Toward New Ion Conductive Liquids via Ionic Liquids.

In the current era that it is strongly expected the SDGs would be achieved, electrolyte solutions in electrochemical devices and processes are being studied from dilute and concentrated solutions, through inorganic molten salts, deep eutectic solvents, and ionic liquids, to super-concentrated solutions. Although concepts based on empirical laws such as the Walden rule and hydrodynamics such as the Stokes rule are still useful for ionic conduction in solution, it is expected that superionic conduction-like mechanisms that are scarcely found in conventional electrolytes. Here, the authors' recent results are described based on the local structure and speciation of ionic species in solution, focusing on protons and lithium ions.

A structural and electrochemical study of lithium-ion battery electrolytes using an ethylene sulfite solvent: from dilute to concentrated solutions.

We report the structural and electrochemical characteristics of lithium (Li)-ion battery (LIB) electrolyte solutions using an ethylene sulfite (ES) solvent that is used as an electrolyte additive for LIBs. From dilute to highly concentrated ES solutions with lithium bis(fluorosulfonyl)amide (LiFSA), the formation of Li-ion complexes was investigated using a combined Raman and infrared spectroscopy study with the aid of density functional theory (DFT) calculations to quantitatively determine their solvation and ion-pair structures depending on the Li salt concentration (cLi). The results reveal that, in the dilute solutions (<1.0 mol dm-3), Li-ions are fully solvated with ES molecules to form a tetrahedral-like [Li(ES)4]+ complex; however, with the increasing cLi (up to 2.5 mol dm-3), the Li-ion complex changes in structure to form contact ion-pairs coordinated with both ES and FSA anions. It also reveals that further increasing cLi to approximately 3.0 mol dm-3 leads to the ionic aggregate formation, i.e., multiple Li-ion complexes linked via several FSA anions. LiFSA/ES electrolyte solutions exhibited a reversible Li-ion insertion/deinsertion reaction into/from the graphite anode irrespective of cLi. This is due to the high-grade ES-derived passivation films on the electrode as a result of the preferential reductive decomposition of the ES molecules trapped within the Li-ion coordination sphere. According to the charge-discharge test, the concentrated LiFSA/ES solutions exhibited the high C-rate performance, which is superior to the concentrated electrolyte solutions using conventional organic solvents.

Regulation of Adipogenesis Through Differential Modulation of ROS and Kinase Signaling Pathways by 3,4'-Dihydroxyflavone Treatment.

Studies on adipogenesis may be important for regulating human and/or animal obesity, which causes several complications such as, type II diabetes, hypertension, and cardiovascular disease, thus giving rise to increased economic burden in many countries. Previous reports revealed that various flavonoids have anti-apoptotic, antioxidant, and cell differentiation-regulating activities with a number of physiological benefits, including protection from cardiovascular disease, cancers, and oxidative stress. As we found that the hydroxylation patterns of the flavonoid B ring are known to play a critical role in their function, we screened several flavonoids containing different numbers and positions of OH substitutions in B ring for their modulatory property on adipogenesis. In this study, we revealed the anti-adipogenic activity of the naturally derived flavonoid, 3,4'-dihydroxyflavone (3,4'-DHF) in murine 3T3-L1 pre-adipocytes and equine adipose-derived stromal cells (eADSCs). We found that treatment with 3,4'-dihydroxyflavone (3,4'-DHF) led to decreased expression of adipogenic markers and lipid deposition with differential modulation of ROS and kinase signaling pathways. Regulation of ROS generation through the differential modulation of ROS-regulating gene expression was revealed to have an important role in the suppression of adipogenesis and increase of osteogenesis in eADSCs following 3,4'-DHF treatment. These results suggest that the flavonoid 3,4'-DHF can be used to regulate adipogenesis in ADSCs, which has potential therapeutic application in regenerative medicine or health care for humans and many sport or companion animals. J. Cell. Biochem. 118: 1065-1077, 2017. © 2016 Wiley Periodicals, Inc.

Recent Advances in Disease Modeling and Drug Discovery for Diabetes Mellitus Using Induced Pluripotent Stem Cells.

Diabetes mellitus (DM) is a widespread metabolic disease with a progressive incidence of morbidity and mortality worldwide. Despite extensive research, treatment options for diabetic patients remains limited. Although significant challenges remain, induced pluripotent stem cells (iPSCs) have the capacity to differentiate into any cell type, including insulin-secreting pancreatic ß cells, highlighting its potential as a treatment option for DM. Several iPSC lines have recently been derived from both diabetic and healthy donors. Using different reprogramming techniques, iPSCs were differentiated into insulin-secreting pancreatic ßcells. Furthermore, diabetes patient-derived iPSCs (DiPSCs) are increasingly being used as a platform to perform cell-based drug screening in order to develop DiPSC-based cell therapies against DM. Toxicity and teratogenicity assays based on iPSC-derived cells can also provide additional information on safety before advancing drugs to clinical trials. In this review, we summarize recent advances in the development of techniques for differentiation of iPSCs or DiPSCs into insulin-secreting pancreatic ß cells, their applications in drug screening, and their role in complementing and replacing animal testing in clinical use. Advances in iPSC technologies will provide new knowledge needed to develop patient-specific iPSC-based diabetic therapies.

Molecular Mechanisms of the Anti-Obesity and Anti-Diabetic Properties of Flavonoids.

Obesity and diabetes are the most prevailing health concerns worldwide and their incidence is increasing at a high rate, resulting in enormous social costs. Obesity is a complex disease commonly accompanied by insulin resistance and increases in oxidative stress and inflammatory marker expression, leading to augmented fat mass in the body. Diabetes mellitus (DM) is a metabolic disorder characterized by the destruction of pancreatic ß cells or diminished insulin secretion and action insulin. Obesity causes the development of metabolic disorders such as DM, hypertension, cardiovascular diseases, and inflammation-based pathologies. Flavonoids are the secondary metabolites of plants and have 15-carbon skeleton structures containing two phenyl rings and a heterocyclic ring. More than 5000 naturally occurring flavonoids have been reported from various plants and have been found to possess many beneficial effects with advantages over chemical treatments. A number of studies have demonstrated the potential health benefits of natural flavonoids in treating obesity and DM, and show increased bioavailability and action on multiple molecular targets. This review summarizes the current progress in our understanding of the anti-obesity and anti-diabetic potential of natural flavonoids and their molecular mechanisms for preventing and/or treating obesity and diabetes.

Characterizing the Perceived Need for CRC Screening among the Elderly Living in Rural Areas in the Pacific Northwest US: Roles of Miscommunication, Experience of Discrimination, and Dependence.

PURPOSE: Increasing the perceived need for CRC screening can facilitate undertaking CRC screening. This study aims to identify factors associated with the need for CRC screening in rural populations. DESIGN: A cross-sectional online survey. SETTING: The survey was conducted in June - September 2022 in the rural areas of Alaska, Idaho, Oregon, and Washington, US. SUBJECTS: The subjects of this study were 250 adults (completion rate: 65%) aged 45-75 residing in rural Alaska, Idaho, Oregon, and Washington. MEASURES: Perceived need for CRC screening, internet usage for health purposes, demographics, and intrapersonal, interpersonal, community, and environmental characteristics. RESULTS: Perceived need for CRC screening were negatively associated with patient-provider miscommunication (ß = -.23, P < .001) and perceived discrimination (ß = -.21, P < .001), cancer fatalism (ß = -.16, P < .05), individualism (ß = -.15, P < .05), and dependence on community (ß = -.11, P < .05), but positively with compliance with social norms (ß = .16, P < .05), trust in health care providers (ß = .16, P < .05), knowledge about colorectal cancer (ß = .12, P < .05). CONCLUSIONS: Our study showed potential individual and situational characteristics that might help increase colorectal cancer screening. Future efforts might consider addressing discrimination in health care settings, improving patient-provider communication, and tailoring messaging to reflect the rural culture.

Analytical chemistry toward on-site diagnostics.

Analytical Chemistry, through quantitative and/or qualitative analysis (identification), is a discipline that involves the development of methodologies and the exploration of new principles to obtain answers to given problems. In situ analysis techniques have attracted attention for its ability to elucidate phenomena occurring and to evaluate amount of a certain component in substances at real time and biological samples as applications of such analysis technology. Lots of techniques have been performed to understand the fundamental phenomena in varied fields such as X-ray, vibrational, and electrochemical impedance spectroscopies and also analytical reagents that enable to semi-quantitative analysis just observation. In fact, applying various in situ techniques in analytical chemistry expands to the medical diagnosis, which leads to be able to detect early diseases. Here, we describe some of previous researches in many fields such as electrochemical device for energy storage, biology, environment, and pathology and briefly introduce our recent challenges to analytical chemistry toward the on-site diagnosis.

Tools for studying ion solvation and ion pair formation in ionic liquids: isotopic substitution Raman spectroscopy.

Isotopic H/D or 6/7Li substitution Raman spectroscopy was applied to new kinds of ionic liquids; N-methylimidazole (C1Im) and acetic acid (CH3COOH) as the pseudo-protic ionic liquid (pPIL), and both of the neat and the 2,2,3,3-tetrafluoropropyl ether (HFE) diluted Li-glyme solvate ionic liquids (SIL) [Li(Gn)][TFSA] (Gn, glyme n = 3 or 4); TFSA, bis(trifluoromethanesulfonyl)amide) to clarify the proton transfer or the Li+ solvation/ion pair formation. The isotopic substitution Raman (ISR) spectra were obtained as the difference between the samples containing the same composition except the substituted isotope. The calculated and theoretical ISR spectra were also evaluated for comparison. With the C1Im-CH3COOH(D) pPIL, the Raman bands attributable to the C1Im/C1HIm+ gave signals of differential shape, and they were well reproduced with the curve fitting by taking the small amount of C1HIm+ and CH3COO- generation into consideration. The ISR spectra for the SIL were well explained by the formation of the Li-TFSA contact ion pair (CIP) and the solvent shared ion pair (SSIP) in the [Li(G3)][TFSA] SIL. In addition, the ISR spectra for the HFE-diluted [Li(G4)][TFSA] SIL clearly proved that the HFE hardly coordinates to the Li+ in the HFE-diluted SIL. Here, the ISR spectroscopy is proposed as a new tool for studying the ion solvation and the ion pair formation in ionic liquids.

Modulation of Osteogenic Differentiation of Adipose-Derived Stromal Cells by Co-Treatment with 3, 4'-Dihydroxyflavone, U0126, and N-Acetyl Cysteine.

Background and Objectives: Flavonoids form the largest group of plant phenols and have various biological and pharmacological activities. In this study, we investigated the effect of a flavonoid, 3, 4'-dihydroxyflavone (3, 4'-DHF) on osteogenic differentiation of equine adipose-derived stromal cells (eADSCs). Methods and Results: Treatment of 3, 4'-DHF led to increased osteogenic differentiation of eADSCs by increasing phosphorylation of ERK and modulating Reactive Oxygen Species (ROS) generation. Although PD98059, an ERK inhibitor, suppressed osteogenic differentiation, another ERK inhibitor, U0126, apparently increased osteogenic differentiation of the 3, 4'-DHF-treated eADSCs, which may indicate that the effect of U0126 on bone morphogenetic protein signaling is involved in the regulation of 3, 4'-DHF in osteogenic differentiation of eADSCs. We revealed that 3, 4'-DHF could induce osteogenic differentiation of eADSCs by suppressing ROS generation and co-treatment of 3, 4'-DHF, U0126, and/or N-acetyl cysteine (NAC) resulted in the additive enhancement of osteogenic differentiation of eADSCs. Conclusions: Our results showed that co-treatment of 3, 4'-DHF, U0126, and/or NAC cumulatively regulated osteogenesis in eADSCs, suggesting that 3, 4'-DHF, a flavonoid, can provide a novel approach to the treatment of osteoporosis and can provide potential therapeutic applications in therapeutics and regenerative medicine for human and companion animals.

Local Structure of Li+ in Superconcentrated Aqueous LiTFSA Solutions.

It has been reported that aqueous lithium ion batteries (ALIBs) can operate beyond the electrochemical window of water by using a superconcentrated electrolyte aqueous solution. The liquid structure, particularly the local structure of the Li+, which is rather different from conventional dilute solution, plays a crucial role in realizing the ALIB. To reveal the local structure around Li+, the superconcentrated LiTFSA (TFSA: bis(trifluoromethylsulfonil)amide) aqueous solutions were investigated by means of Raman spectroscopic experiments, high-energy X-ray total scattering measurements, and the neutron diffraction technique with different isotopic composition ratios of 6Li/7Li and H/D. The Li+ local structure changes with the increase of the LiTFSA concentration; the oligomer ([Lip(TFSA)q](p-q)+ (q > 2) forms at the molar fraction of LiTFSA (xLiTFSA) > 0.25. The average structure can be determined in which two water molecules and two oxygen atoms of TFSA anion(s) coordinate to the Li+ in the superconcentrated LiTFSA aqueous solution (LiTFSA)0.25(H2O)0.75. In addition, the intermolecular interaction between the neighboring water molecules was not found, and the hydrogen-bonded interaction in the solution should be significantly weak. According to the coordination number of the oxygen atom (TFSA or H2O), a variety of TFSA- and H2O coordination manners would exist in this solution; in particular, the oligomer is formed in which the monodentate TFSA cross-links Li+.

Correction: Necrosis-inducing peptide has the beneficial effect on killing tumor cells through neuropilin (NRP-1) targeting.

[This corrects the article DOI: 10.18632/oncotarget.8719.].

Necrosis-inducing peptide has the beneficial effect on killing tumor cells through neuropilin (NRP-1) targeting.

The therapeutic efficacy of most anti-cancer drugs depends on their apoptosis-inducing abilities. Previously, we showed that a peptide containing the mitochondrial targeting domain (MTD) found in Noxa, a BH-3 only protein of Bcl-2 family, induces necrosis. Here, a fusion peptide of neuropilin-1 (NRP-1) targeting peptide and MTD peptide, designated tumor homing motif 17:MTD (TU17:MTD), was found to induce necrosis in cancer cells in vitro and to cause the regression of tumors when intravenously injected into mice bearing subcutaneous CT26 colorectal carcinoma tumors. The necrosis within tumor tissues was evident upon administering TU17:MTD. TU17:MTD penetrated into tumor cells by targeting to Neuropilin-1, which could be blocked by anti-NRP-1 antibody. The efficacy of TU17:MTD on tumor regression was higher than that of TU17:D(KLAKLAK)2, a fusion peptide of NRP-1 targeting peptide and a pro-apoptotic peptide. The necrotic cell death within tumor tissues was evident at day 1 after administering TU17:MTD systemically. Transplanted subcutaneous substantially reduced in size within two weeks and 5 days, respectively, with no apparent side effects. Together, these results propose that the pro-necrotic peptide MTD may present an alternative approach for development of targeted anti-cancer agents.

Efficient mRNA delivery with graphene oxide-polyethylenimine for generation of footprint-free human induced pluripotent stem cells.

Clinical applications of induced pluripotent stem cells (iPSCs) require development of technologies for the production of "footprint-free" (gene integration-free) iPSCs, which avoid the potential risk of insertional mutagenesis in humans. Previously, several studies have shown that mRNA transfer can generate "footprint-free" iPSCs, but these studies did not use a delivery vehicle and thus repetitive daily transfection was required because of mRNA degradation. Here, we report an mRNA delivery system employing graphene oxide (GO)-polyethylenimine (PEI) complexes for the efficient generation of "footprint-free" iPSCs. GO-PEI complexes were found to be very effective for loading mRNA of reprogramming transcription factors and protection from mRNA degradation by RNase. Dynamic suspension cultures of GO-PEI/RNA complexes-treated cells dramatically increased the reprogramming efficiency and successfully generated rat and human iPSCs from adult adipose tissue-derived fibroblasts without repetitive daily transfection. The iPSCs showed all the hallmarks of pluripotent stem cells including expression of pluripotency genes, epigenetic reprogramming, and differentiation into the three germ layers. These results demonstrate that mRNA delivery using GO-PEI-RNA complexes can efficiently generate "footprint-free" iPSCs, which may advance the translation of iPSC technology into the clinical settings.

3,2'-Dihydroxyflavone-Treated Pluripotent Stem Cells Show Enhanced Proliferation, Pluripotency Marker Expression, and Neuroprotective Properties.

Efficient maintenance of the undifferentiated status of embryonic stem cells (ESCs) may be important for preparation of high-quality cell sources that can be successfully used for stem cell research and therapy. Here we tried to identify a compound that can enhance the quality of pluripotent stem cells. Treatment of ESCs and induced pluripotent stem cells (iPSCs) with 3,2'-dihydroxyflavone (3,2'-DHF) led to increases in cell growth, colony formation, and cell proliferation. Treatment with 3,2'-DHF resulted in high expression of pluripotency markers (OCT4, SOX2, and NANOG) and significant activation (STAT3 and AKT) or suppression (GSK3ß and ERK) of self-renewal-related kinases. 3,2'-DHF-treated high-quality pluripotent stem cells also showed enhanced differentiation potential. In particular, treatment of iPSCs with 3,2'-DHF led to elevated expression of ectodermal differentiation markers and improved differentiation into fully matured neurons. Next, we investigated the in vivo effect of 3,2'-DHF-pretreated iPSCs (3,2'-DHF iPSCs) in a peripheral nerve injury model and found that transplantation of 3,2'-DHF iPSCs resulted in more efficient axonal regeneration and functional recovery than in controls. Upon histopathological and gene expression analyses, we found that transplantation of 3,2'-DHF iPSCs stimulated expression of cytokines, such as TNF-α, in the early phase of injury and successfully reduced convalescence time of the injured peripheral nerve, showing an effective neuroprotective property. Taken together, our data suggest that 3,2'-DHF can be used for more efficient maintenance of pluripotent stem cells as well as for further applications in stem cell research and therapy.

Biologically synthesized silver nanoparticles induce neuronal differentiation of SH-SY5Y cells via modulation of reactive oxygen species, phosphatases, and kinase signaling pathways.

Nano-scale materials are noted for unique properties, distinct from those of their bulk material equivalents. In this study, we prepared spherical silver nanoparticles (AgNPs) with an average size of about 30 nm and tested their potency to induce neuronal differentiation of SH-SY5Y cells. Human neuroblastoma SH-SY5Y cells are considered an ideal in vitro model for studying neurogenesis, as they can be maintained in an undifferentiated state or be induced to differentiate into neuron-like phenotypes in vitro by several differentiation-inducing agents. Treatment of SH-SY5Y cells by biologically synthesized AgNPs led to cell morphological changes and significant increase in neurite length and enhanced the expression of neuronal differentiation markers such as Map-2, ß-tubulin III, synaptophysin, neurogenin-1, Gap-43, and Drd-2. Furthermore, we observed an increase in generation of intracellular reactive oxygen species (ROS), activation of several kinases such as ERK and AKT, and downregulation of expression of dual-specificity phosphatases (DUSPs) in AgNPs-exposed SH-SY5Y cells. Our results suggest that AgNPs modulate the intracellular signaling pathways, leading to neuronal differentiation, and could be applied as promising nanomaterials for stem cell research and therapy.