Antitumor effects of IOX1 combined with bevacizumab-induced apoptosis and immunity on colorectal cancer cells.

Colorectal cancer (CRC), as a fatal cancer, is one of the most common cancers worldwide. Although the standard treatment for colorectal cancer is well researched and established, long-term patient survival remains poor, and mortality remains high. Therefore, more and more effective treatment options are needed. To evaluate the efficacy of bevacizumab, the histone demethylase inhibitor IOX1, or their combination for the treatment of colorectal cancer, we examined the effects of IOX1, bevacizumab, and IOX1 combined with bevacizumab on cell activity, proliferation, and migration of colorectal cancer cell lines HCT116, RKO, and CT26 by CCK8, colony formation assay, wound healing assay, and transwell assay. The effects of the drugs alone as well as in combination on apoptosis in colorectal cancer cell lines were examined by flow cytometry and further validated by Western blotting for apoptosis-related proteins. The antitumor effects of treatment alone or in combination on colorectal cancer cells were examined in animal models. Mice were injected subcutaneously with CT26 cells and the growth and immune infiltration in tumor tissues were detected by IHC after drug treatment. We found that IOX1 could effectively inhibit the activity of CRC cells and had a significant inhibitory effect on the proliferation and migration of CRC cells. The apoptosis rate increased in a dose-dependent manner after IOX1 treatment on colorectal cancer cells, and the expression of apoptosis-related proteins changed accordingly. Further combination with bevacizumab revealed that the combination had a more significant effect on the proliferation, migration, and apoptosis of CRC cells than either IOX1 or bevacizumab alone. In vivo experiments have found that both alone and combination drugs can inhibit the growth of mouse tumors, but the effect of combination inhibition is the most obvious. Combination therapy significantly inhibited the expression of proliferative marker (Ki67) in tumor xenograft models, and increased content of antigen-specific CD4+, CD8+T cell growth, and granzymeB (GZMB), which is associated with T cell cytotoxicity, was detected in combination therapy. Immunoassays suppressed the expression of relevant PD-1 and decreased. The anticancer drug bevacizumab and the histone demethylase inhibitor IOX1 may inhibit colon cancer cell growth by regulating apoptosis. The inhibitory effect of combination therapy on tumor growth may be achieved, in part, through upregulation of infiltration-mediated tumor immunity by T lymphocytes. The combination of IOX1 and bevacizumab produced significant synergistic effects. This study aims to provide a new direction for CRC combination therapy.

Identification of whole-genome mutations and structural variations of bile cell-free DNA in cholangiocarcinoma.

Bile cell-free DNA (cfDNA) has been reported as a promising liquid biopsy tool for cholangiocarcinoma (CCA), however, the whole-genome mutation landscape and structural variants (SVs) of bile cfDNA remains unknown. Here we performed whole-genome sequencing on bile cfDNA and analyzed the correlation between mutation characteristics of bile cfDNA and clinical prognosis. TP53 and KRAS were the most frequently mutated genes, and the RTK/RAS, homologous recombination (HR), and HIPPO were top three pathways containing most gene mutations. Ten overlapping putative driver genes were found in bile cfDNA and tumor tissue. SVs such as chromothripsis and kataegis were identified. Moreover, the hazard ratio of HR pathway mutations were 15.77 (95% CI: 1.571-158.4), patients with HR pathway mutations in bile cfDNA exhibited poorer overall survival (P = 0.0049). Our study suggests that bile cfDNA contains genome mutations and SVs, and HR pathway mutations in bile cfDNA can predict poor outcomes of CCA patients.

Effects of Benzo[α]pyrene on Mucus Secretion and Tissue Remodeling in a Rat Model of Allergic Rhinitis.

OBJECTIVES: Exposure to benzo[α]pyrene (BaP) increases the incidence and severity of allergic rhinitis (AR), but the underlying mechanisms remain unclear. Thus, we investigated the in vivo effects of BaP exposure on mucus hypersecretion and tissue remodeling in a rat model of AR. METHODS: Female Sprague-Dawley rats were randomly divided into 4 groups: a negative control group, a group of healthy rats exposed to BaP, a group of rats with ovalbumin (OVA)-induced AR, and a group of AR model rats exposed to BaP. Nasal symptoms and levels of OVA-specific serum immunoglobulin E (IgE) were measured in each individual rat. Moreover, examination of goblet cell hyperplasia and collagen deposition was carried out with periodic acid-Schiff (PAS) staining and Masson trichrome (MT) staining. Mucin 5AC (MUC5AC) expression was assessed by immunohistochemistry. RESULTS: BaP significantly increased the number of sneezes, the number of nasal rubs and the levels of OVA-specific serum IgE in rats with AR. Statistically significant differences in goblet cell hyperplasia and collagen deposition were observed between the BaP-exposed AR model group and the AR model group. Immunohistochemical results showed that the nasal mucosa of AR model rats displayed markedly elevated MUC5AC expression after BaP exposure. CONCLUSION: Our data indicate that mucus hypersecretion and the development of nasal remodeling might be pathophysiologic mechanisms underlying increased susceptibility to AR after exposure to BaP.

Study on the application of a segmented sodium citrate solution anticoagulation strategy in critically ill patients receiving CRRT: a prospective, randomized controlled study.

BACKGROUND: To explore the feasibility and effectiveness of a segmented sodium citrate solution anticoagulation strategy in patients receiving CRRT. METHODS: A prospective, randomized controlled study was conducted. RESULTS: According to the inclusion and exclusion criteria, 80 patients were included and randomly divided into two groups. Moreover, coagulation indices, liver function indices, renal function indices, and SOFA and APACHE II scores did not significantly differ between the two groups (P > 0.05). The coagulation grade of the venous ports in the experimental group was lower than that in the control group and the two groups of filters, but the difference was not statistically significant (P = 0.337). Both sodium citrate solution infusion methods maintained a low blood calcium concentration (0.25-0.45 mmol/L) in the peripheral circulation pathway, and no patient developed hypocalcaemia (< 1.0 mmol/L). The lifespans of the extracorporeal circulation tube in the experimental group and the control group were 69.43 ± 1.49 h and 49.39 ± 2.44 h, respectively (t = 13.316, P = 0.001). CONCLUSION: The segmented citrate solution anticoagulation strategy could extend the lifespan of the extracorporeal circulation tube and improve CRRT efficacy. TRIAL REGISTRATION: The Chinese Clinical Trial Registry number is ChiCTR2200057272. Registered on March 5, 2022.

A plug-and-play monofunctional platform for targeted degradation of extracellular proteins and vesicles.

Existing strategies use bifunctional chimaeras to mediate extracellular protein degradation. However, these strategies rely on specific lysosome-trafficking receptors to facilitate lysosomal delivery, which may raise resistance concerns due to intrinsic cell-to-cell variation in receptor expression and mutations or downregulation of the receptors. Another challenge is establishing a universal platform applicable in multiple scenarios. Here, we develop MONOTAB (MOdified NanOparticle with TArgeting Binders), a plug-and-play monofunctional degradation platform that can drag extracellular targets into lysosomes for degradation. MONOTAB harnesses the inherent lysosome-targeting ability of certain nanoparticles to obviate specific receptor dependency and the hook effect. To achieve high modularity and programmable target specificity, we utilize the streptavidin-biotin interaction to immobilize antibodies or other targeting molecules on nanoparticles, through an antibody mounting approach or by direct binding. Our study reveals that MONOTAB can induce efficient degradation of diverse therapeutic targets, including membrane proteins, secreted proteins, and even extracellular vesicles.

Soluble RAGE attenuates myocardial I/R injury by suppressing interleukin-6.

BACKGROUND: Inflammatory responses play a central role in myocardial ischemia/reperfusion (I/R) injury. Previous studies have demonstrated that the receptor for advanced glycation end-products (RAGE) is involved in the pro-inflammatory process of myocardial I/R injury by binding to diverse ligands. Thus, the inhibitory effects of soluble receptor for advanced glycation end-products (sRAGE), a decoy receptor for RAGE, on myocardial I/R injury may be associated with a reduced inflammatory state. METHODS: In this study, plasma levels of several inflammatory mediators were measured in patients with acute myocardial infarction (AMI) and I/R-treated cardiomyocyte-specific sRAGE knock-in (sRAGE-CKI) mice. Cardiac function, infarct size, and macrophage phenotypes were examined and documented in mouse hearts. RESULTS: We enrolled 38 patients diagnosed with myocardial infarction (AMI) [mean age, 58.81 ±â€…10.40 years] and 26 control with negative coronary arteriographic findings [mean age, 61.84 ±â€…8.57 years]. The results showed that sRAGE levels were significantly elevated in the AMI patient group compared with the control group (1905.00 [1462.50, 2332.5] vs 1570.00 [1335.00, 1800.00] pg/mL, p < 0.05), which were negatively correlated with interleukin (IL)-1, IL-6, and IL-8 levels. Cardiac-specific overexpression of sRAGE dramatically improved cardiac function and reduced infarct size during myocardial I/R. Furthermore, sRAGE overexpression decreased the plasma IL-6 levels and pro-inflammatory iNOS+ M1-macrophages, and increased CD206+ M2-macrophages in the mouse hearts. CONCLUSIONS: Our findings suggested that sRAGE protects the heart from myocardial I/R injury by inhibiting the infiltration of pro-inflammatory M1-macrophages, and subsequently decreasing IL-6 secretion.

Differential distribution of fibrovascular proliferative membranes in 25-gauge vitrectomy for proliferative diabetic retinopathy.

AIM: To analyze the distribution of fibrovascular proliferative membranes (FVPMs) in proliferative diabetic retinopathy (PDR) patients that treated with pars plana vitrectomy (PPV), and to evaluate the outcomes separately. METHODS: This was a retrospective and cross-sectional study. Consecutive 25-gauge (25-G) PPV cases operated for PDR from May 2018 to April 2020. According to the FVPMs images outlined after operations, subjects were assigned into three groups: arcade type group, juxtapapillary type group, and central type group. All patients were followed up for over one year. General characteristics, operation-related variables, postoperative parameters and complications were recorded. RESULTS: Among 103 eyes recruited, the FVPMs distribution of nasotemporal and inferiosuperioral was significantly different (both P<0.01), with 95 (92.23%) FVPMs located in the nasal quadrants, and 74 (71.84%) in the inferior. The eyes with a central FVPM required the longest operation time, with silicon oil used in most patients, generally combined with tractional retinal detachment (RD) and rhegmatogenous RD, the worst postoperative best-corrected visual acuity (BCVA) and the highest rates of recurrent RD (all P<0.05). FVPM type, age of onset diabetes mellitus, preoperative BCVA, and combined with tractional RD and rhegmatogenous RD were significantly associated with BCVA improvement (all P<0.05). Compared with the central type group, the arcade type group had higher rates of BCVA improvement. CONCLUSION: FVPMs are more commonly found in the nasal and inferior mid-peripheral retina in addition to the area of arcade vessels. Performing 25-G PPV for treating PDR eyes with central FVPM have relatively worse prognosis.

TREM2 on microglia cell surface binds to and forms functional binary complexes with heparan sulfate modified with 6-O-sulfation and iduronic acid.

The Triggering Receptor Expressed on Myeloid Cells-2 (TREM2), a pivotal innate immune receptor, orchestrates functions such as inflammatory responses, phagocytosis, cell survival, and neuroprotection. TREM2 variants R47H and R62H have been associated with Alzheimer's disease, yet the underlying mechanisms remain elusive. Our previous research established that TREM2 binds to heparan sulfate (HS) and variants R47H and R62H exhibit reduced affinity for HS. Building upon this groundwork, our current study delves into the interplay between TREM2 and HS and its impact on microglial function. We confirm TREM2's binding to cell surface HS and demonstrate that TREM2 interacts with HS, forming HS-TREM2 binary complexes on microglia cell surfaces. Employing various biochemical techniques, including Surface Plasmon Resonance, low molecular weight HS microarray screening, and serial HS mutant cell surface binding assays, we demonstrate TREM2's robust affinity for HS, and the effective binding requires a minimum HS size of approximately 10 saccharide units. Notably, TREM2 selectively binds specific HS structures, with 6-O-sulfation and, to a lesser extent, the iduronic acid residue playing crucial roles. N-sulfation and 2-O-sulfation are dispensable for this interaction. Furthermore, we reveal that 6-O-sulfation is essential for HS-TREM2 ternary complex formation on the microglial cell surface, and HS and its 6-O-sulfation are necessary for TREM2-mediated ApoE3 uptake in microglia. By delineating the interaction between HS and TREM2 on the microglial cell surface and demonstrating its role in facilitating TREM2-mediated ApoE uptake by microglia, our findings provide valuable insights that can inform targeted interventions for modulating microglial functions in Alzheimer's disease.

Dissection of potential anti-osteoporosis mechanism of isopsoralen - a quality control marker in Psoraleae Fructus - by metabolite profiling and network pharmacology.

RATIONALE: Isopsoralen (ISO), a quality control marker (Q-marker) in Psoraleae Fructus, is proven to present an obvious anti-osteoporosis effect. Until now, the metabolism and anti-osteoporosis mechanisms of ISO have not been fully elucidated, greatly restricting its drug development. METHODS: The metabolites of ISO in rats were profiled by using ultrahigh-performance liquid chromatography coupled with time-of-flight mass spectrometry. The potential anti-osteoporosis mechanism of ISO in vivo was predicted by using network pharmacology. RESULTS: A total of 15 metabolites were characterized in rats after ingestion of ISO (20 mg/kg/day, by gavage), including 2 in plasma, 12 in urine, 6 in feces, 1 in heart, 3 in liver, 1 in spleen, 1 in lung, 3 in kidney, and 2 in brain. The pharmacology network results showed that ISO and its metabolites could regulate AKT1, SRC, NFKB1, EGFR, MAPK3, etc., involved in the prolactin signaling pathway, ErbB signaling pathway, thyroid hormone pathway, and PI3K-Akt signaling pathway. CONCLUSIONS: This is the first time for revealing the in vivo metabolism features and potential anti-osteoporosis mechanism of ISO by metabolite profiling and network pharmacology, providing data for further verification of pharmacological mechanism.

Defect detection of printed circuit board assembly based on YOLOv5.

Detection of printed circuit board assembly (PCBA) defects is crucial for improving the efficiency of PCBA manufacturing. This paper proposes PCBA-YOLO, a YOLOv5-based method that can effectively increase the accuracy of PCBA defect detection. First, the spatial pyramid pooling module with cross-stage partial structure is replaced in the neck network of YOLOv5 to capture the resolution features at multiple scales. Second, large kernel convolution is introduced in the backbone network to obtain larger effective receptive fields while reducing computational overhead. Finally, an SIoU loss function that considers the angular cost is utilized to enhance the convergence speed of the model. In addition, an assembled PCBA defect detection dataset named PCBA-DET is created in this paper, containing the corresponding defect categories and annotations of defect locations. The experimental results on the PCB defect dataset demonstrate that the improved method has lower loss values and higher accuracy. Evaluated on the PCBA-DET dataset, the mean average precision reaches 97.3 % , achieving a real-time detection performance of 322.6 frames per second, which considers both the detection accuracy and the model size compared to the YOLO series of detection networks. The source code and PCBA-DET dataset can be accessed at https://github.com/ismh16/PCBA-Dataset .

A nomogram prediction model for postoperative seroma/hematoma in elderly subjects after TAPP.

BACKGROUND: Formation of seroma/hematoma is one of the most common postoperative complications following laparoscopic inguinal hernia repair. This study aimed to identify risk factors associated with seroma/hematoma and construct a prediction model. METHODS: Elderly subjects undergoing laparoscopic Transabdominal preperitoneal Patch Plasty (TAPP) were included in this study. The observation endpoint was set as the occurrence of seroma/hematoma within 3 months after TAPP surgery. Independent risk factors were identified through preliminary univariate screening and binary logistic regression analysis. These risk factors were then used to construct a nomogram predictive model using R software. RESULTS: A total of 330 patients were included in the analysis, of which 51 developed seroma/hematoma, resulting in an incidence rate of 15.5%. Obesity (OR: 3.54, 95%CI: 1.45-8.66, P = 0.006), antithrombotic drug use (OR: 2.73, 95%CI: 1.06-7.03, P = 0.037), C-reactive protein (CRP) ≥ 8 (OR: 2.72, 95%CI: 1.04-7.10, P = 0.041, albumin/fibrinogen ratio (AFR) < 7.85 (OR: 2.99, 95%CI: 1.28-7.00, P = 0.012), and lymphocyte/monocyte ratio (LMR) < 4.05 (OR: 12.62, 95%CI: 5.69-28.01, P < 0.001) were five independent risk factors for seroma/hematoma. The nomogram model has well predictive value for seroma/hematoma, with an AUC of 0.879. CONCLUSIONS: The nomogram model based on obesity, antithrombotic drug, CRP, AFR, and LMR has a proved good predictive value and it has potential in clinical practice.

Design of hollow structured nanoreactors for liquid-phase hydrogenations.

Inspired by the attractive structures and functions of natural matter (such as cells, organelles and enzymes), chemists are constantly exploring innovative material platforms to mimic natural catalytic systems, particularly liquid-phase hydrogenations, which are of great significance for chemical upgrading and synthesis. Hollow structured nanoreactors (HSNRs), featuring unique nanoarchitectures and advantageous properties, offer new opportunities for achieving excellent catalytic activity, selectivity, stability and sustainability. Notwithstanding the great progress made in HSNRs, there still remain the challenges of precise synthetic chemistry, and mesoscale catalytic kinetic investigation, and smart catalysis. To this extent, we provide an overview of recent developments in the synthetic chemistry of HSNRs, the unique characteristics of these materials and catalytic mechanisms in HSNRs. Finally, a brief outlook, challenges and further opportunities for their synthetic methodologies and catalytic application are discussed. This review might promote the creation of further HSNRs, realize the sustainable production of fine chemicals and pharmaceuticals, and contribute to the development of materials science.

Exploring the cationic surfactant adsorption efficiency at concentrations relative to the critical micelle concentration by SA/SiO2 microspheres.

Studying the adsorption behavior of cationic surfactants can help to develop more effective strategies to limit their dispersion in the environment. However, there have few studies on the adsorption of cationic surfactants from the perspective of critical micelle concentration (CMC). In this study, with cetyltrimethylammonium bromide (CTAB) and octadecyl trimethylammonium bromide (OTAB) serving as the model cationic surfactants, the effect of CMC on the adsorption behavior of cationic surfactant onto the surface of sodium alginate/silica (SA/SiO2) microspheres was systematically revealed. The adsorption mechanism relative to CMC was investigated under different conditions, including surfactant concentration, pH, temperature, and adsorption time. The results suggest that at identical concentrations, the smaller the CMC value of the cationic surfactants, the greater the adsorption amount (qt). qt for CTAB and OTAB were 583.2 and 678.0 mg/g respectively, with the concentration higher than their CMC value. When the concentration was lower than the CMC value of the cationic surfactants, qt for CTAB and OTAB were 123.2 and 138.7 mg/g, respectively. The CMC value of CTAB was lower than that of OTAB under identical conditions, suggesting that the adsorption of cationic surfactants is related to their CMC. These results are beneficial for the removal of cationic surfactants by adsorption methods.

Microbial enhanced manganese-autotrophic denitrification in reactor: performance, microbial diversity, potential functions.

Autotrophic denitrification technology has gained increasing attention in recent years owing to its effectiveness, economical, and environmentally friendly nature. However, the sluggish reaction rate has emerged as the primary impediment to its widespread application. Herein, a bio-enhanced autotrophic denitrification reactor with modified loofah sponge (LS) immobilized microorganisms was established to achieve efficient denitrification. Under autotrophic conditions, a nitrate removal efficiency of 59.55 % (0.642 mg/L/h) and a manganese removal efficiency of 86.48 % were achieved after bio-enhance, which increased by 20.92 % and 36.34 %. The bioreactor achieved optimal performance with denitrification and manganese removal efficiencies of 99.84 % (1.09 mg/L/h) and 91.88 %. ETSA and 3D-EEM analysis reveled manganese promoting electron transfer and metabolic activity of microorganisms. High-throughput sequencing results revealed as the increase of Mn(II) concentration, Cupriavidus became one of the dominant strains in the reactor. Prediction of metabolic functions results proved the great potential for Mn(II)-autotrophic denitrification of LS bioreactor.

Hepatoprotective dibenzocyclooctadiene lignans from the fruits of Kadsura coccinea.

The phytochemical investigations on the fruits of Kadsura coccinea led to the isolation of six undescribed dibenzocyclooctadiene lignans named kadcolignans B-G, together with eleven previously described analogues. The structures of these compounds were established by spectroscopic methods including NMR, HRESIMS, and CD experiments. All isolated compounds were evaluated for their hepatoprotective activity by measuring the levels of triglyceride (TG), total cholesterol (TC), and reactive oxygen species (ROS) in FFA-induced HepG2 cells. As a result, compounds 4, 5, 9, 13, and 15 showed potent inhibitory effects on hepatocyte lipid accumulation at a concentration of 100 µM. Our research not only broadens the understanding on the chemical composition of K. coccinea but also provides experimental and theoretical evidences supporting the fruit's active ingredients in alleviating nonalcoholic fatty liver disease (NAFLD).

Decoding dynamic visual scenes across the brain hierarchy.

Understanding the computational mechanisms that underlie the encoding and decoding of environmental stimuli is a crucial investigation in neuroscience. Central to this pursuit is the exploration of how the brain represents visual information across its hierarchical architecture. A prominent challenge resides in discerning the neural underpinnings of the processing of dynamic natural visual scenes. Although considerable research efforts have been made to characterize individual components of the visual pathway, a systematic understanding of the distinctive neural coding associated with visual stimuli, as they traverse this hierarchical landscape, remains elusive. In this study, we leverage the comprehensive Allen Visual Coding-Neuropixels dataset and utilize the capabilities of deep learning neural network models to study neural coding in response to dynamic natural visual scenes across an expansive array of brain regions. Our study reveals that our decoding model adeptly deciphers visual scenes from neural spiking patterns exhibited within each distinct brain area. A compelling observation arises from the comparative analysis of decoding performances, which manifests as a notable encoding proficiency within the visual cortex and subcortical nuclei, in contrast to a relatively reduced encoding activity within hippocampal neurons. Strikingly, our results unveil a robust correlation between our decoding metrics and well-established anatomical and functional hierarchy indexes. These findings corroborate existing knowledge in visual coding related to artificial visual stimuli and illuminate the functional role of these deeper brain regions using dynamic stimuli. Consequently, our results suggest a novel perspective on the utility of decoding neural network models as a metric for quantifying the encoding quality of dynamic natural visual scenes represented by neural responses, thereby advancing our comprehension of visual coding within the complex hierarchy of the brain.

Harmine promotes megakaryocyte differentiation and thrombopoiesis by activating the Rac1/Cdc42/JNK pathway through a potential target of 5-HTR2A.

Harmine (HM), a ß-carboline alkaloid extracted from plants, is a crucial component of traditional Chinese medicine (TCM) known for its diverse pharmacological activities. Thrombocytopenia, a common and challenging hematological disorder, often coexists with serious illnesses. Previous research has shown a correlation between HM and thrombocytopenia, but the mechanism needs further elucidation. The aim of this study was to clarify the mechanisms underlying the effects of HM on thrombocytopenia and to develop new therapeutic strategies. Flow cytometry, Giemsa staining, and Phalloidin staining were used to assess HM's impact on Meg-01 and HEL cell differentiation and maturation in vitro. A radiation-induced thrombocytopenic mouse model was employed to evaluate HM's effect on platelet production in vivo. Network pharmacology, molecular docking, and protein blotting were utilized to investigate HM's targets and mechanisms. The results demonstrated that HM dose-dependently promoted Meg-01 and HEL cell differentiation and maturation in vitro and restored platelet levels in irradiated mice in vivo. Subsequently, HM was found to be involved in the biological process of platelet production by upregulating the expressions of Rac1, Cdc42, JNK, and 5-HTR2A. Furthermore, the targeting of HM to 5-HTR2A and its correlation with downstream Rac1/Cdc42/JNK were also confirmed. In conclusion, HM regulates megakaryocyte differentiation and thrombopoiesis through the 5-HTR2A and Rac1/Cdc42/JNK pathways, providing a potential treatment strategy for thrombocytopenia.

Angong Niuhuang Wan ameliorates LPS-induced cerebrovascular edema by inhibiting blood‒brain barrier leakage and promoting the membrane expression of AQP4.

Introduction: Angong Niuhuang Wan (AGNHW), developed during the Qing dynasty (18th century) for the treatment of consciousness disturbances caused by severe infections, has been used to treat brain edema caused by ischemia‒reperfusion. However, it remains unclear whether AGNHW can ameliorate vascular-origin brain edema caused by lipopolysaccharides (LPS). This study explored the ameliorative effects of AGNHW on LPS-induced cerebrovascular edema in mice, as well as the potential underlying mechanisms. Methods: A cerebrovascular edema model was established in male C57BL/6N mice by two intraperitoneal injections of LPS (15 mg/kg), at 0 and 24 h. AGNHW was administered by gavage at doses of 0.2275 g/kg, 0.455 g/kg, and 0.91 g/kg, 2 h after LPS administration. In control mice, normal saline (NS) or AGNHW (0.455 g/kg) was administered by gavage 2 h after intraperitoneal injection of NS. The survival rate, cerebral water content, cerebral venous FITC-dextran leakage, Evans blue extravasation, and expression of vascular endothelial cadherin (VE-cadherin), zonula occludens-1 (ZO-1), claudin-5, phosphorylated caveolin-1 (CAV-1), and cytomembrane and cytoplasmic aquaporin 1 (AQP1) and aquaporin 4 (AQP4) were evaluated. The cerebral tissue phosphoproteome, blood levels of AGNHW metabolites, and the relationships between these blood metabolites and differentially phosphorylated proteins were analyzed. Results: AGNHW inhibited the LPS-induced decrease in survival rate, increase in cerebral water content, decrease in VE-Cadherin expression and increase in phosphorylated CAV-1 (P-CAV-1). AGNHW treatment increased the expression of AQP4 on astrocyte membrane after LPS injection. AGNHW also inhibited the LPS-induced increases in the phosphorylation of 21 proteins, including protein kinase C-α (PKC-α) and mitogen-activated protein kinase 1 (MAPK1), in the cerebral tissue. Eleven AGNHW metabolites were detected in the blood. These metabolites might exert therapeutic effects by regulating PKC-α and MAPK1. Conclusion: AGNHW can ameliorate cerebrovascular edema caused by LPS. This effect is associated with the inhibition of VE-Cadherin reduction and CAV-1 phosphorylation, as well as the upregulation of AQP4 expression on the astrocyte membrane, following LPS injection.

Oropharyngeal microbiome profiling and its association with age and heart failure in the elderly population from the northernmost province of China.

Respiratory tract infections are the most common triggers for heart failure in elderly people. The healthy respiratory commensal microbiota can prevent invasion by infectious pathogens and decrease the risk of respiratory tract infections. However, upper respiratory tract (URT) microbiome in the elderly is not well understood. To comprehend the profiles of URT microbiota in the elderly, and the link between the microbiome and heart failure, we investigated the oropharyngeal (OP) microbiome of these populations in Heilongjiang Province, located in the North-East of China, a high-latitude and cold area with a high prevalence of respiratory tract infection and heart failure. Taxonomy-based analysis showed that six dominant phyla were represented in the OP microbial profiles. Compared with young adults, the OP in the elderly exhibited a significantly different microbial community, mainly characterized by highly prevalent Streptococcus, unidentified_Saccharibacteria, Veillonella, unidentified_Pre votellaceae, and Neisseria. While unidentified_Prevotellaceae dominated in the young OP microbiome. There was competition for niche dominance between Streptococcus and member of Prevotellaceae in the OP. Correlation analysis revealed that the abundance of unidentified_Saccharibacteria was positive, while Streptococcus was negatively correlated to age among healthy elderly. The bacterial structure and abundance in the elderly with heart failure were much like healthy controls. Certain changes in microbial diversity indicated the potential OP microbial disorder in heart failure patients. These results presented here identify the respiratory tract core microbiota in high latitude and cold regions, and reveal the robustness of OP microbiome in the aged, supplying the basis for microbiome-targeted interventions.IMPORTANCETo date, we still lack available data on the oropharyngeal (OP) microbial communities in healthy populations, especially the elderly, in high latitude and cold regions. A better understanding of the significantly changed respiratory tract microbiota in aging can provide greater insight into characteristics of longevity and age-related diseases. In addition, determining the relationship between heart failure and OP microbiome may provide novel prevention and therapeutic strategies. Here, we compared OP microbiome in different age groups and elderly people with or without heart failure in northeastern China. We found that OP microbial communities are strongly linked to healthy aging. And the disease status of heart failure was not a powerful factor affecting OP microbiome. The findings may provide basic data to reveal respiratory bacterial signatures of individuals in a cold geographic region.

Collective Asymmetric Synthesis of Thiosilvatins.

Thiosilvatins are a family of biologically active sulfenylated diketopiperazine natural products. The first members were reported over 40 years ago, but total synthesis of a thiosilvatin has remained elusive. Here, we describe the first, collective, synthesis of the parent epidithiodiketopiperazine (-)-dithiosilvatin and ten related thiosilvatins. Several of the targets are structurally revised. A catalytic asymmetric sulfenylation of triketopiperazines efficiently controls absolute configuration at the thioaminal units. Further synthetic highlights include a diastereoconvergent installation of the requisite cis-orientation of the sulfur atoms and a tandem epidisulfide formation/O-prenylation under mild Mitsunobu conditions. The described methods for late-stage diversification of sensitive bis(methylthio)diketopiperazines offer a blueprint for systematically exploring this interesting 3D-pharmacophore in stereochemically pure form.