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.

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.

Downhole parameter prediction method based on multi-layer water injection model and historical data-based model parameter identification.

Wireless communication has become a preferred direction for the development of layered water injection tools due to its low cost and high reliability. However, the wireless system relies on the underground battery for power supply，and each communication will consume a significant amount of energy. In order to save energy consumption, the wireless system adopts the intermittent sleep communication mode, with intervals of usually more than one month. During the idle time of communication, the downhole parameters such as pressure and flowrate will change as the pressure and flowrate at the wellhead. Therefore, it is crucial to predict downhole parameters based on the wellhead pressure and flowrate. In this study, a downhole parameter prediction method based on multi-layer water injection model is proposed. A multilayer injection prediction model was established based on the hydraulic analysis of the tubing string, and the model parameters were identified and updated using the historical data uploaded each time. The pressure and flow rate measured at the wellhead were used as inputs to the model, and the recursive relationship between layers in the multilayer model was utilized to predict downhole parameters for each layer. A model parameter optimization method based on time-weighting is proposed in order to address the gradual changes in model parameters during water injection. This method assigns greater weight to more recent historical data, resulting in optimized model parameters. Experimental results show that the proposed method can effectively predict the flowrate and pressure of each layer, with a prediction deviation of less than 5% F.S., which provides technical support for the application and popularization of the wireless layered water injection system.

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/.

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.

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.

[Development of a first-class undergraduate major in bioengineering facing the emerging engineering direction of biomedicine].

In the "Tutorial for outline of the healthy China 2030 plan", biomedicine was listed as a key planning and development area. Shanghai government also lists biomedicine as an emerging pillar industry. The rapid development of biomedicine industry put higher requirement for talents. Taking the idea of cross integration, mutually beneficial development, inheritance and innovation, the School of Biotechnology of East China University of Science and Technology organically integrates bioengineering and pharmaceutical majors to develop a new undergraduate engineering program of biomedicine, which specially reforms the talent training practice from the aspects of developing a "trinity teaching" standard system, a "three integration, three convergence" curriculum system, and a "three comprehensive education" innovative talent training system. We put forward the trinity of "value guidance, knowledge system, technology and non-technical core competence literacy" to foster emerging biomedicine engineering talents, and developed a comprehensive innovative talents training mode featured by "covering class-in and class-out, covering every student, and covering ideology and curriculum". Moreover, we established effective connections between courses and training goals, between general education courses and professional courses, and between top-notch talent training systems and training programs. Based on the achievements of teaching reform of the emerging engineering program "intelligent bio-manufacturing", the experience we obtained may provide ideas for development of the first-class bioengineering major in China.

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/.

Development of gliclazide ionic liquid and the transdermal patches: An effective and noninvasive sustained release formulation to achieve hypoglycemic effects.

Ionic liquids (IL) technology provides a useful platform to achieve the topical delivery of therapeutic agents, because of its capability to improve skin permeability. While the majority of the researches aimed to achieve local action by topical IL delivery, systemic action of therapeutic agents by local topical application has rarely been reported. In the present work, Gliclazide (GLI), a second-generation sulfonylurea drug was transformed into an IL with tributyl(tetradecyl)phosphonium for the first time. The physicochemical properties of this IL were systematically characterized by DSC, TGA, FT-IR, NMR, and HPLC. The transdermal patch based on this IL was further prepared using DURO-TAK®87-4098. The fabricated gliclazide based ionic liquid [P6,6,6,14][GLI] transdermal patch displayed satisfactory in vitro and in vivo performance. The [P6,6,6,14][GLI] patch released 88.17% of the loaded drug within a 3-day period in the in vitro dissolution test, confirming its sustained release property. Meanwhile, GLI effectively permeated through the artificial skin from [P6,6,6,14][GLI] transdermal patch in the in vitro skin permeation test, with the permeation rate and lag time of 16.571 ± 0.328 µg/cm2/h and 3.027 ± 0.154 h respectively. The [P6,6,6,14][GLI] transdermal patch showed favorable PK profile in rat as compared with GLI oral suspension. The relative bioavailability of GLI reached 92.06% of GLI oral suspension, while the Cmax was significantly reduced. Most importantly, [P6,6,6,14][GLI] transdermal patch demonstrated superior hypoglycemic effect to the oral suspension both in the fasted and fed condition, confirming the feasibility of systemic action by local topical delivery of IL. In addition, the [P6,6,6,14][GLI] transdermal patch caused no skin irritation based on histopathological analysis.

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.

Development of a gliclazide ionic liquid and its mesoporous silica particles: an effective formulation strategy to improve oral absorption properties.

Ionic liquid (IL) technology provides a useful platform to enhance the oral absorption of therapeutic agents. In the present work, gliclazide (GLI), a second-generation sulfonylurea drug was transformed into an IL with tetrabutylphosphonium. The physicochemical properties of this IL were systematically characterized by DSC, TGA, FT-IR, NMR, and HPLC. For the further preparation development, a solution stability test was conducted. GLI-based IL could improve the solution stability in a neutral environment. To assess oral potential, the solubility characteristics including equilibrium solubility, 24 h kinetic saturation solubilities and supersaturation profiles were first explored. Significant enhancement of solubilities, supersaturation ratio and duration of supersaturation was found for the synthesized IL. Computational methodology was utilized to better understand the improved solubility results. From the simulated results, [TBP][GLI] showed a longer time period when the distance between cation and anion was far above the baseline and a higher deviation degree, indicating less stable ion pairs of [TBP][GLI] in an aqueous environment and it being easy for the cation and anion to tear apart and form interactions with water molecules. The prepared [TBP][GLI] exhibited intestinal transportation ability and safety as evidenced by the in vitro gastrointestinal tract artificial membrane permeability assays (GIT-PAMPA) and cytotoxicity experiments with Caco-2 cells. A mesoporous carrier, AEROPERL® 300 Pharma, was chosen to load the IL and then encapsuled into enteric capsules. The prepared oral capsules containing GLI-based IL loaded mesoporous silica particles released fast and could realize 100% release within 60 min.

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.

Enhancing the solubility of natural compound xanthotoxin by modulating stability via cocrystallization engineering.

A comprehensive cocrystal study for the insoluble natural pharmaceutical compound xanthotoxin (XT) was conducted, in which xanthotoxin-para aminobenzoic acid (XT-PABA) and xanthotoxin-oxalic acid (XT-OA) cocrystals were obtained. The xanthotoxin cocrystals were characterized by powder X-ray diffraction, thermal analysis, and FT-IR spectra, and the crystal structures were determined by single-crystal X-ray diffraction. Crystal structures and thermal analysis showed that XT-OA was more stable than XT-PABA. Energy framework calculation indicated that H-bond and π···π interactions generated in XT-OA were stronger than that in XT-PABA and xanthotoxin. The powder dissolution experiments of xanthotoxin and its cocrystals suggested the XT-OA cocrystal might be applied as an alternative formulation of API, on account of its enhanced solubility and stability in the hydrochloric acid buffer solution (pH 1.2). The cocrystallization engineering can prolong the enhanced apparent solubility via modulating the stability.

Investigating molecular interactions of high-loaded glipizide-HPMCAS microparticles by integrated experimental and modeling techniques.

Molecular interactions between drug and polymeric carriers are believed to be the key for high drug loading and better physical stability of micro-particles. However, molecular interactions between drug and polymer are still difficult to investigate using only experimental tools. In this study, high-loaded glipizide (GLP)/hydroxypropyl methylcellulose acetate succinate (HPMCAS) (1/1 w/w) micro-particles were prepared using an in situ pH-dependent solubility method. Molecular interactions within the micro-particles were investigated by integrated experimental and modeling techniques. The dissolution rate of GLP/HPMCAS micro-particles was significantly better than those of solid dispersions and physical mixtures. Scanning electron microscopy images showed that the polymer inhibited GLP recrystallization. Experimental (FTIR spectroscopy, differential scanning calorimetry, powder X-ray diffraction and nuclear magnetic resonance spectroscopy) and molecular dynamics simulation revealed that hydrogen-bonding was the key to the properties of the micro-particles. Our research developed high drug-loading GLP/HPMCAS micro-particles and investigated the interactions between drug and polymer at the molecular level. This integrated approach could be practical methodology for future formulation design.

Solvatochromism and mechanochromism observed in a triphenylamine derivative.

A donor-π-acceptor fluorescent dye, 4-[N,N-di(4-phenyl)amino]benzaldehyde 4-chlorobenzoyl hydrazone (TPA-CBH), based on a triphenylamine derivative (TPA) and 4-chlorobenzoyl hydrazine (CBH) was designed and synthesized. The optical properties of this luminogen were investigated in solutions as well as in the solid states. In the intramolecular charge-transfer (CT) mechanism, TPA-CBH exhibits solvatochromism when dissolved in various polar solvents. Aggregation-induced emission was observed with the changes of tetrahydrofuran/water ratios. In the solid state, mechanochromic fluorescence is observed when the samples are stressed under different conditions. Based on structural analyses and theoretical calculations, it is found that intra- and intermolecular CT processes play a key role in the diversity of fluorescent properties.

Antisolvent Recrystallization Strategy to Screen Appropriate Carriers to Stabilize Filgotinib Amorphous Solid Dispersions.

Drugs in amorphous solid dispersions (ASDs) are highly dispersed in hydrophilic polymeric carriers, which also help to restrain recrystallization and stabilize the ASDs. In this study, microscopic observation after antisolvent recrystallization was developed as a rapid screening method to select appropriate polymers for the initial design filgotinib (FTN) ASDs. Using solvent evaporation, FTN ASDs with the polymers were prepared, and accelerated experimentation validated this screening method. Fourier-transform infrared spectroscopy, Raman scattering, and nuclear magnetic resonance revealed hydrogen-bonding formation in the drug-polymer binary system, which was critical for ASDs stabilization. A Flory-Huggins interaction parameter and water sorption isotherms were applied to evaluate the strength of the interaction between FTN and the polymers. The dissolution rate was also significantly improved by ASDs formulation, and the presence of the polymers exerted solubilization effects. These results suggested the efficacy of this screening method as a preliminary tool for polymer selection in ASDs design.

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.

Complexes of Felodipine Nanoparticles With Zein Prepared Using a Dual Shift Technique.

To improve the dissolution of felodipine, felodipine-zein complexes were prepared using a dual shift technique, with zein as both stabilizer and carrier. The complexes were characterized by particle size, zeta potential, morphology, crystalline properties, and release behavior. The complexes could be prepared in high yield and showed good redispersibility. The mean diameters of the felodipine particles in complexes were 150-300 nm, with negative zeta potentials of -30 to -25 mV after rehydration, and the particle sizes of the complexes were in the range 10-80 µm. The size of the felodipine nanoparticles incorporated into zein increased gradually with increasing drug content. Powder X-ray diffraction and differential scanning calorimetry indicated that felodipine in the complexes was markedly less crystalline than the pure drug. Both the rate and extent of dissolution of the complexes were significantly greater than those of the active pharmaceutical ingredient or physical mixtures. Spectroscopic analyses indicated that intermolecular interactions, especially hydrophobic interactions, are the major driving forces for the formation of the felodipine nanoparticles and contribute to the stabilization effect. This study provides a promising strategy for enhancing the dissolution rate of drugs using simplified preparation processes and showcases the design of zein-based oral delivery systems for bioactive components.

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.