Transcriptome and Animal Model Integration Reveals Inhibition of Calcium Homeostasis-Associated Gene ITPKB Alleviates Amyloid Plaque Deposition.

Alzheimer's disease (AD) is a severe neurological illness that causes memory loss and is a global problem. The calcium hypothesis recently steadily evolved in AD. The prospective targets for calcium homeostasis therapy, however, are limited, and gene expression-level research connected to calcium homeostasis in AD remains hazy. In this study, we analyzed the microarray dataset (GSE132903) taken from the Gene Expression Omnibus (GEO) database to investigate calcium homeostasis-related genes for AD. Using immunoblot analysis, we examined the association of ITPKB with inflammation in AD. Additionally, the immunofluorescence technique was employed to assess the impact of pharmacological inhibition of ITPKB on the amyloid-ß (Aß) plaque deposition in APP/PS1 mice. This article's further exploration of calcium homeostasis-related genes has propelled the validation of the calcium homeostasis theory in AD.

Thermal structure regulates the dynamics of carbon dioxide flux in alpine saline lake on the Qinghai-Tibet Plateau, China.

Thermal stratification and mixing play important roles in the physicochemical composition of lakes and affect the geochemical cycle. However, the regulation of lake carbon exchange at the water-air interface by seasonal thermal structures remains unclear, especially for alpine saline lake on the Qinghai-Tibet Plateau (QTP). Based on continuous field sampling, carbon dioxide flux (FCO2) at the water-air interface in Qinghai Lake during the ice-free period was quantitatively analyzed by thin boundary layer model, as well as the driving factors of the change in FCO2 at the water-air interface. The findings revealed that the FCO2 was -22.16 ±â€¯11.73 mmol m-2d-1 during the stratification period, and - 45.32 ±â€¯29.67 mmol m-2d-1 during the mixing period. We found that thermal stratification limits the matter-energy exchange between the upper and bottom water columns, and carbonate precipitation results in a higher FCO2 than during mixing stage. However, the mixing process reduces the limiting effect of thermal stratification. During the carbonate process, water with higher salinity and pH at the bottom of the water column enters the upper part of the water column, reducing the partial pressure of carbon dioxide (pCO2) in the water column and causing the absorption of CO2 by the lake. Thermal stratification affects the vertical material-energy exchange and atmospheric CO2 uptake of lake. The present study further explains the possible underlying regulation of CO2 uptake in saline lake on the QTP involving the varied thermal structure.

Silver-catalyzed direct conversion of epoxides into cyclopropanes using N-triftosylhydrazones.

Epoxides, as a prominent small ring O-heterocyclic and the privileged pharmacophores for medicinal chemistry, have recently represented an ideal substrate for the development of single-atom replacements. The previous O-to-C replacement strategy for epoxides to date typically requires high temperatures to achieve low yields and lacks substrate range and functional group tolerance, so achieving this oxygen-carbon exchange remains a formidable challenge. Here, we report a silver-catalyzed direct conversion of epoxides into trifluoromethylcyclopropanes in a single step using trifluoromethyl N-triftosylhydrazones as carbene precursors, thereby achieving oxygen-carbon exchange via a tandem deoxygenation/[2 + 1] cycloaddition. The reaction shows broad tolerance of functional groups, allowing routine cheletropic olefin synthesis in a strategy for the net oxygen-carbon exchange reaction. The utility of this method is further showcased with the late-stage diversification of epoxides derived from bioactive natural products and drugs. Mechanistic experiments and DFT calculations elucidate the reaction mechanism and the origin of the chemo- and stereoselectivity.

Lung single-cell RNA profiling reveals response of pulmonary capillary to sepsis-induced acute lung injury.

Background: Sepsis-induced acute lung injury (ALI) poses a significant threat to human health. Endothelial cells, especially pulmonary capillaries, are the primary barriers against sepsis in the lungs. Therefore, investigating endothelial cell function is essential to understand the pathophysiological processes of sepsis-induced ALI. Methods: We downloaded single-cell RNA-seq expression data from GEO with accession number GSE207651. The mice underwent cecal ligation and puncture (CLP) surgery, and lung tissue samples were collected at 0, 24, and 48 h. The cells were annotated using the CellMarker database and FindAllMarkers functions. GO enrichment analyses were performed using the Metascape software. Gene set enrichment Analysis (GSEA) and variation Analysis (GSVA) were performed to identify differential signaling pathways. Differential expression genes were collected with the "FindMarkers" function. The R package AUCell was used to score individual cells for pathway activities. The Cellchat package was used to explore intracellular communication. Results: Granulocytes increased significantly as the duration of endotoxemia increased. However, the number of T cells, NK cells, and B cells declined. Pulmonary capillary cells were grouped into three sub-clusters. Capillary-3 cells were enriched in the sham group, but declined sharply in the CLP.24 group. Capillary-1 cells peaked in the CLP.24 group, while Capillary-2 cells were enriched in the CLP.48 group. Furthermore, we found that Cd74+ Capillary-3 cells mainly participated in immune interactions. Plat+ Capillary-1 and Clec1a+ Capillary-2 are involved in various physiological processes. Regarding cell-cell interactions, Plat+ Capillary-1 plays the most critical role in granulocyte adherence to capillaries during ALI. Cd74+ Capillary cells expressing high levels of major histocompatibility complex (MHC) and mainly interacted with Cd8a+ T cells in the sham group. Conclusion: Plat+ capillaries are involved in the innate immune response through their interaction with neutrophils via ICAM-1 adhesion during endotoxemia, while Cd74+ capillaries epxressed high level of MHC proteins play a role in adaptive immune response through their interaction with T cells. However, it remains unclear whether the function of Cd74+ capillaries leans towards immunity or tolerance, and further studies are needed to confirm this.

Silver-Catalyzed Dearomative Skeletal Editing of Indazoles by Donor Carbene Insertion.

Given the prevalence of heterocyclic scaffolds in drug-related molecules, converting these highly modular heterocyclic scaffolds into structural diversified and dearomatized analogs is an ideal strategy for improving their physicochemical and pharmacokinetic properties. Here, we described an efficient method for silver carbene-mediated dearomative N-N bond cleavage leading to skeletal hopping between indazole and 1,2-dihydroquinazoline via a highly selective single-carbon insertion procedure. Using this methodology, a series of dihydroquinazoline analogues with diarylmethylene-substituted quaternary carbon centers were constructed with excellent yields and good functional group compatibility, which was further illustrated by the late-stage diversification of important pharmaceutically active ingredients. DFT calculations indicated that the silver catalyst not only induces the formation of the silver carbene, but also activates the diazahexatriene intermediate, which plays a crucial role in the formation of the C-N bond.

Traditional Chinese medicines treat ischemic stroke and their main bioactive constituents and mechanisms.

Ischemic stroke (IS) remains one of the leading causes of death and disability in humans. Unfortunately, none of the treatments effectively provide functional benefits to patients with IS, although many do so by targeting different aspects of the ischemic cascade response. The advantages of traditional Chinese medicine (TCM) in preventing and treating IS are obvious in terms of early treatment and global coordination. The efficacy of TCM and its bioactive constituents has been scientifically proven over the past decades. Based on clinical trials, this article provides a review of commonly used TCM patent medicines and herbal decoctions indicated for IS. In addition, this paper also reviews the mechanisms of bioactive constituents in TCM for the treatment of IS in recent years, both domestically and internationally. A comprehensive review of preclinical and clinical studies will hopefully provide new ideas to address the threat of IS.

Integrated bioinformatics and network pharmacology identifying the mechanisms and molecular targets of Guipi Decoction for treatment of comorbidity with depression and gastrointestinal disorders.

BACKGROUND: Guipi decoction (GPD) not only improves gastrointestinal (GI) function, but also depressive mood. The bioinformatics study aimed to reveal potential crosstalk genes and related pathways between depression and GI disorders. A network pharmacology approach was used to explore the molecular mechanisms and potential targets of GPD for the simultaneous treatment of depression comorbid GI disorders. METHODS: Differentially expressed genes (DEGs) of major depressive disorder (MDD) were identified based on GSE98793 and GSE19738, and GI disorders-related genes were screened from the GeneCards database. Overlapping genes between MDD and GI disorders were obtained to identify potential crosstalk genes. Protein-protein interaction (PPI) network was constructed to screen for hub genes, signature genes were identified by LASSO regression analysis, and single sample gene set enrichment analysis (ssGSEA) was performed to analyze immune cell infiltration. In addition, based on the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, we screened the active ingredients and targets of GPD and identified the intersection targets of GPD with MDD and GI disorder-related genes, respectively. A "component-target" network was constructed using Cytoscape, the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed. RESULTS: The MDD-corrected dataset contained 2619 DEGs, and a total of 109 crosstalk genes were obtained. 14 hub genes were screened, namely SOX2, CRP, ACE, LEP, SHH, CDH2, CD34, TNF, EGF, BDNF, FN1, IL10, PPARG, and KIT. These genes were identified by LASSO regression analysis for 3 signature genes, including TNF, EGF, and IL10. Gamma.delta.T.cell was significantly positively correlated with all three signature genes, while Central.memory.CD4.T.cell and Central.memory.CD8.T.cell were significantly negatively correlated with EGF and TNF. GPD contained 134 active ingredients and 248 targets, with 41 and 87 relevant targets for the treatment of depression and GI disorders, respectively. EGF, PPARG, IL10 and CRP overlap with the hub genes of the disease. CONCLUSION: We found that GPD may regulate inflammatory and oxidative stress responses through EGF, PPARG, IL10 and CRP targets, and then be involved in the treatment of both depression and GI disorders.

Structure-Related Thyroid Disrupting Effect of Perfluorooctanesulfonate-like Substances in Zebrafish Larvae.

Chlorinated polyfluorooctane ether sulfonate (6:2 Cl-PFESA), hydrogenated polyfluorooctane ether sulfonate (6:2 H-PFESA), and chlorinated polyfluorooctanesulfonate (Cl-PFOS) share structural similarities with the regulated perfluorooctanesulfonate (PFOS), but their toxic potential is rarely known. Here, the thyroid disrupting potential of these four compounds in zebrafish larvae has been comparably investigated. PFOS, Cl-PFOS, and 6:2 Cl-PFESA were accumulated in the larvae at similar levels, approximately 1.3-1.6 times higher than 6:2 H-PFESA. Additionally, PFOS, Cl-PFOS, and 6:2 Cl-PFESA exhibited stronger disruption than 6:2 H-PFESA on genetic regulation, particularly concerning thyroid hormone (TH) activation and action and on TH homeostasis in both free and total forms of thyroxine (T4) and 3,5,3'-triiodothyronine (T3). These results indicate that chlorination or oxygen insertion does not substantially alter the thyrotoxicity of PFOS, but hydrogenation mitigates it. Molecular docking analysis and the luciferase reporter gene assay provided mechanistic perspectives that the PFOS-like substances could competitively replace THs to bind with TH plasma and membrane transporters, thereby disrupting TH transport and action, respectively. Moreover, they are also potent to disrupt TH synthesis and activation through Na+/K+-dependent transport of I- or competitive binding to the sites of deiodinases.

Epidemiology of healthcare-associated infections and outcomes among open and robotic pancreatoduodenectomy: A retrospective study from 2013 to 2022.

BACKGROUND AND AIM: Healthcare-associated infections (HAIs) after pancreaticoduodenectomy (PD) are one of the common postoperative complications. This study aims to investigate the epidemiology of postoperative HAIs in patients with open pancreaticoduodenectomy (OPD) and robotic pancreaticoduodenectomy (RPD). METHODS: This retrospective cohort study described the trend of HAIs in patients undergoing PD from January 2013 to December 2022 at a tertiary hospital. Patients were divided into OPD and RPD, and the HAIs and outcomes were compared. RESULTS: Among 2632 patients who underwent PD, 230 (8.7%, 95% confidence interval [CI] 7.7-9.9%) were diagnosed with HAIs, with a decreasing trend from 2013 to 2022 (P < 0.001 for trend). The incidence of postoperative HAIs was significantly higher in patients with OPD than RPD (9.6% vs 5.8%; P = 0.003). The incidence of HAIs for patients with OPD showed a decreasing trend (P = 0.001 for trend), and the trend for RPD was not significant (P = 0.554 for trend). Logistic regression showed that RPD was significantly associated with postoperative HAIs after adjusting for covariates (adjusted odds ratio = 0.654; 95% CI 0.443-0.965; P = 0.032), especially in the subgroup of patients without preoperative biliary drainage (adjusted odds ratio = 0.486; 95% CI 0.292-0.809; P = 0.006). Regarding clinical outcomes, RPD has a shorter length of stay and a more expensive charge than OPD (all P < 0.05). CONCLUSION: Postoperative HAIs in patients with PD showed a decreasing trend in recent years, especially in OPD. RPD was significantly associated with reduced postoperative HAIs and length of stay, although the charge is more expensive. Attention should be paid to postoperative HAIs in OPD, and it is imperative to continue reducing the costs of RPD.

Spatial analysis enables priority selection in conservation practices for landscapes that need ecological security.

Global urbanization has not only promoted social and economic development, but also contributed to seriously ecological challenges. As a type of sustainable landscape patterns, ecological security pattern is considered as an effective spatial pathway to simultaneously conserve ecological security and maintain social-economic development. However, the fragmentation issue of ecological sources of ecological security pattern has not been effectively addressed, although many case studies have been conducted to identify ecological security pattern. In this study, we used spatial conservation prioritization to identify the ecological security pattern of the city belt along the Yellow River in Ningxia, China. Ecological sources were selected using Zonation model while ecological corridors and key ecological nodes were identified with circuit model. The results showed that the ecological security pattern was composed of 97 ecological sources, 226 ecological corridors, 267 pinch points and 22 barriers, covering a total area of 7713.1 km2 and accounting for 34% of the study area. Ecological sources were concentrated in the Helan Mountain, Xiang Mountain and along the Yellow River. Besides, ecological corridors were dense in the southern and eastern part of the study area. Both indicated that the Yellow River and Helan Mountain were the conservation hotspots. Landscape connectivity of ecological sources identified through Zonation-based spatial conservation prioritization was better than that with the scoring approach based on ecosystem service importance. Particularly, in the Zonation approach the landscape connectivity increased with 44% while the average patch area increased with 28% when comparing with the scoring approach. The spatial conservation prioritization approach proposed in this study provides a new effective tool to construct ecological security pattern, which is conducive to the synergic enhancement of landscape connectivity and ecosystem services conservation.

Underlying Mechanisms for the Sex- and Chemical-Specific Hepatotoxicity of Perfluoroalkyl Phosphinic Acids in Common Carp (Cyprinus carpio).

The hepatotoxicities of perfluoroalkyl and polyfluoroalkyl substances (PFASs) have been extensively investigated, while little is known about the sex-specific differences. In this study, common carp were exposed to the emerging perfluoroalkyl phosphinic acids (6:6 and 8:8 PFPiAs) for 14 days to disclose sex-specific hepatotoxicity. Apparent hepatotoxicity, including cell necrosis, apoptosis, and steatosis, was observed in both male and female carp liver. The observed hepatocyte steatosis was predominantly attributed to the dysregulation of hepatic lipid metabolism but was based on sex-specific mechanisms. It was manifested as inhibited oxidative decomposition of fatty acids (FAs) in the female liver, whereas it enhanced the uptake of FAs into the male liver, both of which led to excessive lipid accumulation. Untargeted lipidomics validated that the metabolism pathways of FA, sphingolipid, glycerolipid, and glycerophospholipid were disrupted by both compounds, leading to the generation of reactive oxygen species and oxidative stress. The oxidative stress further evolved into inflammation, manifested as promoted expression of proinflammatory cytokines and repressed expression of anti-inflammatory cytokines. Consistently, all of the changes were more noticeable in male carp, suggesting that male fish were more susceptible to PFPiA disruption. 8:8 PFPiA was less accumulated but caused stronger hepatotoxicity than 6:6 PFPiA, possibly because of the stronger binding capacity of 8:8 PFPiA to nuclear transcription factors mediating lipid metabolism and inflammation. The findings of this study highlight the significance of sex- and chemical-dependent bioaccumulation and the toxicity of PFASs in organisms.

Inhibition of cluster antigen 36 protects against fatty acid-induced lipid accumulation, oxidative stress, and inflammation in bovine hepatocytes.

When ketosis occurs, supraphysiological concentrations of nonesterified fatty acids (NEFA) display lipotoxicity and are closely related to the occurrence of hepatic lipid accumulation, oxidative stress, and inflammation, resulting in hepatic damage and exacerbating the progression of ketosis. However, the mechanism of these lipotoxic effects caused by high concentrations of NEFA in ketosis is still unclear. Cluster antigen 36 (CD36), a fatty acid transporter, plays a vital role in the development of hepatic pathological injury in nonruminants. Thus, the aim of this study was to investigate whether CD36 plays a role in NEFA-induced hepatic lipotoxicity in dairy cows with clinical ketosis. Liver tissue and blood samples were collected from healthy (n = 10) and clinically ketotic (n = 10) cows at 3 to 15 d in milk. In addition, hepatocytes isolated from healthy calves were treated with 0, 0.6, 1.2, or 2.4 mM NEFA for 12 h; or infected with CD36 expressing adenovirus or CD36 silencing small interfering RNA for 48 h and then treated with 1.2 mM NEFA for 12 h. Compared with healthy cows, clinically ketotic cows had greater concentrations of serum NEFA and ß-hydroxybutyrate and activities of aspartate aminotransferase and alanine aminotransferase but lower serum glucose. In addition, dairy cows with clinical ketosis displayed excessive hepatic lipid accumulation. More importantly, these alterations were accompanied by an increased abundance of hepatic CD36. In the cell culture model, exogenous NEFA (0, 0.6, 1.2, or 2.4 mM) treatment could dose-dependently increase the abundance of CD36. Meanwhile, NEFA (1.2 mM) increased the content of triacylglycerol, reactive oxygen species and malondialdehyde, and decreased the activities of glutathione peroxidase and superoxide dismutase. Moreover, NEFA upregulated phosphorylation levels of nuclear factor κB (NF-κB) and the inhibitor of NF-κB (IκB) α, along with the upregulation of protein abundance of NLR family pyrin domain containing 3 (NLRP3) and caspase-1, and mRNA abundance of IL1B, IL6, and tumor necrosis factor α (TNFA). These alterations induced by NEFA in bovine hepatocytes were associated with increased lipid accumulation, oxidative stress and inflammation, which could be further aggravated by CD36 overexpression. Conversely, silencing CD36 attenuated these NEFA-induced detriments. Overall, these data suggest that CD36 may be a potential therapeutic target for NEFA-induced hepatic lipid accumulation, oxidative stress, and inflammation in dairy cows.

AdipoRon alleviates fatty acid-induced lipid accumulation and mitochondrial dysfunction in bovine hepatocytes by promoting autophagy.

During the transition period in dairy cows, high circulating concentrations of nonesterified fatty acids (NEFA) increase hepatic lipid deposits and are considered a major pathological factor for liver damage. We investigated whether AdipoRon, a synthetic small-molecule agonist of adiponectin receptors 1 and 2 shown to prevent liver lipid accumulation in nonruminants, could alleviate NEFA-induced lipid accumulation and mitochondrial dysfunction. Bovine hepatocytes were isolated from 5 healthy Holstein female newborn calves (1 d of age, 30-40 kg, fasting), and independently isolated hepatocytes from at least 3 different calves were used for each subsequent experiment. The composition and concentration of NEFA used in this study were selected according to hematological criteria of dairy cows with fatty liver or ketosis. First, hepatocytes were cultured with various concentrations of NEFA (0, 0.6, 1.2, or 2.4 mM) for 12 h. In a second experiment, hepatocytes were treated with AdipoRon at different concentrations (0, 5, 25, or 50 µM for 12 h) and times (25 µM for 0, 6, 12, or 24 h) with or without NEFA (1.2 mM) treatment. In the last experiment, hepatocytes were treated with AdipoRon (25 µM), NEFA (1.2 mM), or both for 12 h after treatment with or without the autophagy inhibitor chloroquine. Hepatocytes treated with NEFA had increased protein abundance of sterol regulatory element-binding protein 1c (SREBP-1c) and mRNA abundance of acetyl-CoA carboxylase 1 (ACACA), and decreased protein abundance of peroxisome proliferator-activated receptor α (PPARA), proliferator-activated receptor gamma coactivator-1 α (PGC-1α), mitofusin 2 (MFN2), cytochrome c oxidase subunit IV (COX IV), and mRNA abundance of carnitine palmitoyltransferase 1A (CPT1A), along with lower ATP concentrations. AdipoRon treatment reversed these effects, suggesting this compound had a positive effect on lipid metabolism and mitochondrial dysfunction during the NEFA challenge. In addition, upregulated expression of microtubule-associated protein 1 light chain 3-II (LC3-II, encoded by MAP1LC3) and downregulated expression of sequestosome-1 (SQSTM1, also called p62) indicated that AdipoRon enhanced autophagic activity in hepatocytes. The fact that chloroquine impeded the beneficial effects of AdipoRon on lipid accumulation and mitochondrial dysfunction suggested a direct role for autophagy during NEFA challenge. Our results suggest that autophagy is an important cellular mechanism to prevent NEFA-induced lipid accumulation and mitochondrial dysfunction in bovine hepatocytes, which is consistent with other studies. Overall, AdipoRon may represent a promising therapeutic agent to maintain hepatic lipid homeostasis and mitochondrial function in dairy cows during the transition period.

Low abundance of insulin-induced gene 1 contributes to SREBP-1c processing and hepatic steatosis in dairy cows with severe fatty liver.

Fatty liver is a major metabolic disorder of high-producing dairy cows during the transition period. In nonruminants, it is well established that insulin-induced gene 1 (INSIG1) plays a crucial role in regulating hepatic lipogenesis by controlling the anchoring of sterol regulatory element-binding protein 1 (SREBP-1) on the endoplasmic reticulum along with SREBP cleavage-activating protein (SCAP). Whether the INSIG1-SCAP-SREBP-1c transport axis is affected in cows experiencing fatty liver is unknown. Thus, the aim of this study was to investigate the potential role of INSIG1-SCAP-SREBP-1c axis in the progression of fatty liver in dairy cows. For in vivo experiments, 24 dairy cows at the start of their fourth lactation (median; range 3-5) and 8 d in milk (median; range 4-12 d) were selected into a healthy group [n = 12; triglyceride (TG) content <1%] and a severe fatty liver group (n = 12; TG content >10%) according to their hepatic TG content. Blood samples were collected for detecting serum concentrations of free fatty acids, ß-hydroxybutyrate, and glucose. Compared with healthy cows, cows with severe fatty liver had higher serum concentrations of ß-hydroxybutyrate and free fatty acids and lower concentration of glucose. Liver biopsies were used to detect the status of INSIG1-SCAP-SREBP-1c axis, and the mRNA expression of SREBP-1c-target lipogenic genes acetyl-CoA carboxylase α (ACACA), fatty acid synthase (FASN), and diacylglycerol acyltransferase 1 (DGAT1). Cows with severe fatty liver had lower protein expression of INSIG1 in the hepatocyte endoplasmic reticulum fraction, greater protein expression of SCAP and precursor SREBP-1c in the hepatocyte Golgi fraction, and greater protein expression of mature SREBP-1c in the hepatocyte nuclear fraction. In addition, the mRNA expression of SREBP-1c-target lipogenic genes ACACA, FASN, and DGAT1 was greater in the liver of dairy cows with severe fatty liver. In vitro experiments were conducted on hepatocytes isolated from 5 healthy 1-d-old female Holstein calves, and hepatocytes from each calf were run independently. First, hepatocytes were treated with 0, 200, or 400 µM palmitic acid (PA) for 12 h. Exogenous PA treatment decreased INSIG1 protein abundance, enhanced the endoplasmic reticulum to Golgi export of SCAP-precursor SREBP-1c complex and the nuclear translocation of mature SREBP-1c, all of which was associated with increased transcriptional activation of lipogenic genes and TG synthesis. Second, hepatocytes were transfected with INSIG1-overexpressing adenovirus for 48 h and treated with 400 µM PA 12 h before the end of transfection. Overexpressing INSIG1 inhibited PA-induced SREBP-1c processing, upregulation of lipogenic genes, and TG synthesis in hepatocytes. Overall, the present in vivo and in vitro results indicated that the low abundance of INSIG1 contributed to SREBP-1c processing and hepatic steatosis in dairy cows. Thus, the INSIG1-SCAP-SREBP-1c axis may be a novel target for treatment of fatty liver in dairy cows.

Study on the Composition and Mechanism of Santiao Decoction in Treating Insomnia Based on UPLC and Network Pharmacology and Molecular Docking Technology.

OBJECTIVE: To identify the chemical components of Santiao Decoction (STD) using Ultra Performance Liquid Chromatography (UPLC) and to conduct a network pharmacological study of STD for the treatment of insomnia based on this technique. METHODS: An ACQUITY UPLC BEH C18 column (2.1 mm×100 mm, 1.7 µm) was used to identify the chemical components of STD by relative molecular weight, mass spectrometry information, and comparison with the control. The active ingredients of the formula and their corresponding gene targets and targets for insomnia were retrieved from several databases, and a visual network diagram of "drug-active ingredient-target-disease" was constructed using Cytoscape 3.8.2 software, and GO functional annotation and KEGG pathway enrichment analysis were performed using various databases such as DAVID. RESULTS: Five active ingredients were identified from STD by UPLC technique, 268 active ingredients of STD were screened from the TCMSP database, and 109 genes related to STD for insomnia were screened by network pharmacology, among which IL6, MMP9, VEGFA, IL10, CCL2 may be the key targets of STD for insomnia. KEGG pathway analysis showed that STD acts on membrane rafts, plasma membrane micro-regions, and other related pathways, such as Toll-like receptor signaling pathway, prolactin signaling pathway, dopaminergic synapse, relaxin signaling pathway, ErbB signaling pathway, steroid hormone biosynthesis and NF-kappa B signaling pathway for regulation. CONCLUSION: The active ingredients in STD, such as (+)-catechin, Swertisin, quercetin, baicalein, and wogonin, may act on IL6, CCL2, VEGFA, MMP9, and other targets to regulate Toll-like receptor signaling pathway, ErbB signaling pathway, NF-kappa B and other signaling pathways, and exert certain therapeutic effects on insomnia, which provide a reference and basis for further research on the mechanism of action of STD.

Simple high-performance liquid chromatography-ultraviolet method for simultaneous separation and detection of 14 bisphenol pollutants in building materials.

A high-performance liquid chromatography-ultraviolet method was developed for rapidly and simultaneously analyzing novel and typical bisphenols in building materials, including bisphenol S, diphenolic acid, bisphenol F, bisphenol E, bisphenol A, bisphenol B, bisphenol AF, bisphenol AP, bisphenol C, bisphenol FL, bisphenol Z, bisphenol BP, bisphenol M, and bisphenol P. By using a Kromasil 100-5 C18 column, these bisphenols were completely separated in 40 min via gradually increasing the concentration of methanol in the mobile phase from 45 to 80% during the elution process. In particular, this method achieved the synchronous analysis of bisphenol S, diphenolic acid, bisphenol FL, bisphenol BP, and bisphenol M through HPLC, which were difficult to separate and had to be identified and detected through mass spectrometry. The limits of detection of the method ranged from 0.002 to 0.040 mg/L for these 14 bisphenols, with a precision of less than 4.9% (n = 7, c = 0.05 mg/L). The analytical results for five types of building materials (phenolic, epoxy, polycarbonate, polyester, and polysulfone resins) indicated that the proposed method is appropriated for the rapid measurement of bisphenols in real samples.

The initiator of neuroexcitotoxicity and ferroptosis in ischemic stroke: Glutamate accumulation.

Glutamate plays an important role in excitotoxicity and ferroptosis. Excitotoxicity occurs through over-stimulation of glutamate receptors, specifically NMDAR, while in the non-receptor-mediated pathway, high glutamate concentrations reduce cystine uptake by inhibiting the System Xc-, leading to intracellular glutathione depletion and resulting in ROS accumulation, which contributes to increased lipid peroxidation, mitochondrial damage, and ultimately ferroptosis. Oxidative stress appears to crosstalk between excitotoxicity and ferroptosis, and it is essential to maintain glutamate homeostasis and inhibit oxidative stress responses in vivo. As researchers work to develop natural compounds to further investigate the complex mechanisms and regulatory functions of ferroptosis and excitotoxicity, new avenues will be available for the effective treatment of ischaemic stroke. Therefore, this paper provides a review of the molecular mechanisms and treatment of glutamate-mediated excitotoxicity and ferroptosis.

Blue, Yellow, and Red Carbon Dots from Aromatic Precursors for Light-Emitting Diodes.

In this work, multicolor fluorescent carbon dots with red (R-CDs), yellow (Y-CDs), and blue (B-CDs) emissions were prepared by choosing proper aromatic precursors with different amounts of benzene rings through a simple solvothermal method. The characterization showed that the prepared carbon dots were spherical with a size under 10 nm, rich surface functional groups, and good stability. The emission wavelengths were located at 440, 530, and 580 nm under the excitation of 370 nm. The relative fluorescence quantum yield (QY) of R-CDs, Y-CDs, and B-CDs was 11%, 59%, and 33%, respectively. The related characterization demonstrated that the redshift in the photoluminescence was caused by the synergistic effect of the increasing graphitic nitrogen content, quantum size effect and surface oxidation state. By mixing the three prepared CDs into a PVA matrix, the transparent and flexible films produced relucent blue, yellow, and red emissions under 365 nm UV light, and solid-state quenching was effectively avoided. LEDs were fabricated by using B-CDs, Y-CDs, and R-CDs/PVA with a semiconductor chip. These CDs-based LEDs produced bright blue, yellow, and red light with CIE color coordinates of (0.16, 0.02), (0.38, 0.58), and (0.50, 0.49) were successfully manufactured utilizing the prepared blue, yellow and red multicolor carbon dots as the solid luminescent materials. The results showed that the synthesized CDs can be potentially applied in multi-color monitors as a promising candidate for light-emitting diodes (LEDs). This work blazes a novel trail for the controllable preparation of multicolor fluorescent carbon dots.

IL-27p28 knockout aggravates Doxorubicin-induced cardiotoxicity by regulating Macrophage polarization.

BACKGROUND: Several interleukins (ILs) have been demonstrated to participate in cardiac injury. This study aimed to investigate whether IL-27p28 plays a regulatory role in doxorubicin (DOX)-induced cardiac injury by regulating inflammation and oxidative stress. METHODS: Dox was used to establish a mouse cardiac injury model, and IL-27p28 was knocked out to observe its role in cardiac injury. In addition, monocytes were adoptively transferred to clarify whether monocyte-macrophages mediate the regulatory role of IL-27p28 in DOX-induced cardiac injury. RESULTS: IL-27p28 knockout significantly aggravated DOX-induced cardiac injury and cardiac dysfunction. IL-27p28 knockout also upregulated the phosphorylation levels of p65 and STAT1 and promoted M1 macrophage polarization in DOX-treated mice, which increased cardiac inflammation and oxidative stress. Moreover, IL-27p28-knockout mice that were adoptively transferred WT monocytes exhibited worse cardiac injury and cardiac dysfunction and higher cardiac inflammation and oxidative stress. CONCLUSIONS: IL-27p28 knockdown aggravates DOX-induced cardiac injury by worsening the M1 macrophage/M2 macrophage imbalance and its associated inflammatory response and oxidative stress.

SMYD Family Members Serve as Potential Prognostic Markers and Correlate with Immune Infiltrates in Gastric Cancer.

Background: The SMYD family comprises a group of genes encoding lysine methyltransferases, which are closely related to tumorigenesis. However, a systematic understanding of their role in gastric cancer (GC) is lacking. Methods: Using databases and tools such as the Cancer Genome Atlas, Human Protein Atlas, Kaplan-Meier Plotter, Gene Expression Profiling Interactive Analysis, and Metascape, we comprehensively analyzed differences in SMYD expression and its prognostic value as well as the association of SMYDs with immune cell infiltration, tumor mutational burden (TMB), and microsatellite instability (MSI). We conducted functional enrichment analysis and explored a competing endogenous RNA mechanism regulating SMYD mRNA and protein levels in patients with GC. Results: In GC, the expression of SMYD2/3/4/5 mRNA was significantly upregulated, as opposed to that of SMYD1 mRNA, which was significantly downregulated. The protein levels of SMYDs were consistent with mRNA levels. SMYD1/2/4/5 was negatively correlated with overall survival; SMYD1/2/3/5 was negatively correlated with progression-free survival. Our SMYD-based signature and nomogram model may be useful for inferring the prognosis of GC. All SMYDs were closely associated with the infiltration of six immune cell types: uncharacterized, CD8+ T, CD4+ T, macrophage, endothelial, and B cells. TMB was significantly negatively correlated with SMYD1 expression, while a significant positive correlation was observed with SMYD2/5. Furthermore, MSI was significantly positively correlated with SMYD2/5 expression. Long non-coding RNAs, such as chr22-38_28785274-29006793.1, XLOC_002309, and CTD-2008N3.1, were suggested to regulate SMYD expression by sponging multiple microRNAs. Conclusion: SMYDs are differentially expressed in GC and are thus potential prognostic markers. SMYD expression is closely related to immune infiltration, TMB, and MSI, all of which are closely related to the response to targeted immune therapy.