vivo data suggested the CP-based micelles are promising anticancer drug vehicles for lung cancer targeting.

Objective: To evaluate the effect of Shin-I essential oil inhalation on blood lactate changes in rats subjected to treadmill exercise., Methods: : Adult male Sprague Dawley rats (n=12) were randomly divided into the control or the Shin-I group. Rats were subjected to a treadmill exercise program (15 m/min for 30 min). After exercise, rats were exposed to 200 µL of water or Shin-I essential oil, respectively, using a nebulizer for 180 min during the recovery period. Blood samples were collected every 15 min. Blood glucose and lactate concentrations were determined in a CMA 600 analyzer., Results: : The basal glucose and lactate levels were no significantly different between two groups. After exercise, glucose levels were slightly increased to about 110%-120% of the basal level in both groups. Lactate levels of both groups reached to 110%-140% of basal levels during exercise. In the recovery period, lactate levels further increased to 180% of the basal level and were maintained at a plateau in the control group. However, lactate levels gradually decreased to 60%-65% of the basal level in the Shin-I group. Lactate clearance was significantly enhanced after Shin-I essential oil inhalation., Conclusions: : Our results provide evidence that Shin-I essential oil inhalation may accelerate recovery after exercise in rats.

Glucose mobilization and utilization in the periphery and central nervous system are important during exercise and are responsible for exercise efficacy. Magnesium (Mg) is involved in energy production and plays a role in exercise performance. This study aimed to explore the effects of Mg on the dynamic changes in glucose and lactate levels in the muscle, blood and brain of exercising rats using a combination of auto-blood sampling and microdialysis. Sprague-Dawley rats were pretreated with saline or magnesium sulfate (MgSO4, 90 mg/kg, i.p.) 30 min before treadmill exercise (20 m/min for 60 min). Our results indicated that the muscle, blood, and brain glucose levels immediately increased during exercise, and then gradually decreased to near basal levels in the recovery periods of both groups. These glucose levels were significantly enhanced to approximately two-fold (P<0.05) in the Mg group. Lactate levels in the muscle, blood, and brain rapidly and significantly increased in both groups during exercise, and brain lactate levels in the Mg group further elevated (P<0.05) than those in the control group during exercise. Lactate levels significantly decreased after exercise in both groups. In conclusion, Mg enhanced glucose availability in the peripheral and central systems, and increased lactate clearance in the muscle during exercise.

Two pentanuclear copper(I) thiolato clusters of the formula [Cu(5)(L)(3)](-) (L = pyridine-2,6-dimethanethiolate (L1), (1); 4-methylpyridine-2,6-dimethanethiolate (L2), (2)) were synthesized utilizing a single-step procedure, and their structures were characterized by X-ray crystallography. The aforementioned pentanuclear complexes possess an interesting propeller-like Cu(5)S(6) core where all Cu centers are three-coordinate. Electrospray ionization mass spectrometry (ESI-MS) investigation of the pentanuclear copper(I) thiolato clusters with added hetero-ligands demonstrated interesting ligand exchange behavior. The product distribution resulting from ligand exchange not only depended on the quantity of added ligand, but also was sensitive to the coordination ability of the ligand. The ESI-MS method used in this study can serve as a useful tool for probing exchange behavior in coordination metal complexes that cannot otherwise be determined by NMR., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The monomeric title complex, [Zn(C14H12NOS)2]·2CHCl3 or L2Zn·2CHCl3, where L is the 2-({[2-(methyl-sulfan-yl)phen-yl]imino}-meth-yl)phenolate anion, may be obtained by the reaction of LZnEt with benzyl alcohol or by the reaction of two equivalents of LH with ZnEt2 in tetra-hydro-furan. The Zn atom, located on a twofold axis, is four-coordinated in a distorted tetra-hedral geometry by two O atoms [Zn-O = 1.9472 (19) Å] from the phenolate anions and two imine N atoms [Zn-N = 2.054 (2) Å].

The new copper(I) nitro complex [(Ph(3)P)(2)N][Cu(HB(3,5-Me(2)Pz)(3))(NO(2))] (2), containing the anionic hydrotris(3,5-dimethylpyrazolyl)borate ligand, was synthesized, and its structural features were probed using X-ray crystallography. Complex 2 was found to cocrystallize with a water molecule, and X-ray crystallographic analysis showed that the resulting molecule had the structure [(Ph(3)P)(2)N][Cu(HB(3,5-Me(2)Pz)(3))(NO(2))]·H(2)O (3), containing a water hydrogen bonded to an oxygen of the nitrite moiety. This complex represents the first example in the solid state of an analogue of the nitrous acid intermediate (CuNO(2)H). A comparison of the nitrite reduction reactivity of the electron-rich ligand containing the CuNO(2) complex 2 with that of the known neutral ligand containing the CuNO(2) complex [Cu(HC(3,5-Me(2)Pz)(3))(NO(2))] (1) shows that reactivity is significantly influenced by the electron density around the copper and nitrite centers. The detailed mechanisms of nitrite reduction reactions of 1 and 2 with acetic acid were explored by using density functional theory calculations. Overall, the results of this effort show that synthetic models, based on neutral HC(3,5-Me(2)Pz)(3) and anionic [HB(3,5-Me(2)Pz)(3)](-) ligands, mimic the electronic influence of (His)(3) ligands in the environment of the type II copper center of copper nitrite reductases (Cu-NIRs).

A series of lithium and sodium iminophenoxide complexes have been successfully synthesized and characterized by X-ray crystallography and investigated as catalysts for the ring opening polymerization of L-lactide. The nature and steric bulk of the ligands coordinated to the central metal ions greatly influence the catalytic properties. Complexes with bidenate ligands exhibit higher catalytic activity than tridentate counterparts because the third coordination atom contends with L-lactide, which decreases activity. Oxygen is the third atom in the tridentate ligand, providing stronger chelation ability with Li and Na than nitrogen or sulfur and occupies the space with which L-lactide is coordinated.