The impact of dysbiosis in oropharyngeal and gut microbiota on systemic inflammatory response and short-term prognosis in acute ischemic stroke with preceding infection.

Background: Stroke is a devastating disease and ranks as the second leading cause of death and disability globally. Several studies have shown that preceding infection (PI) of upper respiratory tract are strongly associated with acute ischemic stroke (AIS). However, the clinical implications and underlying pathological mechanisms remain unclear. Methods: In this study, 16S rRNA gene sequencing was employed to compare the structural characteristics of oropharyngeal and gut microbiota in AIS patients with or without PI and normal controls (NCs; 30 cases each), and systemic inflammatory markers were detected to explore the relationship between upper respiratory tract infections (URTIs) and subsequent stroke severity and functional outcome and the potential mechanism. Results: We found that patients with AIS-PI exhibited elevated serum WBC, NE, CRP, and Hcy levels, as well as a higher 90-day mRS score. Oropharyngeal and gut microbiota analysis showed that AIS and AIS-PI patients exhibited increased microbial richness in sequence. Principal coordinate analysis of the microbiota demonstrated significant differences in microbiota composition among the three groups. In AIS-PI patients, Megamonas, Megasphaera, Ruminococcaceae UCG 004, Rothia, and Streptococcus were significantly enriched in the gut. Opportunistic pathogens, including Thermus, uncultured Veillonella sp., and Oribacterium sinu, were found to be significantly enriched in the oropharynx. The dysregulated microbiota were positively correlated with systemic inflammatory markers, stroke severity, and poor prognosis. In contrast, short-chain fatty acid-producing bacteria Eisenbergiella, bacterium NLAE, Fusicatenibacter, Ruminococcaceae, and Faecalibacterium were enriched in NCs. Their abundances were negatively correlated with systemic inflammatory markers, stroke severity and poor prognosis. Conclusion: Our findings suggest that PIs of the upper respiratory tract may contribute to poor short-term functional outcome in AIS patients by causing disturbance of the oropharyngeal and gut microbiota and promoting elevated systemic inflammation levels.

Strigolactones Negatively Regulate Tobacco Mosaic Virus Resistance in Nicotiana benthamiana.

Strigolactones (SLs) are plant hormones that regulate diverse developmental processes and environmental responses in plants. It has been discovered that SLs play an important role in regulating plant immune resistance to pathogens but there are currently no reports on their role in the interaction between Nicotiana benthamiana and the tobacco mosaic virus (TMV). In this study, the exogenous application of SLs weakened the resistance of N. benthamiana to TMV, promoting TMV infection, whereas the exogenous application of Tis108, a SL inhibitor, resulted in the opposite effect. Virus-induced gene silencing (VIGS) inhibition of two key SL synthesis enzyme genes, NtCCD7 and NtCCD8, enhanced the resistance of N. benthamiana to TMV. Additionally, we conducted a screening of N. benthamiana related to TMV infection. TMV-infected plants treated with SLs were compared to the control by using RNA-seq. The KEGG enrichment analysis and weighted gene co-expression network analysis (WGCNA) of differentially expressed genes (DEGs) suggested that plant hormone signaling transduction may play a significant role in the SL-TMV-N. benthamiana interactions. This study reveals new functions of SLs in regulating plant immunity and provides a reference for controlling TMV diseases in production.

Nomogram to predict ventilator-associated pneumonia in large vessel occlusion stroke after endovascular treatment: a retrospective study.

Background: Ventilator-Associated Pneumonia (VAP) severely impacts stroke patients' prognosis after endovascular treatment. Hence, this study created a nomogram to predict the occurrence of VAP after endovascular treatment. Methods: The individuals with acute ischemic stroke and large vessel occlusion (AIS-LVO) who received mechanical ventilation and endovascular therapy between July 2020 and August 2023 were included in this retrospective study. The predictive model and nomogram were generated by performing feature selection optimization using the LASSO regression model and multifactor logistic regression analysis and assessed the evaluation, verification and clinical application. Results: A total of 184 individuals (average age 61.85 ± 13.25 years, 73.37% male) were enrolled, and the rate of VAP occurrence was found to be 57.07%. Factors such as the Glasgow Coma Scale (GCS) score, duration of stay in the Intensive Care Unit (ICU), dysphagia, Fazekas scale 2 and admission diastolic blood pressure were found to be associated with the occurrence of VAP in the nomogram that demonstrating a strong discriminatory power with AUC of 0.862 (95% CI, 0.810-0.914), and a favorable clinical net benefit. Conclusion: This nomogram, comprising GCS score, ICU duration, dysphagia, Fazekas scale 2 and admission diastolic blood pressure, can aid clinicians in predicting the identification of high-risk patients for VAP following endovascular treatment in large vessel occlusion stroke.

Broad-spectrum nano-bactericide utilizing antimicrobial peptides and bimetallic Cu-Ag nanoparticles anchored onto multiwalled carbon nanotubes for sustained protection against persistent bacterial pathogens in crops.

Worldwide crop yields are threatened by persistent pathogenic bacteria that cause significant damage and jeopardize global food security. Chemical pesticides have shown limited effectiveness in protecting crops from severe yield loss. To address this obstacle, there is a growing need to develop environmentally friendly bactericides with broad-spectrum and sustained protection against persistent crop pathogens. Here, we present a method for preparing a nanocomposite that combines antimicrobial peptides (AMPs) and bimetallic Cu-Ag nanoparticles anchored onto multiwalled carbon nanotubes (MWCNTs). The nanocomposite exhibited dual antibacterial activity by disrupting bacterial cell membranes and splicing nucleic acids. By functionalizing MWCNTs with small AMPs (sAMPs), we achieved enhanced stability and penetration of the nanocomposite, and improved loading capacity of the Cu-Ag nanoparticles. The synthesized MWCNTs&CuNCs@AgNPs@P nanocomposites demonstrated broad-spectrum lethality against both Gram-positive and Gram-negative bacterial pathogens. Glasshouse pot trials confirmed the efficacy of the nanocomposites in protecting rice crops against bacterial leaf blight and tomato crops against bacterial wilt. These findings highlight the excellent antibacterial properties of the MWCNTs&CuNCs@AgNPs@P nanocomposite and its potential to replace chemical pesticides, offering significant advantages for agricultural applications.

Gingerenone A Alleviates Ferroptosis in Secondary Liver Injury in Colitis Mice via Activating Nrf2-Gpx4 Signaling Pathway.

Patients with ulcerative colitis (UC) have been found to be frequently associated with secondary liver injury (SLI). In this study, we investigated the protective effect of GA on dextran sodium sulfate (DSS)-induced SLI in mice and its mechanism. The SLI was established by adding 4% DSS in the drinking water of mice, and the effects of GA (5, 20 mg/kg, p.o., once a day for 7 days) in hepatic tissues were analyzed. HepG2 cells were induced by lipopolysaccharide (LPS) to detect the effect of GA on ferroptosis and the underlying mechanism. Pathological damage was determined by H&E. Liver parameters (AST and ALT), antioxidant enzyme activities (MDA and SOD), and the level of Fe2+ in the liver were detected by kits. Cytokine levels (TNF-α, IL-1ß, and IL-6) and Gpx4 activity in the liver were detected by ELISA. Finally, the activation of nuclear factor erythroid 2-like 2 (Nrf2) was detected to explore the mechanism. The results indicated that GA significantly attenuated DSS-induced hepatic pathological damage, liver parameters, and cytokine levels and increased the antioxidant enzyme activities. Moreover, GA attenuated ferroptosis in DSS-induced liver injury and upregulated Gpx4 expression in DSS-induced mice. Mechanistic experiments revealed that GA activated Nrf2 in mice. Taken together, this study demonstrates that GA can alleviate ferroptosis in SLI in DSS-induced colitis mice, and its protective effects are associated with activating the Nrf2-Gpx4 signaling pathway.

Ethyl Acetate Fraction of Hedyotis diffusa Willd Induces Apoptosis via JNK/Nur77 Pathway in Hepatocellular Carcinoma Cells.

Background: Hepatocellular carcinoma (HCC) is characterized by poor diagnosis and high mortality. Novel and efficient therapeutic agents are urgently needed for the treatment. Hedyotis diffusa Willd (HDW) is used to treat cancers, especially HCC in China. Purpose: The study aimed to identify the main anti-HCC extract in HDW and to explore the mechanism of the active extract. Materials and Methods: The high-performance liquid chromatography-quadrupole-time of flight mass spectrometry (HPLC-QTOF-MS) method was used for the simultaneous determination of main compounds in the ethyl acetate fraction of HDW (EHDW). The toxicity test of different HDW fractions was carried out on larvae at 2 day-post-fertilization (dpf) for 72 h. The in vivo anti-HCC effect of different HDW fractions was evaluated on a zebrafish tumor model by immersion administration. The antiproliferative effect of HDW fractions was determined with MTT assay, as well as hematoxylin and eosin (HE) staining assay. Hoechst 33258 staining was used to observe changes in nucleus morphology. Flow cytometry analysis was used to investigate apoptosis induction. Western blot analysis was used to examine apoptosis-related proteins, and key proteins in JNK/Nur77 signaling pathway. SP600125 was served to validate the apoptotic mechanism. Results: EHDW showed the strongest tumor cell growth inhibitory effect on zebrafish tumor model. Further study revealed that EHDW induced apoptosis in zebrafish tumor model and in cultured Hep3B cells. Meanwhile, it has been shown that the levels of BCL2-associated X (Bax), cytochrome c (cyto c), cleaved-caspase 3, and poly-ADP-ribose polymerase (PARP) cells were upregulated. In contrast, the level of antiapoptotic B cell lymphoma-2 (Bcl-2) was downregulated in Hep3B cells. Additionally, EHDW activated JNK/Nur77 pathway by increasing the levels of p-JNK(Thr183/Tyr185) and p-Nur77(Ser351). Further study showed that blockage of JNK by SP600125 reversed EHDW-induced JNK/Nur77 pathway and the downstream apoptotic proteins. Conclusion: In conclusion, EHDW exerted the anti-HCC effect, which may be attributed to the activation of JNK/Nur77 pathway. This study supported the rationale of HDW as an HCC therapeutic agent.

Efficient Red Thermally Activated Delayed Fluorescence Emitters Based on a Dibenzonitrile-Substituted Dipyrido[3,2-a:2',3'-c]phenazine Acceptor.

How to construct efficient red-emitting thermally activated delayed fluorescence (TADF) materials is a challenging task in the field of organic light-emitting diodes (OLEDs). Herein, an electron acceptor moiety, 3,6-DCNB-DPPZ, with high rigidity and strong acceptor strength was designed by introducing two cyanobenzene groups into the 3,6-positions of a dipyrido[3,2-a:2',3'-c]phenazine unit. A red-emitting compound, 3,6_R, has been designed and synthesized by combining the rigid acceptor unit with two triphenylamine donors. Due to high molecular rigidity and strong intramolecular charge transfer characteristic in donor-acceptor-donor skeleton, 3,6_R exhibited a red emission with a high photoluminescence quantum yield of 86% and distinct TADF nature with short delayed fluorescence lifetime of about 1 microsecond. Accordingly, the OLED using 3,6_R as the guest emitter gained a high external quantum efficiency of 12.0% in the red region with an electroluminescence peak of 619 nm and favorable Commission Internationale de l'Eclairage coordinates of (0.62, 0.38).

1ß-OH-arenobufagin induces mitochondrial apoptosis in hepatocellular carcinoma through the suppression of mTOR signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Chansu, dried secretions from Bufonidae, has long been used for cancer treatment as a traditional Chinese medicine. In searching for effective anti-hepatoma agents from Chansu, our preliminary drug screening found that a bufadienolide, namely 1ß-hydroxyl-arenobufagin (1ß-OH-ABF), displays anti-hepatoma activities. However, the anti-hepatoma effects and molecular mechanisms of 1ß-OH-ABF have not been defined. AIM OF THE STUDY: To evaluate the anti-hepatoma activity of 1ß-OH-ABF against liver cancer Hep3B and HepG2 cells in vitro and in vivo, as well as explore the underlying mechanisms. MATERIALS AND METHODS: The anti-proliferative effects of 1ß-OH-ABF on liver cancer Hep3B, HepG2, HuH7, SK-HEP-1 and normal hepatocyte LO2 cells were examined by MTT assay and colony formation assay. Hoechst 33258 staining and Annexin V-FITC/PI staining assay were used to analyze apoptosis induced by 1ß-OH-ABF. The collapse of the mitochondrial membrane potential (ΔΨm) was detected by JC-1 staining assay. Western blotting was used to examine the expression levels of targeted proteins. The role of mTOR in 1ß-OH-ABF-induced apoptosis was investigated using small interfering RNA (siRNA) transfection. Zebrafish xenograft model was established to evaluate the anti-hepatoma effects of 1ß-OH-ABF in vivo. RESULTS: We found that 1ß-OH-ABF inhibits the proliferation of Hep3B, HepG2, HuH7, SK-HEP-1 cells but has little cytotoxicity towards LO2 cells. 1ß-OH-ABF induces mitochondria dysfunction and triggers mitochondria apoptotic pathway, which is accompanied by the loss of ΔΨm, upregulation and translocation of Bax, as well as cleavages of caspase-9, caspase-3 and PARP. Mechanistically, 1ß-OH-ABF markedly decreases the expression level of p-AKT/AKT and p-mTOR (Ser2248 and Ser2481)/mTOR in a time-dependent manner. Inhibition of mTOR by siRNA strengthens 1ß-OH-ABF-mediated apoptosis. Critically, 1ß-OH-ABF shows a marked in vivo anti-hepatoma effect on human Hep3B cell xenografts in zebrafish model. CONCLUSION: 1ß-OH-ABF induces mitochondrial apoptosis through the suppression of mTOR signaling in vitro and in vivo, indicating that 1ß-OH-ABF may serve as a potential agent for the treatment of liver cancer.

Achieving 21% External Quantum Efficiency for Nondoped Solution-Processed Sky-Blue Thermally Activated Delayed Fluorescence OLEDs by Means of Multi-(Donor/Acceptor) Emitter with Through-Space/-Bond Charge Transfer.

Although numerous thermally activated delayed fluorescence (TADF) organic light-emitting diodes (OLEDs) have been demonstrated, efficient blue or even sky-blue TADF-based nondoped solution-processed devices are still very rare. Herein, through-space charge transfer (TSCT) and through-bond charge transfer (TBCT) effects are skillfully incorporated, as well as the multi-(donor/acceptor) characteristic, into one molecule. The former allows this material to show small singlet-triplet energy splitting (ΔE ST) and a high transition dipole moment. The latter, on the one hand, further lights up multichannel reverse intersystem crossing (RISC) to increase triplet exciton utilization via degenerating molecular orbitals. On the other hand, the nature of the molecular twisted structure effectively suppresses intermolecular packing to obtain high photoluminescence quantum yield (PLQY) in neat flims. Consequently, using this design strategy, T-CNDF-T-tCz containing three donor and three acceptor units, successfully realizes a small ΔE ST (≈0.03 eV) and a high PLQY (≈0.76) at the same time; hence the nondoped solution-processed sky-blue TADF-OLED displays record-breaking efficiency among the solution process-based nondoped sky-blue OLEDs, with high brightness over 5200 cd m-2 and external quantum efficiency up to 21.0%.

Novel Nitrogen-Containing Heterocyclic Non-Fullerene Acceptors for Organic PhotovoltaicCells: Different End-Capping Groups Leading to a Big Difference of Power Conversion Efficiencies.

Novel cores for high performance nonfullerene acceptors (NFAs) remain to be developed. In this work, two new n-type nitrogen-containing organic heterocyclic NFAs, namely, BDTN-BF and BDTN-Th, were designed and synthesized based on a new seven fused-ring core (BDTN) with two different end-capping groups. As a result, BDTN-BF possessed similar absorption spectra in solution and solid state to BDTN-Th, but a slightly higher maximum molar extinction coefficient. Manufacturing the polymer solar cells with PM6 as the donor, the photovoltaic performance of BDTN-BF and BDTN-Th was investigated. The PM6:BDTN-BF-based device achieved the highest power conversion efficiency (PCE) of 11.54% with a high Jsc of 20.20 mA cm-2, a fill factor (FF) of 61.46%, and a large Voc of 0.93 V, and the energy loss (Eloss) was calculated to be 0.48 eV. Comparatively, the PM6:BDTN-Th-based device achieved the maximum PCE value of only 3.53% because of inadequate Jsc and FF. The higher Jsc and FF for the PM6:BDTN-BF-based device was mainly due to the effective electron transfer from PM6 to BDTN-BF, more balanced µh/µe, higher electron mobility of the neat film, better charge collection and dissociation efficiency, and more favorable morphology. These results demonstrate that the acceptors with nearly identical absorption spectra could result in a significant difference in photovoltaic performance, which stress the importance of end-capping units. Furthermore, few NFA-based devices achieve large Voc and high Jsc simultaneously as one based on PM6:BDTN-BF, indicating that nitrogen hybridization of NFAs may be an efficient strategy to realize high and balanced Voc and Jsc.

Experimental evidence and network pharmacology identify the molecular targets of Tong Sheng tablets in cerebral ischemia reperfusion injury.

PURPOSE: Tong Sheng tablets (TSTs) have long been used for treating cerebral ischemic reperfusion injury (CIRI) in clinic, but the underlying mechanism remains unknown. Therefore, in this study, TSTs were evaluated systematically using chemical analysis, network pharmacology and classical pharmacology. METHODS: The first part was TSTs quality control including TSTs fingerprint establishment and chemicals identification. In the second part, network pharmacology analysis and bioinformatics were combined to construct a compound-target-disease network, which can screen out key targets or pathways, revealing complex molecule mechanism of TSTs. The last part was experiment verification. Classical pharmacology of TSTs was investigated in vivo to verify the results of network pharmacology. RESULTS: (1) Fingerprints of TSTs were established, and 11 characteristic peaks were identified using HPLC. (2) Network pharmacology and bioinformatics suggested that the protection of TSTs in treating CIRI might be related to regulation of oxidative stress, inflammation and apoptosis, and some key molecules such as Nrf2, IL-1ß, TNF, Bcl-2 and Cyt-C involved in the pathways. (3) TSTs significantly improved neurologic behavior scores, decreased the areas of ischemic necrosis and neuronal necrosis, and increased Nissl body counts. Besides, TSTs significantly decreased pro-inflammatory cytokine (IL-1ß, TNF-α) and pro-oxidative product levels (LPO, MDA) and increased anti-oxidative product levels (NO, SOD). TSTs downregulated the protein expressions of Nrf2 and HO-1. Meanwhile, TSTs reduced apoptotic cell counts, downregulated the protein expressions of Cyt-C and Bax, and upregulated the protein expression of Bcl-2. In terms of autophagy, TSTs enhanced LC-3B protein expression. CONCLUSION: The present results illustrated that TSTs effectively alleviated CIRI, and the underlying mechanism might be associated with multiple molecular pathways. Herein, we established a primary pattern for studying Chinese herbal compounds and provided basic guidance for future investigation.

Realizing 22.5% External Quantum Efficiency for Solution-Processed Thermally Activated Delayed-Fluorescence OLEDs with Red Emission at 622 nm via a Synergistic Strategy of Molecular Engineering and Host Selection.

Developing high-efficiency solution-processable thermally activated delayed-fluorescence (TADF) emitters, especially in longer wavelength regions, is a formidable challenge. Three red TADF emitters, namely NAI_R1, NAI_R2, and NAI_R3, are developed by phenyl encapsulation and tert-butyl substitution on a prototypical 1,8-naphthalimide-acridine hybrid. This design strategy not only grants these molecules high solubility, excellent thermal stability, and good film-forming ability, but also pulls down their charge-transfer (CT) energy levels excited states. Furthermore, dispersing these emitters into two different host materials of mCP and mCPCN finely tailors their CT-state energy levels. More importantly, a synergistic combination of molecular engineering and host selection can effectively manipulate the competition between the radiative and nonradiative decay rates of the CT singlet states of these emitters and the reverse intersystem crossing from their triplet to singlet states. Consequently, the optimal combination of NAI_R3 emitter and mCP host successfully results in a state-of-the-art external quantum efficiency (EQE) of 22.5% for solution-processed red TADF organic light-emitting diodes (OLEDs) with an emission peak above 620 nm. This finding demonstrates that a synergistic strategy of molecular engineering and host selection with TADF emitters could provide a new pathway for developing efficient solution-processable TADF systems.

Correction: Synthesis of DNA-guided silver nanoparticles on a graphene oxide surface: enhancing the antibacterial effect and the wound healing activity.

[This corrects the article DOI: 10.1039/C8RA04933E.].

A Novel Delivery System of Cyclovirobuxine D for Brain Targeting: Angiopep-Conjugated Polysorbate 80-Coated Liposomes via Intranasal Administration.

The blood-brain barrier (BBB) poses a challenge for the treatment of cerebrovascular diseases including cerebral ischemia-reperfusion injury, Parkinson's syndrome, and cerebral tumors. Nanotechnology has developed as a promising strategy for drug delivery applications to the brain, especially liposomes (Lps) that have shown an intrinsic ability to cross the BBB. Angiopep-2 (ANG), a ligand for low-density lipoprotein receptor-related protein-1 (LRP1), is a good prospect for use as a targeting ligand for brain delivery using Lps. It was also reported that Polysorbate 80 (Tween 80, T80) plays a special role in brain targeting. Moreover, the nasal drug delivery method has attracted increased attention with its brain targeting capability in the clinical treatment of cerebrovascular diseases. The aim of this work was to evaluate the capability of Angiopep-conjugated Polysorbate 80-Coated Liposomes in the delivery of cyclovirobuxine D across the BBB in vitro and in vivo. For this purpose, we first synthesized DSPE-PEG2000-Angiopep-2 then cyclovirobuxine D was encapsulated in Angiopep-conjugated Polysorbate 80-Coated Liposomes (T80-An2-CVB-D-Lps) prepared by thin film evaporation and an ultrasonic technique. Formulations were characterized in terms of encapsulation efficiency, transmission electron microscope (TEM) morphology, size distribution, and zeta potential. Angiopep-conjugated Polysorbate 80-Coated Liposomes enhanced in vitro BBB transport of CVB-D compared to the nontargeted liposomes and the CVB-D solution in the BBB model consisting of brain microvascular endothelial (bEnd.3) cells. To evaluate the brain targeting of T80-An2-CVB-D-Lps in vivo, microdialysis samples were collected from the striatum and blood simultaneously. Rats were dosed with brain-targeting liposomes, CVB-D liposomes and CVB-D solution by intranasal administration and with brain-targeting liposomes by intravenous injection. The results showed that T80-An2-CVB-D-Lps were spherical, small (approximately 80 nm), homogeneously dispersed, negatively charged and possessed a high encapsulation efficiency. T80-An2-CVB-D-Lps crossed the BBB model better than the other treatments did. In addition, in a pharmacodynamic study, there was a higher AUC in the brain after T80-An2-CVB-D-Lps by intranasal administration. In conclusion, T80-An2-Lps can enhance the BBB permeability and improve the transport of CVB-D to the brain. This coadministration strategy can be utilized to enhance the brain accumulation in other cerebrovascular diseases.

Synthesis of DNA-guided silver nanoparticles on a graphene oxide surface: enhancing the antibacterial effect and the wound healing activity.

The occurrence of antibiotic resistance against pathogens is rapidly increasing and endangering the efficacy of antibiotics. Thus, finding a way to address this problem has become a major challenge due to the inability of conventional antibiotics to kill these multidrug-resistant bacteria. In order to further enhance the antibacterial ability and reduce the possibility of antibiotic resistance, we developed a simple two-step approach and synthesized a new nanocomposite by directly loading single-stranded DNA (ssDNA)-guided silver nanoparticles (AgNPs) on graphene oxide (ssDNA-AgNPs@GO). Through systematically evaluating the bactericidal activity and wound healing capability, we found that ssDNA-AgNPs@GO exhibited synergistic antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Bacillus subtilis with low minimum inhibitory concentrations (6.8 µg mL-1, 6.8 µg mL-1, 11.9 µg mL-1 and 10.2 µg mL-1, respectively) and large-diameter inhibition zones (12.83 ± 0.63 mm, 13.14 ± 0.37 mm, 8.6 ± 0.9 mm and 8.93 ± 0.47 mm, respectively). Furthermore, the wound healing experiment indicated that it has a striking ability to remedy wound infection caused by Staphylococcus aureus bacteria. In conclusion, the properties of ssDNA-AgNPs@GO with enhanced antibacterial and wound healing capability will give it broad applications in the future.