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Neonatal jaundice is a common symptom that occurs in neonates during the first month of their life and is generally divided into physiological and pathological subtypes. In serious cases, pathological neonatal jaundice frequently shows complications including seizures, cerebral palsy, and kernicterus. However, due to the unclear pathogenesis of pathological neonatal jaundice, effective drugs for this disease remain unsatisfied. In the present study, we first estimated the protective effects of folic acid (FA) on phenylhydrazine (PHA) or homocysteine (Hcy)-injected neonatal rats (2-3 days aged). Intriguingly, we found that FA significantly decreased the elevated total bilirubin (TBIL) and direct bilirubin (DBIL) concentration, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) activity in PHA- or Hcy-injected rats, indicating that FA improves liver functions. Meanwhile, our results also showed that the plasma Hcy level and N-homocysteinylation (N-Hcy) modification of albumin were significantly elevated in the jaundice rats, which were obviously reversed after FA administration. Furthermore, we identified a novel N-Hcy modification site K545 of human serum albumin (HSA) using LC-MS/MS, and the mutagenesis assay in HEK293 further validated these observations. Besides, we demonstrated that the N-Hcy modification of albumin functionally inhibits the bilirubin-binding ability of albumin without altering its protein level both in vitro and in vivo. Altogether, we highlight a mechanism that FA reduces the plasma Hcy level and thereby enhance the bilirubin-binding ability of albumin, which may provide a novel therapeutic strategy for the treatment of pathological neonatal jaundice.

BackgroundCholestasis patients often suffer from pain desensitization, resulting in serious complications in perioperative period. This study was aim to investigate the mechanism of bilirubin in cholestasis mediating pain desensitization through 5-hydroxytryptamine 3A (5-HT3A) receptor activation in spinal dorsal horn (SDH).MethodsA cholestasis model was established by bile duct ligation (BDL) in rats. Pain thresholds of rats were measured after BDL or intrathecally injecting bilirubin in the presence or absence of agonist (mCPBG) and antagonists (ondansetron, bicuculline, or CGP55845). Expression of 5-HT3 receptors, and the affinity and binding mode of bilirubin to 5-HT3A receptor were determined. Effects of bilirubin on γ-aminobutyric acid (GABA) pathway and the interactions with 5-HT3A receptor were tested.ResultsBilirubin was elevated significantly in both serum and CSF in BDL rats, accompanied with the up-regulation of pain thresholds. Both of 5-HT3A receptor and GABAA receptor antagonists could reverse the increased pain threshold in BDL rats. Further, 5-HT3A and GABAA receptor expressions were increased in BDL rats or intervention with bilirubin. Molecular docking suggested that bilirubin entered the hydrophobic pocket pre-formed in 5-HT3A receptor with potential hydrogen bonding. Bilirubin also increased GABA concentrations in CSF and GABAergic spontaneous inhibitory postsynaptic current in spinal cord, and directly induced inward currents in HEK293 cells which were overexpressed 5-HT3A receptor by lentivirus.ConclusionIn conclusion, bilirubin induced pain desensitization in cholestasis by activating 5-HT3A receptor in spinal cord. The activation of 5-HT3A receptor might regulate pain threshold by acting on the GABA pathway.

Based on data from the World Health Organization, breast cancer is the most common type of cancer among women, accounting for about 15% of all cancer-related deaths. Thus, new treatment options are urgently needed to decrease this mortality rate. In recent years, mesoionic compounds have shown promising potential as anti-cancer agents due to their unique structure and reaction properties. We recently reported that a 1,3-thiazolium-5-thiolate mesoionic compound (MIH 2.4Bl) inhibited oxidative phosphorylation in the MCF-7 breast cancer cell line compared to normal human mammary epithelial cells. Furthermore, MIH 2.4Bl induced cytotoxicity by activating autography-related proteins (Beclin-1 and ATG5) and cell cycle arrest at the G2/M phase. Based on our previous findings, MIH 2.4BI is a promising candidate for treating breast cancer. However, a major challenge facing cancer therapeutics is tumor delivery in vivo for the selective destruction of malignant cells while sparing normal cells to preserve tissue integrity. The development and use of drug delivery systems is a recognized approach to improve the efficacy of chemotherapy agents. Nonetheless, drug delivery systems have been largely unexplored in the context of mesoionic compounds. Lipoproteins are ideal for carrying transporting lipophilic anti-cancer drugs and imaging agents as they circulate in the bloodstream for an extended period. In addition, the hydrophobic core of lipoprotein particles allows the incorporation of lipophilic components (including a number of anti-cancer agents). Reconstituted high-density lipoprotein (rHDL) mimics the structure and function of endogenous (i.e., human plasma) HDL and thus presents a potentially markedly improved therapeutic strategy for cancer drug delivery. Previous studies from our group have shown that a stable reconstituted synthetic rHDL-drug complex could be prepared by combining paclitaxel and other chemotherapy drugs using the natural lipid and protein components of circulating HDL via a novel procedure. In this preliminary work, we present an improved strategy of using a newly developed formulation of MIH 2.4BI compound with rHDL nanoparticles as the delivery agent. Also, physico-chemical characterization of the nanoparticles and cytotoxicity analyses using a panel of breast cancer cell lines were performed. These studies support the potential therapeutic use of MIH 2.4Bl in treating breast cancer. (D. Debnath and R.M. Petty contributed equally to this work) Citation Format: Dipti Debnath, R. Max Petty, Nirupama Sabnis, Jinmin Zhang, Andras G. Lacko, Helivaldo Diógenes Souza, Petrônio Filgueiras Filho, J. Michael Mathis, Rafal Fudala. An improved strategy for delivering the mesoionic compound MIH 2.4Bl utilizing reconstituted high density nanoparticles (rHDL) in treating breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 300.

Polymers of guanidinylated disulfide containing poly(amido amine)s (Gua-SS-PAAs), have shown high transfection efficiency and low cytotoxicity. Previously, we synthesized two Gua-SS-PAA polymers, using guanidino containing monomers (i.e., arginine and agmatine, denoted as ARG and AGM, respectively) and N,N'-cystaminebisacrylamide (CBA). In this study, these two polymers, AGM-CBA and ARG-CBA were complexed with plasmid DNA, and their uptake pathway was investigated. Complexes distribution in MCF-7 cells, and changes on cell endosomes/lysosomes and membrane after the cells were exposed to complexes were tested. In addition, how the transfection efficiency changed with the cell cycle status as well as endocytosis inhibitors were studied. The polymers of AGM-CBA and ARG-CBA can avoid endosomal/lysosomal trap, therefore, greatly delivering plasmid DNA (pDNA) to the cell nucleoli. It is the guanidine groups in the polymers that enhanced complexes' permeation through cell membrane with slight membrane damage, and targeting to the nucleoli. J. Cell. Biochem. 118: 903-913, 2017. © 2016 Wiley Periodicals, Inc.

Ternary photocatalyst, reduced graphene oxide-ZnFe 2 O 4 -polyaniline (RZP), has been successfully developed by the in-situ polymerization of aniline on the reduced graphene oxide-ZnFe 2 O 4 (RG/ZF) surface for sewage purification. The SEM, TEM and STEM images suggest that PANI has coated the RG/ZF composite well. The XRD, TG-DTG and FT-IR analysis confirm that there are some interactions between RG/ZF composite and PANI. Importantly, the decontamination performance of RZP composites has been investigated using RhB as a model organic in view of adsorption and photocatalysis. On one hand, thermodynamic researches indicate that the adsorption behaviors of RZP composites conform to the Langmuir model, and their adsorption mechanism can be well described by the second-order kinetic model. On the other hand, RZP composites with different mass ratios of PANI to RG/ZF ( m P/RZ ) present a better photocatalytic activity than that of RG/ZF composites, and their photocatalytic behaviors under different pH could be described by the first-order kinetic model. Furthermore, it can be observed that the RZP composite with m P/RZ = 0.4 has the excellent photocatalytic activity and photocatalytic stability under pH = 1. Finally, the possible photocatalytic degradation mechanisms of the RZP composite on RhB have been discussed. These results can unveil that the prepared RZP photocatalyst is very promising for application in water purification.

Magnetic reduced graphene oxide-ZnFe 2 O 4 composites (RG/ZF) were successfully prepared through a simple chemical co-precipitation method, and their composition, structure, and morphology were characterized by XRD, Raman, SEM, TEM and STEM. These results indicated that the as-prepared RGO with some defects and few reactive groups containing oxygen possessed the few-layered crystal structure, and the ZnFe 2 O 4 nanoparticles with spinel structure were homogeneously dispersed in the interlayer of graphene sheets. The interactions between two components had been investigated by TG and FT-IR. Importantly, kinetic researches indicated that the adsorption behavior of RG/ZF composite could be well described by the second-order kinetic model. Their adsorption effect on RhB conformed to the Langmuir model and belonged to the monolayer chemical adsorption, which were illustrated by thermodynamic experiment. In addition, RG/ZF composites with different mass ratio of RG to ZF ( m RG/ZF ) presented good photocatalytic activity, and their photocatalytic behavior could be described by the first-order kinetic model under different pH. Among all composites, the RG/ZF composite with m RG/ZF = 0.4 showed the best photocatalytic activity under pH = 1. However, the enhanced photocatalytic activity may arise from the effective separation of photogenerated e − -h + pairs and the positive synergetic effect between two components. Moreover, the obtained optimum RG/ZF composite had the saturation magnetization (9.8747 emu/g) enough to make it easy to be separated from solution by means of an external magnetic field. On the other hand, the antibacterial testing implied that the antibacterial properties of composite were depended on the m RG/ZF , and the RG/ZF with m RG/ZF = 0.4 likewise presented the most excellent antibacterial activity, especially to the C. albicans (its IZD and MID was respectively up to 34.5 mm and 12.5 μg/mL). Finally, the possible mechanisms of photocatalysis and antibacterial have been discussed.

Neuropathic pain (NP) remains a significant clinical problem worldwide. Toll-like rec e ptor 4 (TLR4) expressed on microglia in the spinal cord exert great influence on NP induced hyperalgesia. Impaired γ-aminobutyric acid (GABAergic) neuron activities in the spinal cordare also confirmed to be associated with NP progression. However, the role of TLR4 inducedmicroglial activation on impaired spinal GABAergic neuron activities inneuropathic painconditions remains unclear. Mechanical thr esholds were measured after intrathecal injectionof TLR4 inhibitor (TAK-242) or GABAA receptor agonist (muscimol) in male C57 mice. Microglialactivation, glutamic acid decarboxylase 65 (GAD65), as well as GABA concentrations incerebrospinal fluid (CSF) were further analyzed. Spontaneous inhibitory postsynaptic current(sIPSC) of GABAergic neurons were recorded using electrophysiological test. TLR4 expressionlevel was measured after chronic constriction injury (CCI) surgery and after intrathecaladministration of a TLR4 agonist (lipopolysaccharide, LPS) in naive mice.CCI surgery and TLR4agonist LPS treatment both induced hyperalgesia, while TLR4 inhibitor TAK-242 or GABAAreceptor agonist muscimol increased the mechanical thresholds in both CCI surgery andLPS-treated mice. Furthermore, decreased GAD65 fluorescence, GABA concentrations in CSFand sIPSC in CCI and LPS mice were a lleviated by TAK-242. Moreover, TAK-242 and microg lia activa tion inhibitor (minocycline) suppressed the enhanced microglial activation in CCI surgeryand LPS-treated mice, and GAD65 fluorescence and GABA concentrations were increased byminocycline intervention. Additionally, TLR4 expression levels were up-regulated followingCCI surgery and intrathecal administration of LPS. TLR4 suppresses spinal GABAergic neuronactivities viamicroglial activation.

Carbon microspheres with good dispersibility were synthesized by hydrothermal method using glucose as raw material. Taking the as-prepared carbon microsphere as the template, a series of hollow Zn1−x Ni x Fe2O4 spheres (x = 0–1 with interval of 0.2) were prepared by chemical precipitation method. The composition, morphology, electrical and magnetic properties of the hollow Zn1−x Ni x Fe2O4 spheres were characterized. The results of nitrogen adsorption–desorption isotherms indicates that the Zn1−x Ni x Fe2O4 catalyst with different Ni content presents different specific surface area. And the adsorption–photodegradation of samples on rhodamine B and methyl orange solutions were discussed. In addition, the influence of Ni content on material photocatalytic activity has been discussed. These results indicated that the recyclable ZnFe2O4 had a better decontaminating activity than other Zn1−x Ni x Fe2O4 spheres.

Jiankun Yu,1 Jinmin Zhang,1 Haonan Xing,1 Yanping Sun,1 Zhen Yang,1 Tianzhi Yang,2 Cuifang Cai,1 Xiaoyun Zhao,3 Li Yang,1 Pingtian Ding1 1School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China; 2Department of Basic Pharmaceutical Sciences, School of Pharmacy, Husson University, Bangor, ME, USA; 3Department of Microbiology and Cell Biology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China Abstract: Two different disulfide (SS)-containing poly(amidoamine) (PAA) polymers were constructed using guanidino (Gua)-containing monomers (ie, arginine [Arg] and agmatine [Agm]) and N,N'-cystamine bisacrylamide (CBA) by Michael-addition polymerization. In order to characterize these two Gua-SS-PAA polymers and investigate their potentials as short hairpin RNA (shRNA)-delivery carriers, pSilencer 4.1-CMV FANCF shRNA was chosen as a model plasmid DNA to form complexes with these two polymers. The Gua-SS-PAAs and plasmid DNA complexes were determined with particle sizes less than 90 nm and positive ζ-potentials under 20 mV at nucleic acid:polymer weight ratios lower than 1:24. Bioresponsive release of plasmid DNA was observed from both newly constructed complexes. Significantly lower cytotoxicity was observed for both polymer complexes compared with polyethylenimine and Lipofectamine 2000, two widely used transfection reagents as reference carriers. Arg-CBA showed higher transfection efficiency and gene-silencing efficiency in MCF7 cells than Agm-CBA and the reference carriers. In addition, the cellular uptake of Arg-CBA in MCF7 cells was found to be higher and faster than Agm-CBA and the reference carriers. Similarly, plasmid DNA transport into the nucleus mediated by Arg-CBA was more than that by Agm-CBA and the reference carriers. The study suggested that guanidine and carboxyl introduced into Gua-SS-PAAs polymers resulted in a better nuclear localization effect, which played a key role in the observed enhancement of transfection efficiency and low cytotoxicity. Overall, two newly synthesized Gua-SS-PAAs polymers demonstrated great potential to be used as shRNA carriers for gene-therapy applications. Keywords: short hairpin RNA, gene carrier, bioresponsive, guanidinylated disulfide-containing poly(amido amine), nuclear localization, transfection efficiency, cytotoxicity

A detailed theoretical study of the structural and elastic properties of magnesium silicide Mg2Si under isotropic lattice deformation has been performed based on the first-principles’ pseudopotential method. The results show that isotropic lattice deformation from 94% to 106% results in a linear decrease in the energy gap for the direct Γ15-Γ1 and indirect Γ15-L1 transitions, while the indirect band gap gT15-X1 increases within a range of 94%–104%, and then reduces over the range of 104%. Additionally, isotropic lattice deformation from 94% to 106% also causes a decrease in the elastic constants and modulus of Mg2Si. Furthermore, Mg2Si with lattice deformation from 94% to 106% is brittle, being most brittle at 94% lattice constant.

Graphical Abstract Unlabelled image, A cationic gene delivery vector, guanidinylated disulfide-containing poly(amido amine) (CAR-CBA), was synthesized by Michael addition reaction between N,N′-cystaminebisacrylamide (CBA) and guanidine hydrochloride (CAR). Gel permeation chromatography (GPC) was used to evaluate the molecular weight of synthesized CAR-CBA. Polyethyleneimine (PEI) with molecular weight of 25 kDa was adopted as a reference, and polyethylene glycols (PEG) with different molecular weights were used to establish a standard curve for determining the molecular weight of CAR-CBA. The effects of two critical factors, namely columns and eluents, on the molecular weight measurement of CAR-CBA were investigated to optimize the GPC quantitative method. The results showed that Ultrahydrogel columns (120, 250) and HAc–NaAc (0.5 M, pH 4.5) buffer solution were the optimal column and GPC eluent, respectively. The molecular weight of the synthesized CAR-CBA was analyzed by the optimized GPC method and determined to be 24.66 kDa.

Magnesium films of various thicknesses were first deposited on silicon (1 1 1) substrates by magnetron sputtering method and then annealed in annealing furnace filled with argon gas. The effects of the magnesium film thickness and the annealing temperature on the formation of Mg2Si films were investigated by means of X-ray diffraction (XRD) and scanning electron microscopy (SEM). The Mg2Si thin films thus obtained were found to be polycrystalline and the Mg2Si (2 2 0) orientation is preferred regardless of the magnesium film thickness and annealing temperature. XRD results indicate that high quality magnesium silicide films are produced if the magnesium/silicon samples are annealed at 400 °C for 5 h. Otherwise, the synthesized films annealed at annealing temperatures lower than 350 °C or higher than 450 °C contain magnesium crystallites or magnesium oxide. SEM images have revealed that microstructure grains in the polycrystalline films are about 1–5 μm in dimensions, and the texture of the Mg2Si films becomes denser and more homogeneous as the thickness of the magnesium film increases.

Autonomic dysfunction as a partial contributing factor to cardiovascular instability in jaundiced patients is often associated with increased serum bilirubin levels. Whether increased serum bilirubin levels could directly inhibit sympathetic ganglion transmission by blocking neuronal nicotinic acetylcholine receptors (nAChRs) remains to be elucidated. Conventional patch-clamp recordings were used to study the effect of bilirubin on nAChRs currents from enzymatically dissociated rat superior cervical ganglia (SCG) neurons. The results showed that low concnetrations (0.5 and 2 μM) of bilirubin enhanced the peak ACh-evoked currents, while high concentrations (3 to 5.5 µM) of bilirubin suppressed the currents with an IC50 of 4 ± 0.5 μM. In addition, bilirubin decreased the extent of desensitization of nAChRs in a concentration-dependent manner. This inhibitory effect of bilirubin on nAChRs channel currents was non-competitive and voltage independent. Bilirubin partly improved the inhibitory effect of forskolin on ACh-induced currents without affecting the action of H-89. These data suggest that the dual effects of enhancement and suppression of bilirubin on nAChR function may be ascribed to the action mechanism of positive allosteric modulation and direct blockade. Thus, suppression of sympathetic ganglionic transmission through postganglionic nAChRs inhibition may partially contribute to the adverse cardiovascular effects in jaundiced patients.

Semiconducting magnesium silicide (Mg2Si) thin films were synthesized by solid state reaction on Si substrates deposited at various sputtering powers. X-ray diffraction (XRD), Laser confocal Raman microscopy and Scanning electron microscopy (SEM) were used to characterize the crystal structure and surface morphology of the obtained Mg2Si films. XRD and Raman scattering spectra results show the formation of single phase Mg2Si thin films on Si substrates. SEM images show Mg2Si thin films on Si substrates with fine and compact grains were obtained. (© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)