Mir22hg facilitates ferritinophagy-mediated ferroptosis in sepsis by recruiting the m6A reader YTHDC1 and enhancing Angptl4 mRNA stability.

BACKGROUND: Ferritinophagy-mediated ferroptosis plays a crucial role in fighting pathogen aggression. The long non-coding RNA Mir22hg is involved in the regulation of ferroptosis and aberrantly overexpression in lipopolysaccharide (LPS)-induced sepsis mice, but whether it regulates sepsis through ferritinophagy-mediated ferroptosis is unclear. METHODS: Mir22hg was screened by bioinformatics analysis. Ferroptosis was assessed by assaying malondialdehyde (MDA), reactive oxygen species (ROS), and Fe2+ levels, glutathione (GSH) activity, as well as ferroptosis-related proteins GPX4 and SLC3A2 by using matched kits and performing western blot. Ferritinophagy was assessed by Lyso tracker staining and FerroOrange staining, immunofluorescence analysis of Ferritin and LC-3, and western blot analysis of LC-3II/I, p62, FTH1, and NCOA4. The bind of YTH domain containing 1 (YTHDC1) to Mir22hg or angiopoietin-like-4 (Angptl4) was verified by RNA pull-down and/or immunoprecipitation (RIP) assays. RESULTS: Mir22hg silencing lightened ferroptosis and ferritinophagy in LPS-induced MLE-12 cells and sepsis mouse models, as presented by the downregulated MDA, ROS, Fe2+, NCOA4, and SLC3A2 levels, upregulated GPX4, GSH, and FTH1 levels, along with a decrease in autophagy. Mir22hg could bind to the m6A reader YTHDC1 without affecting its expression. Mechanistically, Mir22hg enhanced Angptl4 mRNA stability through recruiting the m6A reader YTHDC1. Furthermore, Angptl4 overexpression partly overturned Mir22hg inhibition-mediated effects on ferroptosis and ferritinophagy in LPS-induced MLE-12 cells. CONCLUSION: Mir22hg contributed to in ferritinophagy-mediated ferroptosis in sepsis via recruiting the m6A reader YTHDC1 and strengthening Angptl4 mRNA stability, highlighting that Mir22hg may be a potential target for sepsis treatment based on ferroptosis.

TRPM7 mediates endoplasmic reticulum stress and ferroptosis in sepsis-induced myocardial injury.

Transient receptor potential melastatin 7 (TRPM7), a non-selective cation channel, was significantly upregulated in the blood of patients with sepsis. This study focuses on the preliminary exploration of the probable regulatory mechanism of TRPM7 in sepsis-induced myocardial injury (SIMI). HL-1 cardiac muscle cell line was treated with lipopolysaccharide (LPS) to mimic SIMI in vitro, and TRPM7 level was assessed. The impacts of TRPM7 knockdown on cellular inflammation response, oxidative stress, apoptosis, endoplasmic reticulum (ER) stress, and ferroptosis were identified. In order to explore the mechanism, ER stress agonist tunicamycin (TM) or ferroptosis inducer erastin was applied to treat HL-1 cells. The influences of TM and erastin on the aforementioned aspects were evaluated. TRPM7 was elevated in response to LPS stimulation, and its knockdown reduced the secretion of inflammatory factors and oxidative stress degree. Moreover, TRPM7 knockdown significantly suppressed cell apoptosis, ER stress, and ferroptosis. TM and erastin reversed the functions of TRPM7 knockdown, indicating ER stress and ferroptosis mediated in the regulation of TRPM7. This research proposes the possibility of TRPM7 as a marker or target for SIMI, and provides theoretical support for follow-up research.

Pharmaceutical Cocrystal Discovery via 3D-SMINBR: A New Network Recommendation Tool Augmented by 3D Molecular Conformations.

Cocrystals have significant potential in various fields such as chemistry, material, and medicine. For instance, pharmaceutical cocrystals have the ability to address issues associated with physicochemical and biopharmaceutical properties. However, it can be challenging to find proper coformers to form cocrystals with drugs of interest. Herein, a new in silico tool called 3D substructure-molecular-interaction network-based recommendation (3D-SMINBR) has been developed to address this problem. This tool first integrated 3D molecular conformations with a weighted network-based recommendation model to prioritize potential coformers for target drugs. In cross-validation, the performance of 3D-SMINBR surpassed the 2D substructure-based predictive model SMINBR in our previous study. Additionally, the generalization capability of 3D-SMINBR was confirmed by testing on unseen cocrystal data. The practicality of this tool was further demonstrated by case studies on cocrystal screening of armillarisin A (Arm) and isoimperatorin (iIM). The obtained Arm-piperazine and iIM-salicylamide cocrystals present improved solubility and dissolution rate compared to their parent drugs. Overall, 3D-SMINBR augmented by 3D molecular conformations would be a useful network-based tool for cocrystal discovery. A free web server for 3D-SMINBR can be freely accessed at http://lmmd.ecust.edu.cn/netcorecsys/.

Gain equalization for a few-mode erbium-doped fiber amplifier supporting eight spatial modes.

A trench-assisted ring few-mode erbium-doped fiber amplifier (FM-EDFA) supporting eight spatial modes is designed and proposed in this work. The gain equalization for the FM-EDFA is achieved by selecting the appropriate doping radius and concentration using a particle swarm optimization (PSO) algorithm when only the pump in the fundamental mode (L P 01) is applied. When the signals in the eight spatial modes are simultaneously amplified, the average modal gain is about 20 dB, and the DMG is less than 0.3 dB for a signal at 1550 nm. Considering the gain competition of six wavelength signals, the modal gain and DMG are more than 20 and 1 dB, respectively. In addition, the tolerance analysis for manufacturing with this design is also discussed. For a fluctuation in the refractive index, the average modal gain is about 19.5 dB, and the DMG is 0.77 dB, indicating that the structure has good fabrication tolerance.

Transdermal Delivery of Metformin Utilizing Ionic Liquid Technology: Insight Into the Relationship Between Counterion Structures and Properties.

PURPOSE: The purpose of the present study was to explore the feasibility of transdermal delivery of metformin, a commonly used oral antidiabetic drug, by ionic liquid (IL) technology. METHODS: Metformin hydrochloride (MetHCl) was first transformed into three kinds of ILs with different counterions. The physicochemical properties of the obtained ILs were characterized in depth. The simulation of stable configuration and calculation of interaction energies were conducted based on density functional theory (DFT). Skin-PAMPA was used to evaluate the intrinsic transdermal permeation properties. The cytotoxicity assay of these ILs was conducted using HaCaT cells to evaluate the toxicity to skin. These metformin ILs were then formulated into transdermal patch, and the transdermal potential was further evaluated using in vitro dissolution test and skin permeation assay. Finally, the pharmacokinetic profiles of these metformin IL-containing patches were determined. RESULTS: Among all the three Met ILs, metformin dihexyl sulfosuccinate (MetDH) with proper overall physiochemical and biological properties demonstrated the highest relative bioavailability. Metformin docusate (MetD) with the highest lipophilicity and intrinsic transdermal permeability exhibited the most significant sustained release profile in vivo. Both MetDH and MetD were the promising candidates for further clinical investigations. CONCLUSIONS: Overall, the properties of ILs were closely related to the structures of counterion. IL technology provided the opportunities to finely tune the solid-state and biological properties of Metformin and facilitated the successful delivery by transdermal route.

Graphene-coated double D-type low loss optical fiber modulator.

A graphene-coated double D-type low loss all-fiber modulator is proposed. The modulator is improved on the basis of standard fiber. Only the cladding is processed without grinding the original core structure. The upper and lower cladding are cut same distance. This can ensure that the mode field does not deviate in one direction, so that most of the mode field is still tied to the core, which greatly reduces the device loss. The existence of the double graphene layer can also ensure a very excellent modulation efficiency. The calculation results show that the mode loss of our proposed dual-D modulator under X polarization is 0.125 dB/mm, and the mode field mismatch loss is 0.25%. The mode loss in Y polarization is 0.033 dB/mm, and the mode field mismatch loss is 0.32%. When the modulation voltage is 5 V, the modulation depth is 78.4% under the condition of five-layer graphene, while the modulation speed can reach 15.38 GHz. Besides maintaining low modulation voltage and higher modulation efficiency, this structure makes full use of the advantages of good fiber coupling, and will be widely used in future fiber communications and all-fiber systems.

SMINBR: An Integrated Network and Chemoinformatics Tool Specialized for Prediction of Two-Component Crystal Formation.

Two-component crystals such as pharmaceutical cocrystals and salts have been proven as an effective strategy to improve physicochemical and biopharmaceutical properties of drugs. It is not easy to select proper molecular combinations to form two-component crystals. The network-based models have been successfully utilized to guide cocrystal design. Yet, the traditional social network-derived methods based on molecular-interaction topology information cannot directly predict interaction partners for new chemical entities (NCEs) that have not been observed to form two-component crystals. Herein, we proposed an effective tool, namely substructure-molecular-interaction network-based recommendation (SMINBR), to prioritize potential interaction partners for NCEs. This in silico tool incorporates network and chemoinformatics methods to bridge the gap between NCEs and known molecular-interaction network. The high performance of 10-fold cross validation and external validation shows the high accuracy and good generalization capability of the model. As a case study, top 10 recommended coformers for apatinib were all experimentally confirmed and a new apatinib cocrystal with paradioxybenzene was obtained. The predictive capability of the model attributes to its accordance with complementary patterns driving the formation of intermolecular interactions. SMINBR could automatically recommend new interaction partners for a target molecule, and would be an effective tool to guide cocrystal design. A free web server for SMINBR is available at http://lmmd.ecust.edu.cn/sminbr/.

Brillouin scattering induced by shear acoustic mode in a step-index fiber.

We present the mechanism of backward Brillouin scattering induced by shear acoustic mode (SAM) in a step-index fiber. Unlike a longitudinal acoustic mode with negligible transverse displacement, a SAM has both considerable transverse and longitudinal displacements. During the light-sound coupling process, the fundamental and high-order SAMs can be guided and excited, ultimately generating a Brillouin gain spectrum with multipeak structure in a frequency range around 6 GHz. The interaction characteristics of the optical force with the displacement of all excited SAMs determine a partial cancellation effect, which is of great importance for the coupling coefficient of the optical-acoustic modes. The SAM-induced backward Brillouin scattering would provide a promising new approach for application such as multiparameter sensing.

Thermal poling of multi-wire array optical fiber.

We demonstrate in this paper thermal poling of multi-wire array fibers, which extends poling of fibers with two anodes to ~50 and ~500 wire array anodes. The second harmonic microscopy observations show that second order nonlinearity (SON) layers are developed surrounding all the rings of wires in the ~50 anode array fiber with poling of 1.8kV, 250°C and 30min duration, and the outer rings of the ~500 anode array fiber at lower poling temperature. Our simulations based on a two-dimensional charge dynamics model confirm this can be explained by the self-adjustment mechanism, and show the SON layers are induced from the outer rings to the inner rings.

Screen for Inhibitors of Crystal Growth to Identify Desirable Carriers for Amorphous Solid Dispersions Containing Felodipine.

The solvent-shift method was used to identify appropriate polymers that inhibit the growth of felodipine crystals by monitoring particle size in supersaturated drug solutions in the presence of different polymers. We speculated that there would be an intermolecular interaction between the selected polymer (zein) and felodipine by extrapolating the inhibitory effect on crystal growth and then used the selected polymer as a carrier to prepare solid dispersions. The formulations were characterized by crystalline properties, thermodynamics of mixing, dissolution behavior, and physical stability. Powder x-ray diffraction and differential scanning calorimetry experiments indicated that amorphous solid dispersions were formed when the proportion of felodipine was < 30% (w/w). Stability tests showed that a solid dispersion with 20% felodipine remained in an amorphous state and was stable under accelerated storage conditions for 6 months. The dissolution rates of solid dispersions were significantly greater than those of the active pharmaceutical ingredient or physical mixtures. Analysis by Fourier-transform infrared spectroscopy and Raman microspectroscopy indicated the formation of intermolecular interactions between zein and felodipine. The study demonstrates the successful application of the chosen polymer as a carrier in solid dispersions and validates the concept of extrapolating the inhibitory effect on crystal growth to intermolecular interactions.

Plasmonic in-plane total internal reflection: azimuthal polarized beam focusing and application.

Due to the characteristic of surface plasmon polaritons (SPP) excitation, radial polarized beams and circular polarized beams are widely used for plasmonic lens and plasmonic near field focusing. In this paper, a plasmonic lens based on in-plane total internal reflection (TIR) scheme is proposed and numerically demonstrated to achieve the simultaneous nanofocusing of azimuthal and radial polarized beams. By means of the in-plane TIR mechanism, the operation bandwidth of lens ranges from visible light to mid-infrared. The proposed structure has been utilized in the design of a plasmonic liquid refractive index sensor and is expected to find potential applications in near-field optical energy focusing, near-field imaging and sensing.

Simulating the space-charge field formation in thermally poled optical fibers: a new two-rate model for hydrogenated cations.

In thermally poled optical fibers, the second-order nonlinearity has been observed to be distributed in a narrow layer more than 10 µm beneath the anode surface, a result that cannot be explained by current models. In this Letter, we propose a new model based on slow migration of H3O+ and fast H+ migration related to the H3O+ concentration. The numerical simulation results show a narrow layer-shaped distribution of the induced second-order nonlinearity, which retains its magnitude and distribution profile in the migration process, and is in good agreement with the experimental observations.

Guiding terahertz orbital angular momentum beams in multimode Kagome hollow-core fibers.

We explore terahertz (THz) orbital angular momentum (OAM) modes supported in multimode Kagome hollow-core fibers. Numerical models are adopted to characterize the effective indices and confinement losses of vector modes over 0.2-0.9 THz, where two low-loss transmission windows are observed. Linearly combining the vector modes, THz OAM states can be generated. Covering a broad bandwidth of 0.25 THz, the purity values of OAM modes are beyond 0.9. Using numerical simulations, the hollow-core THz fibers with one and two rings of Kagome structures are also comparably investigated. We reveal that the OAM purity is dependent upon the confinement performance of THz fiber.

Bending effect characterization of individual higher-order modes in few-mode fibers.

We propose an approach to directly measure the bending effect on individual modes in few-mode fibers using a wavelength-scanning spatially and spectrally resolved imaging technique. By collecting a fiber output beam profile with a scanning wavelength at different bending diameters and analyzing the peaks of its Fourier transformation, we have distinguished higher-order modes (HOMs) of the fiber and investigated their group delay, beam profile, bend loss, and mode splitting individually. We have experimentally verified with a multilayer core fiber at 1-8 cm bending diameters that its HOMs experience more loss compared to lower-order modes, but delay at approximately the same speed as the bending diameter decreases. Mode splitting of the LP11 mode at a small bending diameter due to bending-induced birefringence is also observed and discussed. This method provides an efficient tool to study the bending effect on individual HOMs in fibers and could be extended to studying fiber stretching and twisting.

Two-dimensional tunable orbital angular momentum generation using a vortex fiber.

We demonstrate the two-dimensional tunable orbital angular momentum (OAM) generation in a ring-core (vortex) fiber. The LP11 mode generated by an all fiber fused coupler is coupled into a vortex fiber. Because the vector modes of the LP11 mode group in the vortex fiber are no longer degenerate, the mode status will change between linearly polarized modes (LPMs) and complex OAM modes periodically during propagation. The generated OAM can be tuned smoothly by filtering the mixed mode with different polarization directions or changing the wavelength at a certain polarization directions. The two-dimensional tuning of OAM from l=-1 to l=+1 is experimentally demonstrated in an all fiber OAM generator.

Discovery of potent 2,4-difluoro-linker poly(ADP-ribose) polymerase 1 inhibitors with enhanced water solubility and in vivo anticancer efficacy.

Poly (ADP-ribose) polymerase 1 (PARP1) is overexpressed in a variety of cancers, especially in breast and ovarian cancers; tumor cells that are deficient in breast cancer gene 1/2 (BRCA1/2) are highly sensitive to PARP1 inhibition. In this study, we identified a series of 2,4-difluorophenyl-linker analogs (15-55) derived from olaparib as novel PARP1 inhibitors. Four potent analogs 17, 43, 47, and 50 (IC50=2.2-4.4 nmol/L) effectively inhibited the proliferation of Chinese hamster lung fibroblast V-C8 cells (IC50=3.2-37.6 nmol/L) in vitro, and showed specificity toward BRCA-deficient cells (SI=40-510). The corresponding hydrochloride salts 56 and 57 (based on 43 and 47) were highly water soluble in pH=1.0 buffered salt solutions (1628.2 µg/mL, 2652.5 µg/mL). In a BRCA1-mutated xenograft model, oral administration of compound 56 (30 mg·kg-1·d-1, for 21 d) exhibited more prominent tumor growth inhibition (96.6%) compared with the same dose of olaparib (56.3%); in a BRCA2-mutated xenograft model, oral administration of analog 43 (10 mg·kg-1·d-1, for 28 d) significantly inhibited tumor growth (69.0%) and had no negative effects on the body weights. Additionally, compound 56 exhibited good oral bioavailability (F=32.2%), similar to that of olaparib (F=45.4%). Furthermore, the free base 43 of the hydrochloride salt 56 exhibited minimal hERG inhibition activity (IC50=6.64 µmol/L). Collectively, these data demonstrate that compound 56 may be an excellent drug candidate for the treatment of cancer, particularly BRCA-deficient tumors.

Vector mode conversion based on an asymmetric fiber Bragg grating in few-mode fibers.

We propose a vector mode conversion approach based on asymmetric fiber Bragg gratings (AFBGs) written in step-index fiber and vortex fiber, respectively. The mode coupling properties of AFBGs are numerically investigated. Compared to step-index fiber, the large mode separation in the vortex fiber is beneficial to extracting the desired vector mode at specific wavelengths. In addition, the polarization of incident light and the attenuation coefficient of index change distribution of the AFBG play critical roles in the mode coupling process. The proposed AFBG provides an efficient method to realize high-order vector mode conversion, and it shows great potential for orbital angular momentum multiplexing and fiber lasers with vortex beam output.

Linearly polarized orbital angular momentum mode purity measurement in optical fibers.

We presented a simple method for measuring the mode purity of linearly polarized orbital angular momentum (OAM) modes in optical fibers. The method is based on the analysis of OAM beam projections filtered by a polarizer. The amplitude spectrum and phase spectrum of a data ring derived from the beam pattern are obtained by Fourier transform. Then the coefficients of the mixed electric field expression can be determined and the mode purity can be obtained. The proposed method is validated and it is experimentally demonstrated in a two-mode fiber.

Characterization of ibuprofen microparticle and improvement of the dissolution.

The objective of this study was to prepare ibuprofen (IBP) microparticles by pH-change method and enhance the dissolution rate in vitro. Tween80 and Cremophor RH40 were selected as stabilizers to change the microparticles morphology. The microparticles were evaluated by dissolution profiles and characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), laser particle size analyzer, scanning electron microscope (SEM) and Fourier transform infrared spectroscopy (FTIR). IBP microparticle prepared with surfactants showed a significant increase in dissolution rate (more than three times within 10 min) and an obvious decrease in mean particle size. The morphology of microparticles was obviously changed. XRD and DSC results revealed that the crystalline state of the untreated IBP and the prepared IBP microparticles were similar. The crystallinity of microparticles produced might be lightly reduced by adding surfactants in preparation process. All results showed that it was useful to prepare high dispersion microparticle by adding surfactants in the preparation process for improving the dissolution.

A mixed solvent system for preparation of spherically agglomerated crystals of ascorbic acid.

The objective of this research was to develop a novel solvent system to prepare spherically agglomerated crystals (SAC) of ascorbic acid with improved flowability for direct compression. A spherical agglomeration method was developed by selecting the mixed solvents (n-butyl and ethyl acetate) as a poor solvent and the process was further optimized by using triangular phase diagram and particle vision measurement. Physiochemical properties of SAC were characterized and compared with original drug crystals. It showed that amount of poor solvent, ratio of solvent mixture, and drug concentration are critical for preparation of SAC with desirable properties. The solid state of SAC was same as original crystals according to DSC, XRD, and FT-IR results. There was no significant difference in solubility and dissolution rate of drug between SAC and original crystals. The flowability and packability of SAC as well as the tensile strength and elastic recovery of tablets made from SAC were all significantly improved when compared with original crystals and tablets from crystals. It is concluded that the present method was suitable to prepare SAC of ascorbic acid for direct compression.