High adsorption of ammonia in a titanium-based metal-organic framework.

We report the high adsorption of NH3 in a titanium-based metal-organic framework, MFM-300(Ti), comprising extended [TiO6]∞ chains linked by biphenyl-3,3',5,5'-tetracarboxylate ligands. At 273 K and 1 bar, MFM-300(Ti) shows an exceptional NH3 uptake of 23.4 mmol g-1 with a record-high packing density of 0.84 g cm-3. Dynamic breakthrough experiments confirm the excellent uptake and separation of NH3 at low concentration (1000 ppm). The combination of in situ neutron powder diffraction and spectroscopic studies reveal strong, yet reversible binding interactions of NH3 to the framework oxygen sites.

mPPTMP195 nanoparticles enhance fracture recovery through HDAC4 nuclear translocation inhibition.

Delayed repair of fractures seriously impacts patients' health and significantly increases financial burdens. Consequently, there is a growing clinical demand for effective fracture treatment. While current materials used for fracture repair have partially addressed bone integrity issues, they still possess limitations. These challenges include issues associated with autologous material donor sites, intricate preparation procedures for artificial biomaterials, suboptimal biocompatibility, and extended degradation cycles, all of which are detrimental to bone regeneration. Hence, there is an urgent need to design a novel material with a straightforward preparation method that can substantially enhance bone regeneration. In this context, we developed a novel nanoparticle, mPPTMP195, to enhance the bioavailability of TMP195 for fracture treatment. Our results demonstrate that mPPTMP195 effectively promotes the differentiation of bone marrow mesenchymal stem cells into osteoblasts while inhibiting the differentiation of bone marrow mononuclear macrophages into osteoclasts. Moreover, in a mouse femur fracture model, mPPTMP195 nanoparticles exhibited superior therapeutic effects compared to free TMP195. Ultimately, our study highlights that mPPTMP195 accelerates fracture repair by preventing HDAC4 translocation from the cytoplasm to the nucleus, thereby activating the NRF2/HO-1 signaling pathway. In conclusion, our study not only proposes a new strategy for fracture treatment but also provides an efficient nano-delivery system for the widespread application of TMP195 in various other diseases.

Tailored Phototherapy Agent by Infection Site In Situ Activated Against Methicillin-Resistant S. aureus.

Phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), is a promising treatment approach for multidrug resistant infections. PDT/PTT combination therapy can more efficiently eliminate pathogens without drug resistance. The key to improve the efficacy of photochemotherapy is the utilization efficiency of non-radiation energy of phototherapy agents. Herein, a facile phototherapy molecule (SCy-Le) with the enhancement of non-radiative energy transfer is designed by an acid stimulation under a single laser. Introduction of the protonated receptor into SCy-Le results in a distorted intramolecular charge in the infected acidic microenvironment, pH ≈ 5.5, which in turn, enhances light capture, reduces the singlet-triplet transition energies (ΔES1-T1), promotes electron system crossing, enhances capacity of reactive oxygen species generation, and causes a significant increase in temperature by improving vibrational relaxation. SCy-Le shows more than 99% bacterial killing rate against both methicillin-resistant Staphylococcus aureus and its biofilms in vitro and causes bacteria-induced wound healing in mice. This work will provide a new perspective for the design of phototherapy agents, and the emerging photochemotherapy will be a promising approach to combat the problem of antibiotic resistance.

Precise Design of TiO2@CoOx Heterostructure via Atomic Layer Deposition for Synergistic Sono-Chemodynamic Oncotherapy.

Sonodynamic therapy (SDT), a tumor treatment modality with high tissue penetration and low side effects, is able to selectively kill tumor cells by producing cytotoxic reactive oxygen species (ROS) with ultrasound-triggered sonosensitizers. N-type inorganic semiconductor TiO2 has low ROS quantum yields under ultrasound irradiation and inadequate anti-tumor activity. Herein, by using atomic layer deposition (ALD) to create a heterojunction between porous TiO2 and CoOx, the sonodynamic therapy efficiency of TiO2 can be improved. Compared to conventional techniques, the high controllability of ALD allows for the delicate loading of CoOx nanoparticles into TiO2 pores, resulting in the precise tuning of the interfaces and energy band structures and ultimately optimal SDT properties. In addition, CoOx exhibits a cascade of H2O2→O2→·O2 - in response to the tumor microenvironment, which not only mitigates hypoxia during the SDT process, but also contributes to the effect of chemodynamic therapy (CDT). Correspondingly, the synergistic CDT/SDT treatment is successful in inhibiting tumor growth. Thus, ALD provides new avenues for catalytic tumor therapy and other pharmaceutical applications.

Direct Synthesis of N-formamides by Integrating Reductive Amination of Ketones and Aldehydes with CO2 Fixation in a Metal-Organic Framework.

Formamides are important feedstocks for the manufacture of many fine chemicals. State-of-the-art synthesis of formamides relies on the use of an excess amount of reagents, giving copious waste and thus poor atom-economy. Here, we report the first example of direct synthesis of N-formamides by coupling two challenging reactions, namely reductive amination of carbonyl compounds, particularly biomass-derived aldehydes and ketones, and fixation of CO2 in the presence of H2 over a metal-organic framework supported ruthenium catalyst, Ru/MFM-300(Cr). Highly selective production of N-formamides has been observed for a wide range of carbonyl compounds. Synchrotron X-ray powder diffraction reveals the presence of strong host-guest binding interactions via hydrogen bonding and parallel-displaced π⋅⋅⋅π interactions between the catalyst and adsorbed substrates facilitating the activation of substrates and promoting selectivity to formamides. The use of multifunctional porous catalysts to integrate CO2 utilisation in the synthesis of formamide products will have a significant impact in the sustainable synthesis of feedstock chemicals.

Exceptional capture of methane at low pressure by an iron-based metal-organic framework.

The selective capture of methane (CH4) at low concentrations and its separation from N2 are extremely challenging owing to the weak host-guest interactions between CH4 molecules and any sorbent material. Here, we report the exceptional adsorption of CH4 at low pressure and the efficient separation of CH4/N2 by MFM-300(Fe). MFM-300(Fe) shows a very high uptake for CH4 of 0.85 mmol g-1 at 1 mbar and 298 K and a record CH4/N2 selectivity of 45 for porous solids, representing a new benchmark for CH4 capture and CH4/N2 separation. The excellent separation of CH4/N2 by MFM-300(Fe) has been confirmed by dynamic breakthrough experiments. In situ neutron powder diffraction, and solid-state nuclear magnetic resonance and diffuse reflectance infrared Fourier transform spectroscopies, coupled with modelling, reveal a unique and strong binding of CH4 molecules involving Fe-OH⋯CH4 and C⋯phenyl ring interactions within the pores of MFM-300(Fe), thus promoting the exceptional adsorption of CH4 at low pressure.

Multimodal imaging and photothermal/chemodynamic therapy of cervical cancer using GSH-responsive MoS2@MnO2 theranostic nanoparticles.

The development of nanoparticles capable of inducing reactive oxygen species (ROS) formation has become an important strategy for cancer therapy. Simultaneously, the preparation of multifunctional nanoparticles that respond to the tumor microenvironment is crucial for the diagnosis and treatment of tumors. In this study, we designed a Molybdenum disulfide (MoS2) core coated with Manganese dioxide (MnO2), which possessed a good photothermal effect and could produce Fenton-like Mn2+ in response to highly expressed glutathione (GSH) in the tumor microenvironment, thereby generating a chemodynamic therapy (CDT). The nanoparticles were further modified with Methoxypoly(Ethylene Glycol) 2000 (mPEG-NH2) to improve their biocompatibility, resulting in the formation of MoS2@MnO2-PEG. These nanoparticles were shown to possess significant Magnetic Resonance Imaging (MRI) and Computed Tomography (CT) imaging capabilities, making them useful in tumor diagnosis. In vitro and in vivo experiments demonstrated the antitumor ability of MoS2@MnO2-PEG, with a significant killing effect on tumor cells under combined treatment. These nanoparticles hold great potential for CDT/photothermal therapy (PTT) combined antitumor therapy and could be further explored in biomedical research.

Effect of industrial sludge particle size on the performance of baking-free sludge bricks.

Cement solidification is essential to reduce heavy metal leaching from industrial sludge and make it recyclable. This paper studied the effect of aggregate grading optimized by sludge containing heavy metal of different particle sizes on the performance of baking-free sludge bricks, which was mixed with industrial sludge cured by both micro-silica fume and cement. First, the gradation of fine natural aggregates was adjusted according to the Fuller curve. Fine aggregates in baking-free bricks were replaced by artificially processed sludge with particle sizes of 0.15 mm ~0.3 mm and 2.36 mm ~4.75 mm. In this case, a mixed proportion scheme was designed. Then, the strength, water absorption, porosity, and heavy metal leaching were measured. With the help of nuclear magnetic resonance (NMR) and scanning electron microscopy (SEM), the phase and pore structures were observed. The test results showed that: (1) Sludge can replace part of the fine aggregates to make baking-free bricks, resulting in the reduction of the strength of baking-free bricks, but the strength still meets the standard strength requirements of GB/T 21,144-2007. (2) When fine aggregates are partly replaced by sludge with finer particle sizes, baking-free sludge bricks exhibit higher strength, lower water absorption, better pore structures and microphase structure, and stronger solidification of heavy metals, the leaching number of heavy metals meets the standard requirements of GB5085.3-2007, which will be provided support for actual industrial production.Implications: Cement solidification is an essential means to reduce the heavy metal leaching from industrial sludge and make it recyclable. This paper studied sludge containing heavy metal of different particle sizes on the performance of baking-free sludge bricks. This paper analyzed the compressive strength, porosity and water absorption of baking-free bricks mixed with sludge of different partical sizes, and adopted the NMR to characterize the pores of baking-free bricks, and the SEM to observe the baking-free bricks resultants and the interfacial transition zone (ITZ). The heavy metal leaching test verified the environmental benefits of baking-free bricks mixed with sludge instead of aggregates. There not only make full use of solid wastes, but also thus minimizing pollution to the environment, which provide support for actual industrial production and a reference for studying industrial sludge recycling technology.

Efficient capture and storage of ammonia in robust aluminium-based metal-organic frameworks.

The development of stable sorbent materials to deliver reversible adsorption of ammonia (NH3) is a challenging task. Here, we report the efficient capture and storage of NH3 in a series of robust microporous aluminium-based metal-organic framework materials, namely MIL-160, CAU-10-H, Al-fum, and MIL-53(Al). In particular, MIL-160 shows high uptakes of NH3 of 4.8 and 12.8 mmol g-1 at both low and high pressure (0.001 and 1.0 bar, respectively) at 298 K. The combination of in situ neutron powder diffraction, synchrotron infrared micro-spectroscopy and solid-state nuclear magnetic resonance spectroscopy reveals the preferred adsorption domains of NH3 molecules in MIL-160, with H/D site-exchange between the host and guest and an unusual distortion of the local structure of [AlO6] moieties being observed. Dynamic breakthrough experiments confirm the excellent ability of MIL-160 to capture of NH3 with a dynamic uptake of 4.2 mmol g-1 at 1000 ppm. The combination of high porosity, pore aperture size and multiple binding sites promotes the significant binding affinity and capacity for NH3, which makes it a promising candidate for practical applications.

Experience of patients with diabetic retinopathy: A qualitative study.

AIMS: To understand the status quo and needs of self-management of patients with diabetic retinopathy (DR) and to provide a reference for formulating management programs that meet the needs of these patients. DESIGN: A qualitative interview study. METHODS: Semi-structured, in-depth interviews were conducted between November and December 2021. A purposive sample of 15 patients with DR who were hospitalized in the Retinal Department of Eye Hospital was recruited. Colaizzi's analysis was used to organize and analyse the interview data. This study followed the Consolidated Criteria for Reporting Qualitative Research (COREQ) checklist. RESULTS: The experience of patients with DR can be summarized into four themes: (1) lack of DR knowledge, (2) low quality of life, (3) poor self-management behaviour and (4) seek for support from many aspects. CONCLUSION: Patients with DR lack disease knowledge and have poor self-management abilities and adherence. Medical staff should provide personalized care according to the patient's self-management status and needs, promote the establishment of self-management behaviours and prevent and delay disease progression. IMPACT: This study helps assist medical staff in the early management of patients with DR and provides a reference for the construction of prevention programs for patients.

Rational design of graphite carbon nitride-decorated zinc oxide nanoarrays on three-dimensional nickel foam for the efficient production of reactive oxygen species through stirring-promoted piezo-photocatalysis.

Stirring-promoted piezo-photocatalysis based on a three-dimensional foam architecture has great potential applications in wastewater treatment and water splitting. However, the detailed mechanism of stirring-promoted piezo-photocatalysis has not been quantitatively studied, and the utilization of visible light needs to be further improved. In this work, the high solar-driven piezo-photocatalytic ability of graphite carbon nitride (g-C3N4)-decorated zinc oxide (ZnO) nanoarrays on nickel (Ni) foam is experimentally achieved and first simulated by the finite element method (FEM). The water flow velocity, depending on the stirring rate, is significantly increased by turbulence-induced fluid eddies while flowing through 3D macropores and nanoarrays, resulting in higher piezoelectricity. Reactive oxygen species (ROS) are experimentally examined by the electron spin resonance (ESR) technique and theoretically calculated by density functional theory (DFT) to confirm the configurations of the heterojunction under photocatalysis and piezo-photocatalysis. In particular, the large enhancement of 1O2 generation suggests the potential of piezo-photocatalysis in biological applications. The mechanism of piezo-photocatalysis is proposed in which the S-scheme heterojunction is realized by piezoelectricity to improve photocatalysis by retaining high redox ability and inhibiting recombination. This work provides a possible approach to harvesting energy sources for piezoelectricity and expands the scope of solar-driven piezo-photocatalysis.

Targeted chemo-photodynamic therapy toward esophageal cancer by GSH-sensitive theranostic nanoplatform.

As the sixth leading cause of cancer death, esophageal cancer is threatening the life of people worldwide. Traditional treatments, such as surgery, chemotherapy, radiotherapy, are facing always augmented challenges including invasion, multidrug resistance (MDR), off-target toxicity. Chemo & Photodynamic synergistic therapy represents one promising strategy for improved treatment efficiency. But it is still hindered by the lack of tumor targeting, deleterious side effects, and unfavorable microenvironment for photodynamic therapy (PDT). To overcome those obstacles, one theranostic nano-assambly drug, GCDs-Ce6/Pt-EGF, was designed and fabricated. Green fluorescence carbon dots (GCDs) with the excellent optical properties, modifiability and low toxicity were prepared as drug carrier. Epidermal growth factor (EGF) was conjugated to the nano-assembly to realize tumor specific targeting. Chlorin e6 (Ce6) in the presence of laser irradiation achieved PDT by generating proapoptosis reactive oxygen species (ROS). Moreover, Ce6 incorporated into GCDs endowed the nano-assambly imaging ability and facilitate image-guided therapy. Pt(IV), cisplatin prodrug, in the nano-assambly depleted the glutathione (GSH) of tumor microenvironment when it was reduced to cytotoxicity Pt(II). Compared with single treatment, GCDs-Ce6/Pt-EGF exhibited enhanced tumor cell killing capacity and better biosafety in vitro and in vivo, especially for EGFR bearing tumor. It paved ways for developing novel theranostic agent to be potentially applied in clinic.

Efficient Optical Modulation of Exciton State Population in Monolayer MoS2 at Room Temperature.

The modulation of exciton energy and state density of layer-structured transition metal dichalcogenides (TMDs) is required for diverse optoelectronic device applications. Here, the spontaneous inversion of exciton state population in monolayer MoS2 is observed by turning the pump light power. The excitons prefer to exist in low energy state under low pump power, but reverse under high pump power. To discuss the mechanism in depth, we propose a semiclassical model by combining the rate equation and photo-exciton interaction. Considering the modifying of exciton-exciton annihilation, the spontaneous inversion of exciton state population is phenomenologically described.

Construction of mitochondria targeted and FRET based ratiometric sensing nanoplatform for sulfur dioxide accurate detection in vitro and in vivo.

Sulfur dioxide (SO2) is a key molecule in organisms that is involved in the regulation of different physiological procedures. Aberrant SO2 causes a variety of diseases, such as cancer and neurodegeneration. Thus, sensitive and selective detection of SO2 is of great importance. Based on the Förster resonance energy transfer (FRET) between green fluorescence carbon dots (GCDs) donor and amide-linked near-infrared fluorescence emissive organic small molecular dye (CDDBT) acceptor, one ratiometric fluorescent nano platform, Mito-GCDs-CDDBT for mitochondria SO2 sensing was constructed. In this FRET sensing system, CDDBT served as the receptor for SO2, and the presence of SO2 enhanced GCDs green fluorescence signal and quenched CDDBT near-infrared fluorescence signal due to the disruption of FRET. Mito-GCDs-CDDBT could sensitively detect SO2 with a detection limit of as low as 0.701 µM. Meanwhile, Mito-GCDs-CDDBT achieved fluorescence imaging to measure the response of cellular exogenous and endogenous SO2 with remarkable mitochondrial targeting. Moreover, Mito-GCDs-CDDBT also realized SO2 sensing in vivo including zebrafish and mice. The as-prepared versatile nanoplatform displayed several advantages, such as mitochondria targeting, FRET-based sensitive detection, and sensing capabilities in biological milieu. Potentially, it could be applied in the diagnostics of SO2 involved diseases.

Direct Visualization of Supramolecular Binding and Separation of Light Hydrocarbons in MFM-300(In).

The purification of light olefins is one of the most important chemical separations globally and consumes large amounts of energy. Porous materials have the capability to improve the efficiency of this process by acting as solid, regenerable adsorbents. However, to develop translational systems, the underlying mechanisms of adsorption in porous materials must be fully understood. Herein, we report the adsorption and dynamic separation of C2 and C3 hydrocarbons in the metal-organic framework MFM-300(In), which exhibits excellent performance in the separation of mixtures of ethane/ethylene and propyne/propylene. Unusually selective adsorption of ethane over ethylene at low pressure is observed, resulting in selective retention of ethane from a mixture of ethylene/ethane, thus demonstrating its potential for a one-step purification of ethylene (purity > 99.9%). In situ neutron powder diffraction and inelastic neutron scattering reveal the preferred adsorption domains and host-guest binding dynamics of adsorption of C2 and C3 hydrocarbons in MFM-300(In).

Diagnostic and Prognostic Value of miRNAs in Hepatoblastoma: A Systematic Review With Meta-Analysis.

Background and aim: Increasing evidence has revealed the valuable diagnostic and prognostic applications of dysregulated microRNAs (miRNAs) in hepatoblastoma (HB), the most common hepatic malignancy during childhood. However, these results are inconsistent and remain to be elucidated. In the present study, we aimed to systematically compile up-to-date information regarding the clinical value of miRNAs in HB. Methods: Articles concerning the diagnostic and prognostic value of single miRNAs for HB were searched from databases. The sensitivity (SEN), specificity (SPE), positive and negative likelihood ratios (PLR and NLR), diagnostic odds ratio (DOR), area under the curve (AUC), and hazard ratios (HRs) were separately pooled to explore the diagnostic and prognostic performance of miRNA. Subgroup and meta-regression analyses were further carried out only in the event of heterogeneity. Results: In all, 20 studies, involving 264 HB patients and 206 healthy individuals, met the inclusion criteria in the 6 included literature articles. For the diagnostic analysis of miRNAs in HB, the pooled SEN and SPE were 0.76 (95% CI: 0.72-0.80) and 0.75 (95% CI: 0.70-0.80), respectively. Moreover, the pooled PLR was 2.79 (95% CI: 2.12-3.66), NLR was 0.34 (95% CI: 0.26-0.45), DOR was 10.24 (95% CI: 6.55-16.00), and AUC was 0.83, indicating that miRNAs had moderate diagnostic value in HB. For the prognostic analysis of miRNAs in HB, the abnormal expressions of miR-21, miR-34a, miR-34b, miR-34c, miR-492, miR-193, miR-222, and miR-224 in patients were confirmed to be associated with a worse prognosis. The pooled HR was 1.74 (95% CI: 1.20-2.29) for overall survival and 1.74 (95% CI: 1.31-2.18) for event-free survival, suggesting its potential as a prognostic indicator for HB. Conclusion: To the best of our knowledge, this is the first comprehensive systematic review and meta-analysis that examines the diagnostic and prognostic role of dysregulated miRNAs in HB patients. The combined meta-analysis results supported the previous individual finds that miRNAs might provide a new, noninvasive method for the diagnostic and prognostic analyses of HB.

Carbon vacancies enriched carbon nitride nanotubes for Pd coordination environment optimization: Highly efficient photocatalytic hydrodechlorination and CO2 cycloaddition.

The use of easily available solar energy to achieve pollutants efficient degradation and waste carbon resource CO2 utilization under mild conditions is highly desired. Herein, novel carbon vacancies enriched nanotubes graphitic carbon nitride (SCNT-500) has been successfully fabricated via melamine (MA) supramolecular hydrogen-bonded self-assembly in the presence of H2SO4. Pd NPs loaded carbon vacancies enriched carbon nitride nanotubes (Pd/SCNT-500) were used for photocatalytic chlorophenols hydrodechlorination and CO2 cycloaddition with styrene oxide. Up to 6.93 s-1 4-chlorophenol hydrodechlorination TOF and obviously improved CO2 cycloaddition efficiency could be realized with Pd/SCNT-500. The improved photocatalytic efficiency should be related to the morphology and carbon vacancies based Pd coordination environment optimization. Such as, the surface area increased nanotubes structure promoted light harvesting along with photoelectrons and holes generation; the carbon vacancies improved excited electrons capture, photoinduced carriers recombination inhibition along with substrates adsorption with electron rich Pd NPs. Mechanism studies not only demonstrated the important role of atomic hydrogen and Pd coordination environment optimization in the chlorophenols hydrodechlorination, but also confirmed the promotion ability of photogenerated electrons on CO2 cycloaddition.

High capacity ammonia adsorption in a robust metal-organic framework mediated by reversible host-guest interactions.

To understand the exceptional adsorption of ammonia (NH3) in MFM-300(Sc) (19.5 mmol g-1 at 273 K and 1 bar without hysteresis), we report a systematic investigation of the mechanism of adsorption by a combination of in situ neutron powder diffraction, inelastic neutron scattering, synchrotron infrared microspectroscopy, and solid-state 45Sc NMR spectroscopy. These complementary techniques reveal the formation of reversible host-guest supramolecular interactions, which explains directly the observed excellent reversibility of this material over 90 adsorption-desorption cycles.

A novel 4 immune-related genes as diagnostic markers and correlated with immune infiltrates in major depressive disorder.

BACKGROUND: Immune response is prevalently related with major depressive disorder (MDD) pathophysiology. However, the study on the relationship between immune-related genes (IRGs) and immune infiltrates of MDD remains scarce. METHODS: We extracted expression data of 148 MDD patients from 2 cohorts, and systematically characterized differentially expressed IRGs by using limma package in R software. Then, the LASSO and multivariate logistic regression analysis was used to identify the most powerful IRGs. Next, we analyzed the relationship between IRGs and immune infiltrates of MDD. Finally, GSE76826 was used to to verificate of IRGs as a diagnostic markers in MDD. RESULTS: 203 different IRGs s in MDD has been identified (P < 0.05). GSEA revealed that the different IRGs was more likely to be enriched in immune-specific pathways. Then, a 9 IRGs was successfully established to predict MDD based on LASSO. Next, 4 IRGs was obtained by multivariate logistic regression analysis, and AUC for CD1C, SPP1, CD3D, CAMKK2, and IRGs model was 0.733, 0.767, 0.816, 0.800, and 0.861, suggesting that they have a good diagnostic performance. Furthermore, the proportion of T cells CD8, T cells γδ, macrophages M0, and NK cells resting in MDD group was lower than that in the healthy controls, suggesting that the immune system in MDD group is impaired. Simultaneously, CD3D was validated a reliable marker in MDD, and was positively correlated with T cells CD8. GSEA revealed high expression CD3D was more likely to be enriched in immune-specific pathways, and low expression CD3D was more likely to be enriched in glucose metabolism metabolism-specific pathways. CONCLUSIONS: We applied bioinformatics approaches to suggest that a 4 IRGs could serve as diagnostic markers to provide a novel direction to explore the pathogenesis of MDD.

Histone H4 induces heparan sulfate degradation by activating heparanase in chlorine gas-induced acute respiratory distress syndrome.

BACKGROUND: Heparan sulfate (HS) degradation mediates pulmonary endothelial hyper-permeability and acute pulmonary edema during acute respiratory distress syndrome (ARDS). The aim of this study was to examine whether histone H4 induced HS degradation by activating heparanase (HPSE) in chlorine gas (Cl2)-induced ARDS. METHODS: Acute lung injury was induced by Cl2 exposure or histone H4 injection in C57BL/6 mice. Histone H4 in bronchoalveolar lavage fluid (BALF) and plasma was measured by ELISA. HS degradation was measured by immunostaining, ELISA, and flow cytometry. HPSE mRNA and protein were measured by real-time qPCR and western blot analysis, respectively, at preset timepoints. The HPSE inhibitor OGT2115 and specific siRNAs were used to study the role of HPSE during HS degradation caused by Cl2 exposure or histone H4 challenge. Blocking antibodies against TLR1, TLR2, TLR4, or TLR6 were used in vitro to investigate which signaling pathway was involved. The transcriptional regulation of HPSE was studied vis-à-vis NF-κB, which was assessed by nuclear translocation of NF-κB p65 and phosphorylation of I-κBα protein. RESULTS: Histone H4 in BALF and plasma increased evidently after Cl2 inhalation. Cl2 exposure or histone H4 challenge caused obvious acute lung injury in mice, and the pulmonary glycocalyx was degraded evidently as observed from endothelial HS staining and measurement of plasma HS fragments. Pretreatment with OGT2115, an HPSE inhibitor, relieved the acute lung injury and HS degradation caused by Cl2 exposure or histone H4 challenge. Targeted knockdown of HPSE by RNA interference (RNAi) significantly inhibited histone H4 induced HS degradation in HPMECs, as measured by immunofluorescence and flow cytometry. By inducing phosphorylation of I-κB α and nuclear translocation of NF-κB p65, histone H4 directly promoted mRNA transcription and protein expression of HPSE in a dose-dependent manner. Additionally, a blocking antibody against TLR4 markedly inhibited both activation of NF-κB and expression of HPSE induced by histone H4. CONCLUSIONS: Histone H4 is a major pro-inflammatory mediator in Cl2-induced ARDS in mice, and induces HS degradation by activating HPSE via TLRs- and NF-κB-signaling pathways.