QSAR Study, Molecular Docking and Molecular Dynamic Simulation of Aurora Kinase Inhibitors Derived from Imidazo[4,5-b]pyridine Derivatives.

Cancer is a serious threat to human life and social development and the use of scientific methods for cancer prevention and control is necessary. In this study, HQSAR, CoMFA, CoMSIA and TopomerCoMFA methods are used to establish models of 65 imidazo[4,5-b]pyridine derivatives to explore the quantitative structure-activity relationship between their anticancer activities and molecular conformations. The results show that the cross-validation coefficients q2 of HQSAR, CoMFA, CoMSIA and TopomerCoMFA are 0.892, 0.866, 0.877 and 0.905, respectively. The non-cross-validation coefficients r2 are 0.948, 0.983, 0.995 and 0.971, respectively. The externally validated complex correlation coefficients r2pred of external validation are 0.814, 0.829, 0.758 and 0.855, respectively. The PLS analysis verifies that the QSAR models have the highest prediction ability and stability. Based on these statistics, virtual screening based on R group is performed using the ZINC database by the Topomer search technology. Finally, 10 new compounds with higher activity are designed with the screened new fragments. In order to explore the binding modes and targets between ligands and protein receptors, these newly designed compounds are conjugated with macromolecular protein (PDB ID: 1MQ4) by molecular docking technology. Furthermore, to study the nature of the newly designed compound in dynamic states and the stability of the protein-ligand complex, molecular dynamics simulation is carried out for N3, N4, N5 and N7 docked with 1MQ4 protease structure for 50 ns. A free energy landscape is computed to search for the most stable conformation. These results prove the efficient and stability of the newly designed compounds. Finally, ADMET is used to predict the pharmacology and toxicity of the 10 designed drug molecules.

Risk factors for diaphragmatic injury in subxiphoid video-assisted thoracoscopic surgery.

BACKGROUND: Subxiphoid video-assisted thoracoscopic surgery (VATS) is considered a safe and feasible operation for anterior mediastinal mass resection. However, diaphragmatic injury, presented as tearing or puncturing, may occur during subxiphoid VATS despite of low incidence. This study aims to explore risk factors for diaphragmatic injury in subxiphoid VATS, as well as strategies to reduce occurrence of the injury. METHODS: We retrospectively reviewed clinical records of 44 consecutive adult patients who underwent subxiphoid VATS. These patients were divided into two groups: diaphragmatic injury group and non-injury group. Perioperative outcomes and anatomic features derived from 3D CT reconstructions were compared between the two groups. RESULTS: Significant differences were observed in operation time (223.25 ± 92.57 vs. 136.28 ± 53.05, P = 0.006), xiphoid length (6.47 ± 0.85 vs. 4.79 ± 1.04, P = 0.001) and length of the xiphoid below the attachment point on the diaphragm (24.86 ± 12.02 vs. 14.61 ± 9.25, P = 0.029). Odds ratio for the length of the xiphoid below the attachment point on the diaphragm was 1.09 (1.001-1.186), P = 0.048 by binary logistic regression analysis. CONCLUSIONS: We identified the length of the xiphoid below the attachment point on the diaphragm as an independent risk factor for diaphragm injury during subxiphoid VATS. Prior to subxiphoid VATS, a 3D chest CT reconstruction is recommended to assess the patients' anatomic variations within the xiphoid process. For patients with longer xiphoid process, a higher incision at the middle and upper part of the xiphoid process, and partial xiphoid process resection or xiphoidectomy is preferred.

Targeting inhibition of TCTP could inhibit proliferation and induce apoptosis in AML cells.

Translationally controlled tumor protein (TCTP) is a highly conserved multifunctional protein, which participates in many important physiological processes. Recently, the roles of TCTP in cell proliferation and apoptosis, especially its close relationship with various tumors, have attracted widespread attention. In this study, we found that the protein level of TCTP was significantly reduced in acute promyelocytic leukemia cell line NB4 transfected with retinoic acid-induced gene G (RIG-G). The RIG-G was found in our previous work as a key mediator of anti-proliferative activity in retinoid/interferon-related pathways. Here, we tried to further explore the function of TCTP in the development of acute myeloid leukemia (AML) from different levels. Our results showed that inhibiting TCTP expression could attenuate AML cells proliferation and induce apoptosis both in AML cell lines and in xenograft of NOD-SCID mice. In addition, either compared with patients in complete remission or non-leukemia patients, we detected that the expression of TCTP was generally high in the fresh bone marrow of AML patients, suggesting that there was a certain correlation between TCTP and AML disease progression. Taken together, our study revealed the role of TCTP in AML development, and provided a potential target for AML treatment.

Combining QSAR techniques, molecular docking, and molecular dynamics simulations to explore anti-tumor inhibitors targeting Focal Adhesion Kinase.

Focal Adhesion Kinase (FAK) is an important target for tumor therapy and is closely related to tumor cell genesis and progression. In this paper, we selected 46 FAK inhibitors with anticancer activity in the pyrrolo pyrimidine backbone to establish 3D/2D-QSAR models to explore the relationship between inhibitory activity and molecular structure. We have established two ideal models, namely, the Topomer CoMFA model (q2= 0.715, r2= 0.984) and the Holographic Quantitative Structure-Activity Relationship (HQSAR) model (q2= 0.707, r2= 0.899). Both models demonstrate excellent external prediction capabilities.Based on the QSAR results, we designed 20 structurally modified novel compounds, which were subjected to molecular docking and molecular dynamics studies, and the results showed that the new compounds formed many robust interactions with residues within the active pocket and could maintain stable binding to the receptor proteins. This study not only provides a powerful screening tool for designing novel FAK inhibitors, but also presents a series of novel FAK inhibitors with high micromolar activity that can be used for further characterization. It provides a reference for addressing the shortcomings of drug metabolism and drug resistance of traditional FAK inhibitors, as well as the development of novel clinically applicable FAK inhibitors.Communicated by Ramaswamy H. Sarma.

Plastid genome and its phylogenetic implications of Asiatic Spiraea (Rosaceae).

BACKGROUND: Spiraea L. is a genus comprising approximately 90 species that are distributed throughout the northern temperate regions. China is recognized as the center of species diversity for this genus, hosting more than 70 species, including 47 endemic species. While Spiraea is well-known for its ornamental value, its taxonomic and phylogenetic studies have been insufficient. RESULTS: In this study, we conducted sequencing and assembly of the plastid genomes (plastomes) of 34 Asiatic Spiraea accessions (representing 27 Asiatic Spiraea species) from China and neighboring regions. The Spiraea plastid genome exhibits typical quadripartite structures and encodes 113-114 genes, including 78-79 protein-coding genes (PCGs), 30 tRNA genes, and 4 rRNA genes. Linear regression analysis revealed a significant correlation between genome size and the length of the SC region. By the sliding windows method, we identified several hypervariable hotspots within the Spiraea plastome, all of which were localized in the SC regions. Our phylogenomic analysis successfully established a robust phylogenetic framework for Spiraea, but it did not support the current defined section boundaries. Additionally, we discovered that the genus underwent diversification after the Early Oligocene (~ 30 Ma), followed by a rapid speciation process during the Pliocene and Pleistocene periods. CONCLUSIONS: The plastomes of Spiraea provided us invaluable insights into its phylogenetic relationships and evolutionary history. In conjunction with plastome data, further investigations utilizing other genomes, such as the nuclear genome, are urgently needed to enhance our understanding of the evolutionary history of this genus.

Repeated radon exposure induced epithelial-mesenchymal transition-like transformation via disruption of p53-dependent mitochondrial function.

Backgrouds: As a human carcinogen, radon and its progeny are the second most important risk factor for lung cancer after smoking. The tumor suppressor gene, p53, is reported to play an important role in the maintenance of mitochondrial function. In this work, we investigated the association between p53 and p53-responsive signaling pathways and radon-induced carcinogenesis. Methods: After repeated radon exposure, the malignant characteristics, cell cycle arrest, cell apoptotic rate, adenosine triphosphate (ATP) content, reactive oxygen species (ROS) level, mitochondrial DNA (mtDNA) copy number as well as indicative biomarkers involved in mitochondrial energy metabolism were evaluated in BEAS-2B cells or BALB-c mouse lung tissue. Results: Radon exposure induced epithelial-mesenchymal transition (EMT)-like transformation in BEAS-2B cells, as indicated by increased cell proliferation and migration. Additional mitochondrial alterations, including decreased ATP content, increased ROS levels, mtDNA copy numbers, cell apoptosis, and G2/M cell cycle arrest were observed. Radon exposure caused an energy generation shift from aerobic respiration to glycolysis as reflected by increased expression of TIGAR and p53R2 proteins and decreased expression of SCO2 protein in BEAS-2B cells, and increased expression of p53, SCO2 and TIGAR proteins in mouse lung tissue, respectively. The effects of p53 deficiency on the prevention of mitochondrial dysfunction suggested a protective role of p53 in radon-induced malignant-like features in BEAS-2B cells. Conclusions: Repeated radon exposure induced EMT-like transformation in BEAS-2B cells via disruption of mitochondrial function. Activation of p53 and p53-responsive signaling pathways in BEAS-2B cells and BALB-c mice may confer a protective mechanism for radon-induced lung injury.

[Clinical characteristics and prognosis in 12 children with SARS-CoV-2 Omicron variant infection-associated acute necrotizing encephalopathy]. / 12ä¾‹æ–°åž‹å† çŠ¶ç— æ¯’Omicronå˜å¼‚æ ªæ„ŸæŸ“ç›¸å ³æ€¥æ€§åæ­»æ€§è„‘ç— å„¿ç«¥çš„ä¸´åºŠç‰¹ç‚¹åŠé¢„åŽåˆ†æž.

OBJECTIVES: To study the clinical characteristics and prognosis of SARS-CoV-2 Omicron variant infection-associated acute necrotizing encephalopathy (ANE) in children. METHODS: A retrospective analysis was conducted on the medical data of 12 children with SARS-CoV-2 Omicron variant infection-associated ANE who were admitted to the Pediatric Intensive Care Unit, Qingdao Women and Children's Hospital from December 18 to 29, 2022. The children were divided into two groups based on outcomes: death group (7 cases) and survival group (5 cases). The clinical manifestations and auxiliary examination results were compared between the two groups. RESULTS: The median age of the 12 patients was 30 months, with a male-to-female ratio of 1:1. All patients presented with persistent high fever, with a median highest body temperature of 41℃. The median time from fever onset to seizure or consciousness disturbance was 18 hours. The death group had a higher proportion of neurogenic shock, coagulation dysfunction, as well as elevated lactate, D-dimer, interleukin-6, interleukin--8, and interleukin-10 levels compared to the survival group (P<0.05). CONCLUSIONS: Children with SARS-CoV-2 Omicron variant infection-associated with ANE commonly present with persistent high fever, rapidly progressing disease, and have a high likelihood of developing consciousness disorders and multiorgan dysfunction within a short period. The occurrence of neurogenic shock, coagulation dysfunction, and significantly elevated cytokine levels suggests an increased risk of mortality.

Poly(A)-specific ribonuclease protein promotes the proliferation, invasion and migration of esophageal cancer cells.

BACKGROUND: Bioinformatics analysis showed that the expression of the poly(A)-specific ribonuclease (PARN) gene in gastric cancer, head and neck squamous cell carcinoma, melanoma, cervical cancer and lung squamous cell carcinoma tissues was significantly higher than that in normal tissues and was associated with high stage and poor prognosis. The expression of the PARN gene in esophageal cancer (EC) tissue is also significantly higher than that in normal tissues, but the effect of PARN on the proliferation, migration and invasion of EC cells remains unclear. AIM: To investigate the relationship between PARN and the proliferation, migration and invasion of EC cells. METHODS: The EC tissues of 91 patients after EC surgery and 63 paired precancerous healthy tissues were collected. PARN mRNA levels were measured using a tissue microarray, and the PARN expression level was evaluated using immunohistochemistry to analyze the relationship between PARN expression and clinicopathologic features as well as the survival and prognosis of patients. In addition, the effects of PARN gene knockout on tumor cell proliferation, invasion and migration were studied by using shRNA during the in vitro culture of EC cell lines Eca-109 and TE-1, and the effects of the PARN gene on tumor growth in vivo were verified by a xenotransplantation nude mice model. RESULTS: The expression of PARN in EC tissues was higher than that in adjacent normal tissues, and the level of PARN expression was significantly positively correlated with lymphatic metastasis. Patients with high PARN levels had poor overall survival. BIM, IGFBP-5 and p21 levels were significantly increased in the PARN knockout group, while the expression levels of the antiapoptotic proteins Survivin and sTNF-R1 were significantly decreased in the apoptotic antibody array data. In addition, the expression levels of Akt, p-Akt, PIK3CA and CCND1 in the downstream signaling pathway regulating EC progression were significantly decreased. The culture of EC cell lines confirmed that the apoptosis rate of EC cells was significantly increased, the growth and proliferation of tumor cells were significantly inhibited, and the invasion and migration ability of tumor cells were significantly decreased after PARN gene knockout. In vivo experiments of BALB/c nude mice transfected with Eca-109 cells expressing control shRNA (sh-NC) and PARN shRNA (sh-PARN) showed that the tumor volume and weight of nude mice treated with sh-PARN were significantly decreased compared with those of nude mice treated with sh-NC, indicating that PARN knockdown significantly inhibited tumor growth in vivo. CONCLUSION: PARN has antiapoptotic effects on EC cells and promotes their proliferation, invasion and migration, which is associated with the development of EC and poor patient prognosis. PARN may become a potential target for the diagnosis, prognosis prediction and treatment of EC.

Abnormal hemispheric specialization and inter-hemispheric functional cooperation in generalized anxiety disorder.

Abnormal hemispheric specialization and inter-hemispheric interactions may contribute to the pathogenesis of general anxiety disorder (GAD). The current study investigated these abnormalities in GAD patients based on the two analytic approaches and examined whether such abnormalities are correlated with anxiety symptom severity. Seventy-three patients with GAD and 60 matched healthy controls were recruited. All participants completed anxiety symptoms assessment and resting-state functional magnetic resonance imaging (rs-fMRI). The autonomy index (AI) and Connectivity between Functionally Homotopic voxels (CFH) were applied to measure and compared between groups. Compared to controls, patients showed stronger AI in the right middle temporal gyrus (MTG). Seed-based analysis revealed stronger functional connectivity (FC) of the right MTG with both right precuneus and right dorsolateral prefrontal cortex (dlPFC) in patients. Patients also exhibited greater CFH in right anterior cingulate cortex (ACC) but decreased CFH in bilateral postcentral gyrus (PCG) and superior occipital gyrus (SOG). Further there were significant correlations between these regional CFH and anxiety symptoms severity. GAD patients demonstrate right hemispheric specialization and aberrant inter-hemispheric functional cooperation, and abnormal inter-hemispheric coordination is associated with anxiety symptom severity. These findings provide a clue to understanding the neuropathological mechanisms of GAD.

Neuroinflammation-induced parvalbumin interneuron and oscillation deficits might contribute to neurobehavioral abnormities in a two-hit model of depression.

Depression is a common neuropsychiatric disorder that causes profound disability worldwide, yet the underlying mechanism remains unclear. Thus, the present study aimed to evaluate the effects of a two-hit model of depression on glial activation, parvalbumin (PV) interneuron, oscillation activity, and behavior alternations, and whether chronic fluoxetine treatment can reverse these abnormalities. Male mice were submitted to lipopolysaccharide (LPS) injection, followed by a modified chronic unpredictable stress (CUS) protocol. In our study, we showed that mice exposed to LPS and CUS exhibited reduced body weight, anhedonic-like behavior as well as cognitive and anxiety symptoms. These behavioral alternations were related to enhanced neuroinflammation, as reflected by significantly increased IL-1ß and IL-6 levels and microglia activation in the prefrontal cortex (PFC). In addition, mice exposed to LPS and CUS displayed significantly decreased PV expression and disturbance of theta and gamma oscillations in the PFC. However, chronic fluoxetine treatment reversed most of these abnormalities. In conclusion, our study suggests that neuroinflammation-induced PV interneuron and oscillation deficits might contribute to neurobehavioral abnormalities in a two-hit model of depression.

Effects of Homogenization Heat Treatment on the Fe Micro-Segregation in Ti-1023 Titanium Alloy.

The segregation of the Fe element in Ti-10V-2Fe-3Al titanium alloy (Ti-1023) can lead to the generation of beta flecks, which seriously affects the performance of Ti-1023 products. During the heat treatment (HT) process at a high temperature, the Fe element in Ti-1023 ingots will migrate, making its distribution more uniform and reducing the segregation index. In this paper, the control of Fe micro-segregation in Ti-1023 ingots by homogenization HT was investigated. Firstly, dissection sampling and SEM-EDS analysis methods were used to study the distribution pattern of the Fe element in the equiaxed grains in the core of Ti-1023 ingots. It was found that the Fe content in the grain gradually increased along with the radial direction from the core to the grain boundary. Then, the homogenization HT experiments and numerical simulations of Ti-1023 at different HT temperatures from 1050 °C to 1200 °C were carried out. The results showed that the uniformity of Fe element distribution within grain can be significantly improved by the homogenization HT. With increasing HT temperature, Fe atoms migration ability increases, and the uniformity of Fe element distribution improves. Homogenization HT at 1150 °C and 1200 °C for 12 h can effectively reduce the degree of Fe element segregation.

Plastome evolution and phylogenomic insights into the evolution of Lysimachia (Primulaceae: Myrsinoideae).

BACKGROUND: Lysimachia L., the second largest genus within the subfamily Myrsinoideae of Primulaceae, comprises approximately 250 species worldwide. China is the species diversity center of Lysimachia, containing approximately 150 species. Despite advances in the backbone phylogeny of Lysimachia, species-level relationships remain poorly understood due to limited genomic information. This study analyzed 50 complete plastomes for 46 Lysimachia species. We aimed to identify the plastome structure features and hypervariable loci of Lysimachia. Additionally, the phylogenetic relationships and phylogenetic conflict signals in Lysimachia were examined. RESULTS: These fifty plastomes within Lysimachia had the typical quadripartite structure, with lengths varying from 152,691 to 155,784 bp. Plastome size was positively correlated with IR and intron length. Thirteen highly variable regions in Lysimachia plastomes were identified. Additionally, ndhB, petB and ycf2 were found to be under positive selection. Plastid ML trees and species tree strongly supported that L. maritima as sister to subg. Palladia + subg. Lysimachia (Christinae clade), while the nrDNA ML tree clearly placed L. maritima and subg. Palladia as a sister group. CONCLUSIONS: The structures of these plastomes of Lysimachia were generally conserved, but potential plastid markers and signatures of positive selection were detected. These genomic data provided new insights into the interspecific relationships of Lysimachia, including the cytonuclear discordance of the position of L. maritima, which may be the result of ghost introgression in the past. Our findings have established a basis for further exploration of the taxonomy, phylogeny and evolutionary history within Lysimachia.

Lysimachiafenghwaiana (Primulaceae), a new species from Hunan Province, China.

A new species, Lysimachiafenghwaiana G.Hao & H.F.Yan (Primulaceae), from Hunan Province, China, is described and illustrated. This new species belongs to Lysimachiasubgen.Lysimachiasect.Nummularia and is morphologically similar to L.crista-galli and L.carinata, but is distinctive in its leaf shape and arrangement of flowers. It can be further distinguished from L.crista-galli by the absence of calyx lobule spur, and from L.carinata by the black glandular striates in the corolla lobes, rather than punctate.

Construction and validation of a nomogram for HBV-related hepatocellular carcinoma: A large, multicenter study.

INTRODUCTION AND OBJECTIVES: We initiated this multicenter study to integrate important risk factors to create a nomogram for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) for clinician decision-making. PATIENTS AND METHODS: Between April 2011 and March 2022, 2281 HCC patients with an HBV-related diagnosis were included. All patients were randomly divided into two groups in a ratio of 7:3 (training cohort, n = 1597; validation cohort, n = 684). The nomogram was built in the training cohort via Cox regression model and validated in the validation cohort. RESULTS: Multivariate Cox analyses revealed that the portal vein tumor thrombus, Child-Pugh class, tumor diameter, alanine aminotransferase level, tumor number, extrahepatic metastases, and therapy were independent predictive variables impacting overall survival. We constructed a new nomogram to predict 1-, 2-, and 3-year survival rates based on these factors. The nomogram-related receiver operating characteristics (ROC) curves indicated that the area under the curve (AUC) values were 0.809, 0.806, and 0.764 in predicting 1-, 2-, and 3-year survival rates, respectively. Furthermore, the calibration curves revealed good agreement between real measurements and nomogram predictions. The decision curve analyses (DCA) curves demonstrated excellent therapeutic application potential. In addition, stratified by risk scores, low-risk groups had longer median OS than medium-high-risk groups (p < 0.001). CONCLUSIONS: The nomogram we constructed showed good performance in predicting the 1-year survival rate for HBV- related HCC.

Adipose mesenchymal stem cell-derived extracellular vesicles reduce glutamate-induced excitotoxicity in the retina.

Adipose mesenchymal stem cells (ADSCs) have protective effects against glutamate-induced excitotoxicity, but ADSCs are limited in use for treatment of optic nerve injury. Studies have shown that the extracellular vesicles (EVs) secreted by ADSCs (ADSC-EVs) not only have the function of ADSCs, but also have unique advantages including non-immunogenicity, low probability of abnormal growth, and easy access to target cells. In the present study, we showed that intravitreal injection of ADSC-EVs substantially reduced glutamate-induced damage to retinal morphology and electroretinography. In addition, R28 cell pretreatment with ADSC-EVs before injury inhibited glutamate-induced overload of intracellular calcium, downregulation of α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptor (AMPAR) subunit GluA2, and phosphorylation of GluA2 and protein kinase C alpha in vitro. A protein kinase C alpha agonist, 12-O-tetradecanoylphorbol 13-acetate, inhibited the neuroprotective effects of ADSC-EVs on glutamate-induced R28 cells. These findings suggest that ADSC-EVs ameliorate glutamate-induced excitotoxicity in the retina through inhibiting protein kinase C alpha activation.

The efficacy and safety of using pyrotinib combined with capecitabine as neoadjuvant therapy in elderly patients with HER2-positive breast cancer: a single-arm prospective clinical trial.

Background: Pyrotinib combined with capecitabine has been approved for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer in China. To date, the management of early-stage or locally advanced HER2-positive breast cancer in the clinic remains challenging. We conducted this trial to investigate the efficacy and safety of pyrotinib combined with capecitabine as neoadjuvant therapy (NAT) in elderly patients with HER2-positive breast cancer. Due to the stimulation of blood vessels by chemotherapy drugs, the elasticity of blood vessels in the elderly decreases, and then chemotherapy infusion is more likely to lead to phlebitis. Both pyrotinib and capecitabine can be taken to facilitate home treatment for elderly patients with HER2-positive breast cancer (BC). Methods: From January 2020 to March 2021, patients aged between 70 and 81 years old with stage IIA-IIIB HER2-positive breast cancer were screened, enrolled, and assigned to receive six cycles of pyrotinib (320-400 mg, orally, once daily) plus capecitabine (1,250 mg/m2, orally, twice daily) on days 1-14 in every 21-day cycle. The primary endpoint was the objective response rate (ORR). Adverse events (AEs) were assessed in every neoadjuvant cycle. Surgery was performed after the last cycle, and the total pathological complete response (tpCR) was evaluated postoperatively. Results: Of the 23 patients enrolled, the ORR was 100% (23/23; 95% confidence intervals: 85 to 100). All patients underwent surgery with a tpCR rate of 43.5% (10/23; 95% confidence intervals: 23 to 66). The most common AE was diarrhea, occurring in 19 of 23 patients (82.6%); most of these patients sustained mild diarrhea (Grade 1 or Grade 2) and only three had moderate diarrhea (Grade 3). The incidences of other AEs, including weakness, loss of appetite, leukopenia, nausea, vomiting, hand-foot syndrome, etc., were low and the symptoms were mild. No severe AEs (Grade 4 or 5) were observed throughout the treatment. Conclusion: In our study, pyrotinib combined with capecitabine as neoadjuvant therapy in elderly women with HER2-positive breast cancer is safe and showed efficacy in this population, which may be widely used as a protocol for clinical neoadjuvant therapy.

The role of MAPK/NF-κB-associated microglial activation in T-2 toxin-induced mouse learning and memory impairment.

T-2 toxin is a mycotoxin with multiple toxic effects and has emerged as an important food pollutant. Microglia play a significant role in the toxicity of various neurotoxins. However, whether they participate in the neurotoxicity of T-2 toxin has not been reported. To clarify this point, an in vivo mouse model of T-2 toxin (4 mg/kg) poisoning was established. The results of Morris water maze and open-field showed that T-2 toxin induced learning and memory impairment and locomotor inhibition. Meanwhile, T-2 toxin induced microglial activation, while inhibiting microglia activation by minocycline (50 mg/kg) suppressed the toxic effect of the T-2 toxin. To further unveil the potential mechanisms involved in T-2 toxin-induced microglial activation, an in vitro model of T-2 toxin (0, 2.5, 5, 10 ng/mL) poisoning was established using BV-2 cells. Transcriptomic sequencing revealed lots of differentially expressed genes related to MAPK/NF-κB pathway. Western blotting results further confirmed that T-2 toxin (5 ng/mL) induced the activation of MAPKs and their downstream NF-κB. Moreover, the addition of inhibitors of NF-κB and MAPKs reversed the microglial activation induced by T-2 toxin. Overall, microglial activation may contribute a considerable role in T-2 toxin-induced behavioral abnormalities, which could be MAPK/NF-κB pathway dependent.

Discovery of novel BRD4-BD2 inhibitors via in silico approaches: QSAR techniques, molecular docking, and molecular dynamics simulations.

Bromodomain-containing protein 4(BRD4) plays an important role in the occurrence and development of various malignant tumors, which has attracted the attention of scientific research institutions and pharmaceutical companies. The structural modification of most currently available BRD4 inhibitors is relatively simple, but the drug effectiveness is limited. Research has found that the inhibition of BD1 may promote the differentiation of oligodendrocyte progenitor cell; however, the inhibition of BD2 will not cause this outcome. Therefore, newly potential drugs which target BRD4-BD2 need further research. Herein, we initially built QSAR models out of 49 compounds using HQSAR, CoMFA, CoMSIA, and Topomer CoMFA technology. All of the models have shown suitable reliabilities (q2 = 0.778, 0.533, 0.640, 0.702, respectively) and predictive abilities (r2pred = 0.716, 0.6289, 0.6153, 0.7968, respectively) for BRD4-BD2 inhibitors. On the basis of QSAR results and the search of the R-group in the topomer search module, we designed 20 new compounds with high activity that showed appropriate docking score and suitable ADMET. Docking studies and MD simulation were carried out to reveal the amino acid residues (Asn351, Cys347, Tyr350, Pro293, and Asp299) at the active site of BRD4-BD2. Free energy calculations and free energy landscapes verified the stable binding results and indicated stable conformations of the complexes. These theoretical studies provide guidance and theoretical basis for designing and developing novel BRD4-BD2 inhibitors.

Integrated Proteomic and Phosphoproteomic Analysis of the Hippocampus in a Mouse Model of Early Life Inflammation.

INTRODUCTION: Inflammation in early life is a risk factor for the development of neuropsychiatric diseases later in adolescence and adulthood, yet the underlying mechanism remains elusive. In the present study, we performed an integrated proteomic and phosphoproteomic analysis of the hippocampus to identify potential molecular mechanisms of early life inflammation-induced cognitive impairment. METHODS: Both female and male mice received a single intraperitoneal injection of 100 µg/kg lipopolysaccharide (LPS) on postnatal day 10 (P10). Behavioral tests, including open field, elevated plus-maze, and Y-maze tests, were performed on P39, P40, and P41, respectively. After behavioral tests, male mice were sacrificed. The whole brain tissues and the hippocampi were harvested on P42 for proteomic, phosphoproteomic, Western blot, and Golgi staining. RESULTS: Early life LPS exposure induced cognitive impairment in male mice but not in female mice, as assessed by the Y-maze test. Therefore, following biochemical tests were conducted on male mice. By proteomic analysis, 13 proteins in LPS group exhibited differential expression. Among these, 9 proteins were upregulated and 4 proteins were downregulated. For phosphoproteomic analysis, a total of 518 phosphopeptides were identified, of which 316 phosphopeptides were upregulated and 202 phosphopeptides were downregulated in the LPS group compared with the control group. Furthermore, KEGG analysis indicated that early life LPS exposure affected the glutamatergic synapse and neuroactive ligand-receptor interaction, which were associated with synaptic function and energy metabolism. Increased level of brain protein i3 (Bri3), decreased levels of PSD-95 and mGLUR5, and dendritic spine loss after early life LPS exposure further confirmed the findings of proteomic and phosphoproteomic analysis. CONCLUSIONS: Our findings demonstrated that neuroinflammation and impaired synapse may be involved in early life inflammation-induced cognitive impairment. Future studies are required to confirm our preliminary results.

Association between ambient carbon monoxide levels and hospitalization costs of patients with myocardial infarction: Potential effect modification by ABO blood group.

Previous researches have reported the association between air pollution and various diseases. However, few researches have investigated whether air pollutants are associated with the economic loss resulting from patients' hospitalization, especially the economic loss of hospitalization due to acute cardiovascular events. The purpose of our research was to explore the association between the levels of carbon monoxide (CO), taken as an index of pollution, and the hospitalization costs of myocardial infarction (MI), and the potential effect modification by the ABO blood group. A total of 3237 MI inpatients were included in this study. A multiple linear regression model was used to evaluate the association between ambient CO levels and hospitalization costs of MI patients. Moreover, we performed stratified analyses by age, gender, body mass index (BMI), season, hypertension, and ABO blood types. There was a positive association between the levels of CO in the air and the costs of hospitalization caused by MI. Furthermore, such association was stronger in males, BMI ≥25, <65 years, with hypertension, and non-O blood group. Interestingly, we found the association was particularly significant in patients with blood group B. Overall, our study first found that ambient CO levels could have an impact on the hospitalization costs for MI patients, and those with blood group B can be more sensitive.