Nucleic acid-based nanotherapeutics for treating sepsis and associated organ injuries.

In recent years, gene therapy has been made possible with the success of nucleic acid drugs against sepsis and its related organ dysfunction. Therapeutics based on nucleic acids such as small interfering RNAs (siRNAs), microRNAs (miRNAs), messenger RNAs (mRNAs), and plasmid DNAs (pDNAs) guarantee to treat previously undruggable diseases. The advantage of nucleic acid-based therapy against sepsis lies in the development of nanocarriers, achieving targeted and controlled gene delivery for improved efficacy with minimal adverse effects. Entrapment into nanocarriers also ameliorates the poor cellular uptake of naked nucleic acids. In this study, we discuss the current state of the art in nanoparticles for nucleic acid delivery to treat hyperinflammation and apoptosis associated with sepsis. The optimized design of the nanoparticles through physicochemical property modification and ligand conjugation can target specific organs-such as lung, heart, kidney, and liver-to mitigate multiple sepsis-associated organ injuries. This review highlights the nanomaterials designed for fabricating the anti-sepsis nanosystems, their physicochemical characterization, the mechanisms of nucleic acid-based therapy in working against sepsis, and the potential for promoting the therapeutic efficiency of the nucleic acids. The current investigations associated with nanoparticulate nucleic acid application in sepsis management are summarized in this paper. Noteworthily, the potential application of nanotherapeutic nucleic acids allows for a novel strategy to treat sepsis. Further clinical studies are required to confirm the findings in cell- and animal-based experiments. The capability of large-scale production and reproducibility of nanoparticle products are also critical for commercialization. It is expected that numerous anti-sepsis possibilities will be investigated for nucleic acid-based nanotherapeutics in the future.

Correction: A detailed study of the electronic and optical properties of germanium nanotubes.

Correction for 'A detailed study of the electronic and optical properties of germanium nanotubes' by Hsin-Yi Liu et al., Phys. Chem. Chem. Phys., 2024, 26, 17830-17837, https://doi.org/10.1039/D4CP00812J.

[MMPs/pH synergically responsive XTS-Prussian blue nanoparticles inhibiting proliferation and migration of RAFLS assisted with laser irradiation].

Rheumatoid arthritis(RA) is a condition in which the joints are in a weakly acidic environment. In RA, RA fibroblastlike synoviocytes( RAFLS) in the joints become abnormally activated and secrete a large amount of matrix metalloproteinases(MMPs), and the receptor protein CD44 on the cell membrane is specifically upregulated. Xuetongsu(XTS), an active ingredient in the Tujia ethnomedicine Xuetong, is known to inhibit the proliferation of RAFLS. However, its development and utilization have been limited due to poor targeting ability. A biomimetic XTS-Prussian blue nanoparticles(PB NPs) drug delivery system called THMPX NPs which can target CD44 was constructed in this study. The surface of THMPX NPs was modified with hyaluronic acid(HA) and a long chain of triglycerol monostearate(TGMS) and 3-aminobenzeneboronic acid(PBA)(PBA-TGMS). The overexpressed MMPs and H+ in inflammatory RAFLS can synergistically cleave the PBA-TGMS on the surface of the nanoparticles, exposing HA to interact with CD44. This allows THMPX NPs to accumulate highly in RAFLS, and upon near-infrared light irradiation, generate heat and release XTS, thereby inhibiting the proliferation and migration of RAFLS. Characterization revealed that THMPX NPs were uniform cubes with a diameter of(190. 3±4. 7) nm and an average potential of(-15. 3± 2. 3) m V. Upon near-infrared light irradiation for 5 min, the temperature of THMPX NPs reached 41. 5 ℃, indicating MMPs and H+-triggered drug release. Safety assessments showed that THMPX NPs had a hemolysis rate of less than 4% and exhibited no cytotoxicity against normal RAW264. 7 and human fibroblast-like synoviocytes(HFLS). In vitro uptake experiments demonstrated the significant targeting ability of THMPX NPs to RAFLS. Free radical scavenging experiments revealed excellent free radical clearance capacity of THMPX NPs, capable of removing reactive oxygen species in RAFLS. Cell counting kit-8 and scratch assays demonstrated that THMPX NPs significantly suppressed the viability and migratory ability of RAFLS. This study provides insights into the development of innovative nanoscale targeted drugs from traditional ethnic medicines for RA treatment.

Organophosphorus mineralizing-Streptomyces species underpins uranate immobilization and phosphorus availability in uranium tailings.

Phosphate-solubilizing bacteria (PSB) are important but often overlooked regulators of uranium (U) cycling in soil. However, the impact of PSB on uranate fixation coupled with the decomposition of recalcitrant phosphorus (P) in mining land remains poorly understood. Here, we combined gene amplicon sequencing, metagenome and metatranscriptome sequencing analysis and strain isolation to explore the effects of PSB on the stabilization of uranate and P availability in U mining areas. We found that the content of available phosphorus (AP), carbonate-U and Fe-Mn-U oxides in tailings was significantly (P < 0.05) higher than their adjacent soils. Also, organic phosphate mineralizing (PhoD) bacteria (e.g., Streptomyces) and inorganic phosphate solubilizing (gcd) bacteria (e.g., Rhodococcus) were enriched in tailings and soils, but only organic phosphate mineralizing-bacteria substantially contributed to the AP. Notably, most genes involved in organophosphorus mineralization and uranate resistance were widely present in tailings rather than soil. Comparative genomics analyses supported that organophosphorus mineralizing-Streptomyces species could increase soil AP content and immobilize U(VI) through organophosphorus mineralization (e.g., PhoD, ugpBAEC) and U resistance related genes (e.g., petA). We further demonstrated that the isolated Streptomyces sp. PSBY1 could enhance the U(VI) immobilization mediated by the NADH-dependent ubiquinol-cytochrome c reductase (petA) through decomposing organophosphorous compounds. This study advances our understanding of the roles of PSB in regulating the fixation of uranate and P availability in U tailings.

A detailed study of the electronic and optical properties of germanium nanotubes.

We employed first-principles calculations to investigate the electronic and optical properties of germanene nanotubes (GeNTs). Significant multi-orbital hybridizations lead to metallic and semiconducting behaviors in small-sized armchair and zigzag GeNTs, respectively. The changes in band gaps and subband dispersions with increasing diameter have been thoroughly understood by analyzing spatial charge densities and projected density of states. The optical absorption spectra exhibit diameter-dependent anisotropy and suggest a dimensional transition beyond a critical diameter. This comprehensive study not only deepens our understanding of GeNTs but also reveals new possibilities for various nanotechnology applications.

Strigolactones shape the assembly of root-associated microbiota in response to phosphorus availability.

Plants rely on strigolactones (SLs) to regulate their development and form symbiotic relationships with microbes as part of the adaptive phosphorus (P) efficiency strategies. However, the impact of SLs on root-associated microbial communities in response to P availability remains unknown. Here, root microbiota of SL biosynthesis (max3-11) and perception (d14-1) were compared to wild-type Col-0 plants under different P concentrations. Using high-throughput sequencing, the relationship between SLs, P concentrations, and the root-associated microbiota was investigated to reveal the variation in microbial diversity, composition, and interaction. Plant genotypes and P availability played important but different roles in shaping the root-associated microbial community. Importantly, SLs were found to attract Acinetobacter in low P conditions, which included an isolated CP-2 (Acinetobacter soli) that could promote plant growth in cocultivation experiments. Moreover, SLs could change the topologic structure within co-occurrence networks and increase the number of keystone taxa (e.g., Rhizobiaceae and Acidobacteriaceae) to enhance microbial community stability. This study reveals the key role of SLs in mediating root-associated microbiota interactions.IMPORTANCEStrigolactones (SLs) play a crucial role in plant development and their symbiotic relationships with microbes, particularly in adapting to phosphorus levels. Using high-throughput sequencing, we compared the root microbiota of plants with SL biosynthesis and perception mutants to wild-type plants under different phosphorus concentrations. These results found that SLs can attract beneficial microbes in low phosphorus conditions to enhance plant growth. Additionally, SLs affect microbial network structures, increasing the stability of microbial communities. This study highlights the key role of SLs in shaping root-associated microbial interactions, especially in response to phosphorus availability.

Low preoperative serum uric acid is associated with early acute kidney injury after living donor liver transplantation.

BACKGROUND: Liver transplantation is treatment option for patients with end-stage liver disease and hepatocellular carcinoma. Renal function deterioration significantly impacts the survival rates of liver recipients, and serum uric acid (SUA) is associated with both acute and chronic renal function disorders. Thus, our study aimed to assess the relationship and predictive value of preoperative SUA level and postoperative acute kidney injury (AKI) in living donor liver transplantation (LDLT). METHODS: We conducted a prospective observational study on 87 patients undergoing LDLT. Blood samples were collected immediately before LDLT, and renal function status was followed up for 3 consecutive days postoperatively. RESULTS: Low SUA levels (cutoff value 4.15 mg/dL) were associated with a high risk of early posttransplantation AKI. The area under the curve was 0.73 (sensitivity, 79.2%; specificity, 59.4%). Although not statistically significant, there were no deaths in the non-AKI group but two in the early AKI group secondary to liver graft dysfunction in addition to early AKI within the first month after LDLT. CONCLUSION: AKI after liver transplantation may lead to a deterioration of patient status and increased mortality rates. We determined low preoperative SUA levels as a possible risk factor for early postoperative AKI.

Strictosamide promotes wound healing through activation of the PI3K/AKT pathway.

Nauclea officinalis, as a Chinese medicine in Hainan province, had the effect of treating lower limb ulcers, burn infections. In this paper, we studied the effect of Strictosamide (STR), the main bioactive compound in Nauclea officinals, on wound healing and explored its internal mechanism. Firstly, the wound healing potential of STR was evaluated in a rat model, demonstrating its ability to expedite wound healing, mitigate inflammatory infiltration, and enhance collagen deposition. Additionally, immunofluorescence analysis revealed that STR up-regulated the expression of CD31 and PCNA. Subsequently, target prediction, protein-protein interaction (PPI), gene ontology (GO), and pathway enrichment analyses were used to obtain potential targets, specific biological processes, and molecular mechanisms of STR for the potential treatment of wound healing. Furthermore, molecular docking was conducted to predict the binding affinity between STR and its associated targets. Additionally, in vivo and in vitro experiments confirmed that STR could increase the expression of P-PI3K, P-AKT and P-mTOR by activating the PI3K/AKT signaling pathway. In summary, this study provided a new explanation for the mechanism by which STR promotes wound healing through network pharmacology, suggesting that STR may be a new candidate for treating wound.

Toughening Hydrogels with Fibrillar Connected Double Networks.

Biological tissues, such as tendons or cartilage, possess high strength and toughness with very low plastic deformations. In contrast, current strategies to prepare tough hydrogels commonly utilize energy dissipation mechanisms based on physical bonds that lead to irreversible large plastic deformations, thus limiting their load-bearing applications. This article reports a strategy to toughen hydrogels using fibrillar connected double networks (fc-DN), which consist of two distinct but chemically interconnected polymer networks, that is, a polyacrylamide network and an acrylated agarose fibril network. The fc-DN design allows efficient stress transfer between the two networks and high fibril alignment during deformation, both contributing to high strength and toughness, while the chemical crosslinking ensures low plastic deformations after undergoing high strains. The mechanical properties of the fc-DN network can be readily tuned to reach an ultimate tensile strength of 8 MPa and a toughness of above 55 MJ m-3, which is 3 and 3.5 times more than that of fibrillar double network hydrogels without chemical connections, respectively. The application potential of the fc-DN hydrogel is demonstrated as load-bearing damping material for a jointed robotic lander. The fc-DN design provides a new toughening mechanism for hydrogels that can be used for soft robotics or bioelectronic applications.

[Chemical constituents from roots of Kadsura heteroclita].

The dichloromethane fraction of Kadsura heteroclita roots was separated and purified by chromatographic techniques(e.g., silica gel, Sephadex LH-20, ODS, MCI column chromatography) and semi-preparative HPLC. Twenty compounds were isolated from K. heteroclita, and their structures were identified by NMR, MS, UV, and X-ray single crystal diffraction techniques. Twenty compounds were isolated from K. heteroclita, which were identified as xuetongdilactone G(1), mallomacrostin C(2), 3,4-seco(24Z)-cychmrt-4(28),24-diene-3,26-dioic acid 3-methyl ester(3), nigranoic acid(4), methyl ester schizanlactone E(5), schisandronic acid(6), heteroclic acid(7), wogonin(8),(2R,3R)-4'-O-methyldihydroquercetin(9), 15,16-bisnor-13-oxo-8(17),11E-labdadien-19-oic acid(10), stigmast-4-ene-6ß-ol-3-one(11), psoralen(12),(1R,2R,4R)-trihydroxy-p-menthane(13), homovanillyl alcohol(14), 2-(4-hydroxyphenyl)-ethanol(15), coniferaldehyde(16),(E)-7-(4-hydroxy-3-methoxyphenyl)-7-methylbut-8-en-9-one(17), acetovanillone(18), vanillic acid(19) and vanillin(20). Compound 1 is a new compound named xuetongdilactone G. Compounds 2-3 and 8-20 are isolated from K. heteroclita for the first time.

Nitrogen and sulfur cycling and their coupling mechanisms in eutrophic lake sediment microbiomes.

Microorganisms play important roles in the biogeochemical cycles of lake sediment. However, the integrated metabolic mechanisms governing nitrogen (N) and sulfur (S) cycling in eutrophic lakes remain poorly understood. Here, metagenomic analysis of field and bioreactor enriched sediment samples from a typical eutrophic lake were applied to elucidate the metabolic coupling of N and S cycling. Our results showed significant diverse genes involved in the pathways of dissimilatory sulfur metabolism, denitrification and dissimilatory nitrate reduction to ammonium (DNRA). The N and S associated functional genes and microbial groups generally showed significant correlation with the concentrations of NH4+, NO2- and SO42, while with relatively low effects from other environmental factors. The gene-based co-occurrence network indicated clear cooperative interactions between N and S cycling in the sediment. Additionally, our analysis identified key metabolic processes, including the coupled dissimilatory sulfur oxidation (DSO) and DNRA as well as the association of thiosulfate oxidation complex (SOX systems) with denitrification pathway. However, the enriched N removal microorganisms in the bioreactor ecosystem demonstrated an additional electron donor, incorporating both the SOX systems and DSO processes. Metagenome-assembled genomes-based ecological model indicated that carbohydrate metabolism is the key linking factor for the coupling of N and S cycling. Our findings uncover the coupling mechanisms of microbial N and S metabolism, involving both inorganic and organic respiration pathways in lake sediment. This study will enhance our understanding of coupled biogeochemical cycles in lake ecosystems.

Corilagin Inhibits Neutrophil Extracellular Trap Formation and Protects against Hydrochloric Acid/Lipopolysaccharide-Induced Acute Lung Injury in Mice by Suppressing the STAT3 and NOX2 Signaling Pathways.

Acute lung injury (ALI) and its severe manifestation, acute respiratory distress syndrome (ARDS), are characterized by uncontrolled inflammatory responses, neutrophil activation and infiltration, damage to the alveolar capillary membrane, and diffuse alveolar injury. Neutrophil extracellular traps (NETs), formed by activated neutrophils, contribute significantly to various inflammatory disorders and can lead to tissue damage and organ dysfunction. Corilagin, a compound found in Phyllanthus urinaria, possesses antioxidative and anti-inflammatory properties. In this study, we investigated the protective effects and underlying mechanisms of corilagin in hydrochloric acid (HCl)/lipopolysaccharide (LPS)-induced lung injury. Mice received intraperitoneal administration of corilagin (2.5, 5, or 10 mg/kg) or an equal volume of saline 30 min after intratracheal HCl/LPS administration. After 20 h, lung tissues were collected for analysis. Corilagin treatment significantly mitigated lung injury, as evidenced by reduced inflammatory cell infiltration, decreased production of proinflammatory cytokines, and alleviated oxidative stress. Furthermore, corilagin treatment suppressed neutrophil elastase expression, reduced NET formation, and inhibited the expression of ERK, p38, AKT, STAT3, and NOX2. Our findings suggest that corilagin inhibits NET formation and protects against HCl/LPS-induced ALI in mice by modulating the STAT3 and NOX2 signaling pathways.

Strictosamide alleviates acute lung injury via regulating T helper 17 cells, regulatory T cells, and gut microbiota.

BACKGROUND: Nauclea officinalis (Pierre ex Pit.) Merr. & Chun (Rubiaceae) is widely used to treat respiratory diseases in China. Strictosamide is its main active component and has significant anti-inflammatory activity. However, the effects and molecular mechanisms of strictosamide in the treatment of acute lung injury (ALI) remain largely unknown. PURPOSE: This study aimed to examine the regulatory effects of strictosamide on T helper 17 cells (Th17 cells)/Regulatory T cells (Treg cells) and gut microbiota in ALI-affected mice. MATERIALS AND METHODS: The ALI model was induced using lipopolysaccharide (LPS) intraperitoneal injection. Hematoxylin-eosin (H&E) staining, the number of inflammatory cells in broncho-alveolar lavage fluid (BALF), the Wet/Dry (W/D) ratio, and myeloperoxidase (MPO) activity were utilized as evaluation indices for the therapeutic efficacy of strictosamide on ALI. Flow cytometry (FCM), enzyme-linked immune sorbent assay (ELISA), quantitative reverse transcription polymerase chain reaction (qRT-PCR), and western blotting were used to determine the regulation of strictosamide on the Th17/Treg cells and the STAT3/STAT5 signaling pathway. The analysis of gut microbiota was conducted using 16S rDNA sequencing. The verification of the relationship between the gut microbiome and immune function was conducted using Spearman analysis. RESULTS: Strictosamide attenuated inflammation on ALI induced by LPS, which reduced the levels of Th17-related factors interleukin (IL)-6 and IL-17 and increased Treg-related factors IL-10 and transforming growth factor (TGF)-ß. In the spleens and whole blood, strictosamide reduced the proportion of Th17 cells and increased the proportion of Treg cells. Furthermore, strictosamide increased Forkhead/winged helix transcription factor 3 (Foxp3) and p-STAT5 protein expression while inhibiting Retinoid-related orphan nuclear receptors-γt (RORγt) and p-STAT3 expression. Moreover, strictosamide reshaped the diversity and structure of the gut microbiota, and influence the associations between immune parameters and gut microbiota in ALI mice. CONCLUSIONS: In summary, the results of the current investigation showed that strictosamide has a therapeutic impact on LPS-induced ALI. The mechanism of action of this effect may be associated with the modulation of Th17 and Treg cells differentiation via the SATA signaling pathway, as well as the impact of the gut microbiota.

Utilization of nickel-graphite electrode as an electron donor for high-efficient microbial removal of solved U(VI) mediated by Leifsonia sp.

Enzymatically catalyzed reduction of metals by bacteria has potential application value to uranium-mine wastewater. However, its practical implementation has long been restricted by its intrinsic drawbacks such as low efficiency and long treatment-time. This study aims to explore the effect of electrodes on U (VI) removal efficiency by a purified indigenous bacteria isolated from a uranium mining waste pile in China. The effects of current intensity, pH, initial U (Ⅵ) concentration, initial dosage of bacteria and contact time on U (Ⅵ) removal efficiency were investigated via static experiments. The results show that U(VI) removal rate was stabilized above 90% and the contact time sharply shortened within 1 h when utilized nickel-graphite electrode as an electron donor. Over the treatment ranges investigated maximum removal of U (Ⅵ) was 96.04% when the direct current was 10 mA, pH was 5, initial U (Ⅵ) concentration was 10 mg/L, and dosage of Leifsonia sp. was 0.25 g/L. In addition, it is demonstrated that U (VI) adsorption by Leifsonia sp. is mainly chemisorption and/or reduction as the quasi-secondary kinetics is more suitable for fitting the process. FTIR results indicated that amino, amide, aldehyde and phosphate -containing groups played a role in the immobilization of U (VI) more or less. SEM and EDS measurements revealed that U appeared to be more obviously aggregated on the surface of cells. A plausible explanation for this, supported by XPS, is that U (VI) was partially reduced to U (IV) by direct current then precipitated on the cells surface. These observations reveal that Nickel-graphite electrode exhibited good electro-chemical properties and synergistic capacity with Leifsonia sp. which potentially provides a new avenue for uranium enhanced removal/immobilization by indigenous bacteria.

The Modulation of Phospho-Extracellular Signal-Regulated Kinase and Phospho-Protein Kinase B Signaling Pathways plus Activity of Macrophage-Stimulating Protein Contribute to the Protective Effect of Stachydrine on Acetaminophen-Induced Liver Injury.

Stachydrine, a prominent bioactive alkaloid derived from Leonurus heterophyllus, is a significant herb in traditional medicine. It has been noted for its anti-inflammatory and antioxidant characteristics. Consequently, we conducted a study of its hepatoprotective effect and the fundamental mechanisms involved in acetaminophen (APAP)-induced liver injury, utilizing a mouse model. Mice were intraperitoneally administered a hepatotoxic dose of APAP (300 mg/kg). Thirty minutes after APAP administration, mice were treated with different concentrations of stachydrine (0, 2.5, 5, and 10 mg/kg). Animals were sacrificed 16 h after APAP injection for serum and liver tissue assays. APAP overdose significantly elevated the serum alanine transferase levels, hepatic pro-inflammatory cytokines, malondialdehyde activity, phospho-extracellular signal-regulated kinase (ERK), phospho-protein kinase B (AKT), and macrophage-stimulating protein expression. Stachydrine treatment significantly decreased these parameters in mice with APAP-induced liver damage. Our results suggest that stachydrine may be a promising beneficial target in the prevention of APAP-induced liver damage through attenuation of the inflammatory response, inhibition of the ERK and AKT pathways, and expression of macrophage-stimulating proteins.

Protective Effects of Danmu Extract Syrup on Acute Lung Injury Induced by Lipopolysaccharide in Mice through Endothelial Barrier Repair.

OBJECTIVE: To investigate the effects of Danmu Extract Syrup (DMS) on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice and explore the mechanism. METHODS: Seventy-two male Balb/C mice were randomly divided into 6 groups according to a random number table (n=12), including control (normal saline), LPS (5 mg/kg), LPS+DMS 2.5 mL/kg, LPS+DMS 5 mL/kg, LPS+DMS 10 mL/kg, and LPS+Dexamethasone (DXM, 5 mg/kg) groups. After pretreatment with DMS and DXM, the ALI mice model was induced by LPS, and the bronchoalveolar lavage fluid (BALF) were collected to determine protein concentration, cell counts and inflammatory cytokines. The lung tissues of mice were stained with hematoxylin-eosin, and the wet/dry weight ratio (W/D) of lung tissue was calculated. The levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1 ß in BALF of mice were detected by enzyme linked immunosorbent assay. The expression levels of Claudin-5, vascular endothelial (VE)-cadherin, vascular endothelial growth factor (VEGF), phospho-protein kinase B (p-Akt) and Akt were detected by Western blot analysis. RESULTS: DMS pre-treatment significantly ameliorated lung histopathological changes. Compared with the LPS group, the W/D ratio and protein contents in BALF were obviously reduced after DMS pretreatment (P<0.05 or P<0.01). The number of cells in BALF and myeloperoxidase (MPO) activity decreased significantly after DMS pretreatment (P<0.05 or P<0.01). DMS pre-treatment decreased the levels of TNF-α, IL-6 and IL-1 ß (P<0.01). Meanwhile, DMS activated the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway and reversed the expressions of Claudin-5, VE-cadherin and VEGF (P<0.01). CONCLUSIONS: DMS attenuated LPS-induced ALI in mice through repairing endothelial barrier. It might be a potential therapeutic drug for LPS-induced lung injury.

Extracellular proteins enhance Cupriavidus pauculus nickel tolerance and cell aggregate formation.

Heavy metal-resistant bacteria secrete extracellular proteins (e-PNs). However, the role of e-PNs in heavy metal resistance remains elusive. Here Fourier Transform Infrared Spectroscopy implied that N-H, C = O and NH2-R played a crucial role in the adsorption and resistance of Ni2+ in the model organism Cuprividus pauculus 1490 (C. pauculus). Proteinase K treatment reduced Ni2+ resistance of C. pauculus underlining the essential role of e-PNs. Further three-dimension excitation-emission matrix fluorescence spectroscopy analysis demonstrated that tryptophan proteins as part of the e-PNs increased significantly with Ni2+ treatment. Proteomic and quantitative real-time polymerase chain reaction data indicated that major changes were induced in the metabolism of C. pauculus in response to Ni2+. Among those lipopolysaccharide biosynthesis, general secretion pathways, Ni2+-affiliated transporters and multidrug efflux play an essential role in Ni2+ resistance. Altogether the results provide a conceptual model for comprehending how e-PNs contribute to bacterial resistance and adsorption of Ni2+.

Neutrophil-targeted combinatorial nanosystems for suppressing bacteremia-associated hyperinflammation and MRSA infection to improve survival rates.

There is currently no specific and effective treatment for bacteremia-mediated sepsis. Hence, this study engineered a combinatorial nanosystem containing neutrophil-targeted roflumilast-loaded nanocarriers and non-targeted fusidic acid-loaded nanoparticles to enable the dual mitigation of bacteremia-associated inflammation and methicillin-resistant Staphylococcus aureus (MRSA) infection. The targeted nanoparticles were developed by conjugating anti-lymphocyte antigen 6 complex locus G6D (Ly6G) antibody fragment on the nanoparticulate surface. The particle size and zeta potential of the as-prepared nanosystem were about 200 nm and -25 mV, respectively. The antibody-conjugated nanoparticles showed a three-fold increase in neutrophil internalization compared to the unfunctionalized nanoparticles. As a selective phosphodiesterase (PDE) 4 inhibitor, the roflumilast in the nanocarriers largely inhibited cytokine/chemokine release from the activated neutrophils. The fusidic acid-loaded nanocarriers were vital to eliminate biofilm MRSA colony by 3 log units. The nanoparticles drastically decreased the intracellular bacterial count compared to the free antibiotic. The in vivo mouse bioimaging demonstrated prolonged retention of the nanosystem in the circulation with limited organ distribution and liver metabolism. In the mouse bacteremia model, the multifunctional nanosystem produced a 1‒2 log reduction of MRSA burden in peripheral organs and blood. The functionalized nanosystem arrested the cytokine/chemokine overexpression greater than the unfunctionalized nanocarriers and free drugs. The combinatory nanosystem also extended the median survival time from 50 to 103 h. No toxicity from the nanoformulation was found based on histology and serum biochemistry. Furthermore, our data proved that the active neutrophil targeting by the versatile nanosystem efficiently alleviated MRSA infection and organ dysfunction caused by bacteremia. STATEMENT OF SIGNIFICANCE: Bacteremia-mediated sepsis poses a significant challenge in clinical practice, as there is currently no specific and effective treatment available. In our study, we have developed a novel combinatorial nanosystem to address this issue. Our nanosystem consists of neutrophil-targeted roflumilast-loaded nanocarriers and non-targeted fusidic acid-loaded nanoparticles, enabling the simultaneous mitigation of bacteremia-associated inflammation and MRSA infection. Our nanosystem demonstrated the decreased neutrophil activation, effective inhibition of cytokine release, elimination of MRSA biofilm colonies, and reduced intracellular bacterial counts. In vivo experiments showed prolonged circulation, limited organ distribution, and increased survival rates in a mouse bacteremia model. Importantly, our nanosystem exhibited no toxicity based on comprehensive assessments.

Investigation on the current situation and influencing factors of sitting time and health literacy among high school students in China / 北京大学学报(医学版)

Objective:To investigate the current situation of sitting time and health literacy among high school students in China,in order to provide a basis for improving their physical and mental health levels.Methods:A stratified random cluster sampling method was used to investigate the length of sitting time and health literacy of first and second grade high school students from 31 provinces,cities,and au-tonomous regions in China(data did not include that of Hong Kong and Macao Special Administrative Re-gion,and Taiwan Province of China).The Kruskal-Wallis H method,independent sample Mann-Whit-ney U test,and regression model were used to analyze the influencing factors of sitting time and total health literacy score.Results:(1)The total score of health literacy was statistically significant(P＜0.01)in different regions,urban and rural distribution,annual family income,parents'educational background,age,and gender.(2)The length of sitting was statistically significant(P＜0.01)among multiple groups in different regions,family annual income,parental education,and gender.However,there was no statistically significant difference between groups of different ages and urban-rural distribution(P＞0.05).(3)The analysis of multiple linear regression model showed that the total score of health literacy was positively correlated with the family's annual income and the mother's education,and nega-tively correlated with the father's education and the length of sitting.Standardized regression coefficientβcomparison:Father's education(-0.32)＞family annual income(0.15)＞mother's education(0.09)＞average daily sitting time(-0.02),with father's education having the greatest impact,fol-lowed by family annual income.The length of sitting was positively related to the family's annual income and the mother's educational background,and negatively related to the total score of health literacy.Standardized regression coefficientβ comparison:Annual family income(0.14)＞education background of mother(0.13)＞total score of health literacy(-0.02),with the impact of annual family income the largest,followed by education background of mother.Conclusion:China's first and second grade high school students generally spend a long time sitting every day,and the level of health literacy is generally low.The level of health literacy and sitting time are negatively correlated with each other,and are most in-fluenced by the educational background of high school students'parents and their family economic levels.