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Abstract Centromere protein A (CENP‐A), a centromere‐specific histone H3 variant, is crucial for kinetochore positioning and chromosome segregation. However, its regulatory mechanism in human cells remains incompletely understood. A structure‐activity relationship (SAR) study of the cell‐cycle‐arresting indole terpenoid mimic JP18 leads to the discovery of two more potent analogs, (+)‐6‐Br‐JP18 and (+)‐6‐Cl‐JP18. Tubulin is identified as a potential cellular target of these halogenated analogs by using the drug affinity responsive target stability (DARTS) based method. X‐ray crystallography analysis reveals that both molecules bind to the colchicine‐binding site of β‐tubulin. Treatment of human cells with microtubule‐targeting agents (MTAs), including these two compounds, results in CENP‐A accumulation by destabilizing Cdh1, a co‐activator of the anaphase‐promoting complex/cyclosome (APC/C) E3 ubiquitin ligase. This study establishes a link between microtubule dynamics and CENP‐A accumulation using small‐molecule tools and highlights the role of Cdh1 in CENP‐A proteolysis.

Abstract Background Corylifol A (CYA) is one of the main active components of Psoralea corylifolia L. CYA had been reported to have ameliorating effects on dexamethasone‐induced atrophy of C2C12 mouse skeletal myotubes, but its effects on cancer cachexia were unclear. Here, we checked the influence of CYA on muscle atrophy in cancer cachexia mice and tried to clarify its mechanisms. Methods C26 tumour‐bearing mice were applied as the animal model to examine the effects of CYA in attenuating cachexia symptoms. The in vitro cell models of TNF‐α‐induced C2C12 myotubes or ad‐mRFP‐GFP‐LC3B‐transfected C2C12 myotubes were used to check the influence of CYA on myotube atrophy based on both ubiquitin proteasome system (UPS) and autophagy‐lysosome system. The possible direct targets of CYA were searched using the biotin‐streptavidin pull‐down assay and then confirmed using the Microscale thermophoresis binding assay. The levels of related signal proteins in both in vitro and in vivo experiments were examined using western blotting and immunocytochemical assay. Results The administration of CYA prevented body weight loss and muscle wasting in C26 tumour‐bearing mice without affecting tumour growth. At the end of the experiment, the body weight of mice treated with 30 mg/kg of CYA (23.59 ± 0.94 g) was significantly higher than that of the C26 model group (21.66 ± 0.56 g) with P

IntroductionMarine epiphytic diatoms are natural diets for multiple marine invertebrates, including sea cucumbers, sea urchins, etc. They also act as bioindicators in marine waters to assess water quality of coastal ecosystems. Material and methodsWe isolated three strains of Navicula and two strains of Nitzschia from macroalgal epiphytes. Combined concentrations of four macroelements, five trace metals, and three vitamins in f/2 medium were optimized for these diatoms using single-factor and orthogonal tests. Results and discussionThe biomass productivities for 4-L enlarged cultures of the five isolated diatoms in their exclusively optimized f/2 media all increased by nearly 10-fold relative to f/2 medium, and that of Navicula-1 and Nitzschia-2 reached the highest, i.e., 29.52 ± 1.98 and 30.68 ± 2.84 g m-2 d-1, respectively. Moreover, the relative abundance of C20:5n3 in the exclusively optimized f/2 medium-cultured Navicula-1 notably rose by 24%, and that in Nitzschia-2 held stable at > 25%. Thus, Navicula-1 and Nitzschia-2 were screened out with outstanding growth traits and improved fatty acid compositions at high levels of combined nitrogen, phosphorus, iron, and silicon. The two diatoms have potential for becoming quality diets for marine aquaculture, and ideal candidates for effective nutrient removal.

Backgrounds: The Qing-Fei-Pai-Du Decoction (QFPDD) was reported to ameliorate the inflammatory coagulopathy and thrombocytopenia in COVID-19 patients. This work investigated the effects of QFPDD in endotoxaemia rats and then further studied its influence on platelet production using cultured megakaryocytes. Methods: The coagulation indexes and platelet aggregation reactivity of LPS-induced endotoxemia rats with or without QFPDD treatment were analyzed. The platelet parameters, the expression of thrombopoietin (TPO) in the liver and the kidney, number of the megakaryocytes in bone marrow smear of rats were checked. The maturation and platelet production of human megakaryoblastic MEG-01 cells treated with QFPDD or isochlorogenic acid A (ISA), an active component of QFPDD, were observed. Results: QFPDD improved the coagulation indexes of LPS-induced endotoxaemia rats and decreased the hyper-reactivity of platelets. QFPDD ameliorated LPS-induced decrease in platelet number, partially alleviated increase in liver TPO expression and exhibited no influence on increase in the number of bone marrow megakaryocytes. QFPDD promoted maturation and production of platelet-like particles of MEG-01 megakaryocytes. The effects of QFPDD on MEG-01 megakaryocytes might be related to activation of AKT pathway and up-regulation of related transcription factors. ISA also could induce the maturation of MEG-01 cells. Conclusions: QFPDD effectively ameliorated coagulopathy and thrombocytopenia in rats under inflammatory state. The mechanisms of QFPDD in ameliorating thrombocytopenia might be based on both decreasing effects on platelet depletion in coagulation and inducing effects on maturation and platelet production of megakaryocytes. ISA might be one of the components which contribute to the effects of QFPDD on megakaryocytes.

Breast cancer (BC) remains the foremost cause of cancer mortality globally, with neutrophils playing a critical role in its pathogenesis. As an essential tumor microenvironment (TME) component, neutrophils are emerging as pivotal factors in BC progression. Growing evidence has proved that neutrophils play a Janus- role in BC by polarizing into the anti-tumor (N1) or pro-tumor (N2) phenotype. Clinical trials are evaluating neutrophil-targeted therapies, including Reparixin (NCT02370238) and Tigatuzumab (NCT01307891); however, their clinical efficacy remains suboptimal. This review summarizes the evidence regarding the close relationship between neutrophils and BC, emphasizing the critical roles of neutrophils in regulating metabolic and immune pathways. Additionally, we summarize the existing therapeutic approaches that target neutrophils, highlighting the challenges, and affirming the rationale for continuing to explore neutrophils as a viable therapeutic target in BC management.

A cross-sectional study was conducted to estimate the age-stratified normal levels and age-related changes in the risk predictors of benign prostatic hyperplasia (BPH) progression. A total of 4706 male participants aged 40 years or older in Zhengzhou (China) were enrolled. The values of the International Prostate Symptom Score (IPSS), prostate-specific antigen (PSA), prostate volume (PV), and postvoid residual urine volume (PVR) significantly increased with age. Nonlinear relationships between age and IPSS scores ≥8 (P for nonlinearity = 0.046), PSA level ≥1.6 ng ml–1, PV ≥31 ml, or PVR ≥39 ml (all P for nonlinearity 1), regardless of the predictors of the IPSS score, PSA level, PV, or PVR; and the OR values increased gradually. Therefore, after the age of 61 years, the risk predictors related to BPH progression were positively correlated with age.

IntroductionThe masked palm civet (Paguma larvata) serves as a reservoir in transmitting pathogens, such as Toxoplasma gondii, to humans. However, the pathogenesis of T. gondii infection in masked palm civets has not been explored. We studied the molecular changes in the brain tissue of masked palm civets chronically infected with T. gondii ME49.MethodsThe differentially expressed proteins in the brain tissue were investigated using iTRAQ and bioinformatics.ResultsA total of 268 differential proteins were identified, of which 111 were upregulated and 157 were downregulated. KEGG analysis identified pathways including PI3K-Akt signaling pathway, proteoglycans in cancer, carbon metabolism, T-cell receptor signaling pathway. Combing transcriptomic and proteomics data, we identified 24 genes that were differentially expressed on both mRNA and protein levels. The top four upregulated proteins were REEP3, REEP4, TEP1, and EEPD1, which was confirmed by western blot and immunohistochemistry. KEGG analysis of these 24 genes identified signaling cascades that were associated with small cell lung cancer, breast cancer, Toll-like receptor signaling pathway, Wnt signaling pathways among others. To understand the mechanism of the observed alteration, we conducted immune infiltration analysis using TIMER databases which identified immune cells that are associated with the upregulation of these proteins. Protein network analysis identified 44 proteins that were in close relation to all four proteins. These proteins were significantly enriched in immunoregulation and cancer pathways including PI3K-Akt signaling pathway, Notch signaling pathway, chemokine signaling pathway, cell cycle, breast cancer, and prostate cancer. Bioinformatics utilizing two cancer databases (TCGA and GEPIA) revealed that the four genes were upregulated in many cancer types including glioblastoma (GBM). In addition, higher expression of REEP3 and EEPD1 was associated with better prognosis, while higher expression of REEP4 and TEP1 was associated with poor prognosis in GBM patients.DiscussionWe identified the differentially expressed genes in the brain of T. gondii infected masked palm civets. These genes were associated with various cellular signaling pathways including those that are immune- and cancer-related.

Abstract To obtain novel insights into the tumor biology and therapeutic targets of LUAD, we performed a comprehensive analysis of the KCTD family genes. The expression patterns and clinical significance of the KCTD family were identified through multiple bioinformatics mining. Moreover, the molecular functions and potential mechanisms of differentially expressed KCTDs were evaluated using TIMER 2.0, cBioPortal, GeneMANIA, LinkedOmics and GSEA. The results indicated that the mRNA and protein expression levels of KCTD9, KCTD10, KCTD12, KCTD15 and KCTD16 were significantly decreased in LUAD, while those of KCTD5 were significantly increased. High KCTD5 expression was significantly associated with advanced tumor stage, lymph node metastasis, TP53 mutation and poor prognosis. In addition, KCTD5 was positively correlated with CD8 + T cell, neutrophil, macrophage and dendritic cell infiltration. Additionally, KCTDs demonstrate promising prospects in the diagnosis of LUAD. Importantly, high KCTD5 expression was enriched in signaling pathways associated with the malignant progression of tumors, including the inflammatory response, the IL6/JAK/STAT3 signaling pathway, EMT and hypoxia. Further association analysis showed that KCTD5 was positively correlated with hypoxia-related genes such as HIF1. Overall, KCTDs can be used as molecular targets for the treatment of LUAD, as well as effective molecular biomarkers for diagnosis and prognosis prediction.

Abstract From the roots of Campylotropis hirtella (Franch.) Schindl., many natural dihydroflavonol compounds have been extracted, and they possess a structurally novel feature of chiral tertiary alcohol groups. However, the content of the compounds in the plant is extremely low. At this point, to satisfy the needs of further experimental research on these compounds, much effort has been invested in the chemical synthesis of the core structure of 3-hydroxy-3-phenylchroman-4-one. This study aimed to explore a novel method for the synthesis of dihydroflavonol (3), and its application in the production of a natural product (14). The method started with commercially available materials, and provided a foundation for total synthesis of natural compounds of dihydroflavonol.

Background Bronchopneumonia is a disease of the respiratory tract. It leads to other complications and endangers life and health. Long non-coding RNA (lncRNA) participates in the occurrence and development of bronchopneumonia. Nuclear paraspeckle assembly transcript 1 (NEAT1) plays a key role in inflammatory diseases, but the function of NEAT1 in bronchopneumonia remains unclear. Methods RT-qPCR and Western blotting were performed to determine genes and proteins expressions. MTT was applied to test cell viability. Cell apoptosis was detected by flow cytometry. RIP was used to investigate the correlation between NEAT1 and miR-155-5p. The interaction between miR-155-5p and NEAT1 or MyD88 was evaluated by the dual-luciferase reporter gene. Results NEAT1 and MyD88 were upregulated in BEAS-2B cells by LPS, while miR-155-5p was downregulated. Knockdown of NEAT1 inhibited LPS-induced BEAS-2B cells growth inhibition by inhibiting the apoptosis. In addition, NEAT1 silencing suppressed LPS-induced inflammatory responses in BEAS-2B cells via suppression of TNF-α, IL-1β, IL-6, and IL-18. Meanwhile, NEAT1 is directly bound to miR-155-5p to regulate MyD88/NF-κB axis, and overexpression of miR-155-5p increased cell proliferation and suppressed inflammatory factors expression levels and cell apoptosis. Furthermore, sh-NEAT1-induced inhibition of BEAS-2B cells injury was partially reversed by miR-155-5p inhibitor or MyD88 overexpression. Conclusion NEAT1 silencing suppressed LPS-induced BEAS-2B cells injury and inflammation by the mediation of miR-155-5p/MyD88/NF-κB axis. Thus, our study might shed new light on exploring the new strategies for the treatment of bronchopneumonia.

Our drug discovery model has identified two novel STAT3 SH2 domain inhibitors 323–1 and 323–2 (delavatine A stereoisomers) in a series of experiments. In silico computational modeling, drug affinity responsive target stability (DARTS), and fluorescence polarization (FP) assays altogether determined that 323–1 and 323–2 directly target the STAT3 SH2 domain and inhibited both phosphorylated and non-phosphorylated STAT3 dimerization. Computational docking predicted that compound 323s bind to three subpockets of the STAT3 SH2 domain. The 323s inhibition of STAT3 dimerization was more potent than the commercial STAT3 SH2 domain inhibitor S3I-201 in the co-immunoprecipitation assay, correlating with computational docking data. The fluorescence polarization assay further confirmed that the compound 323s target the STAT3 SH2 domain by competitively abrogating the interaction between STAT3 and the SH2-binding peptide GpYLPQTV. Compared with S3I-201, the 323 compounds exhibited stronger inhibition of STAT3 and reduced the level of IL-6-stimulated phosphorylation of STAT3 (Tyr705) in LNCaP cells over the phosphorylation of STAT1 (Tyr701) induced by IFN-ɣ in PC3 cells or the phosphorylation of STAT1 (Ser727) in DU145 cells. Both compounds downregulated STAT3 target genes MCL1 and cyclin D1. Thus, the two compounds are promising lead compounds for the treatment of cancers with hyper-activated STAT3.

Abstract Background Imported malaria has been an important challenge for China. Fatality rates from malaria increased in China, particularly in Henan Province, primarily due to malpractice and misdiagnoses in healthcare institutions, and the level of imported malaria. This study aims to investigate the relationship between the state of diagnosis and subsequent complications among imported malaria cases at healthcare institutions, based on malaria surveillance data in Henan Province from 2012 to 2017. Methods A retrospective descriptive analysis was performed using data from the Centre for Disease Control and Prevention, Zhengzhou City, the capital of Henan Province. A decision tree method was exploited to provide valuable insight into the correlation between imported malaria cases and healthcare institutions. Results From 2012 to 2017, there were 371 imported malaria cases, mostly in males aged between 20 and 50 years, including 319 Plasmodium falciparum cases. First visits of 32.3%, 19.9% and 15.9% malaria cases for treatment were to provincial, municipal and county healthcare institutions, respectively. The time interval between onset and initial diagnosis of 284 cases (76.5%) and the time interval between initial diagnosis and final diagnosis of 197 cases (53.1%) was no more than 72 h. An apparent trend was found that there were notably fewer patients misdiagnosed at first visit to healthcare institutions of a higher administrative level; 12.5% of cases were misdiagnosed in provincial healthcare institutions compared to 98.2% in private clinics, leading to fewer complications at healthcare institutions of higher administrative level due to correct initial diagnosis. In the tree model, the rank of healthcare facilities for initial diagnosis, and number of days between onset and initial diagnosis, made a major contribution to the classification of initial diagnosis, which subsequently became the most significant factor influencing complications developed in the second tree model. The classification accuracy were 82.2 and 74.1%, respectively for the tree models of initial diagnosis and complications developed. Conclusion Inadequate seeking medical care by imported malaria patients, and insufficient capacity to diagnose malaria by healthcare institutions of lower administrative level were identified as major factors influencing complications of imported malaria cases in Henan Province. The lack of connection between uncommon imported malaria cases and superior medical resources was found to be the crucial challenge. A web-based system combined with WeChat to target imported malaria cases was proposed to cope with the challenge.

Abstract Eight new triterpenoids were isolated from Ainsliaea latifolia. The structures of these compounds were elucidated by interpretation of spectroscopic data, including HRESIMS and NMR data. Compounds 4–6 are identified as rare trinorcucurbitane or tetranorcucurbitane triterpenoids. The absolute configurations of compounds 1 and 2 were confirmed by Snatzke’s method. All compounds were evaluated for their inhibition against cyclooxyenase-2 (COX-2), in which compound 4 showed significant inhibitory effect against COX-2 with IC50 value of 3.98 ± 0.32 μM, comparable to that of positive control NS-398 (IC50 4.14 ± 0.28 μM). Graphic Abstract

Abstract Pancreatic cancer (PC) is one of the most fatal diseases with a very high rate of metastasis and low rate of survival. Despite the advances in understanding this devastating disease, PC still accounts for 3% of all cancers and causes almost 7% of death of cancer patients. Recent studies have demonstrated that the transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) and its key negative regulator Kelch-like ECH-associated protein 1 (Keap1) are dysregulated in PC and the Keap1-Nrf2 pathway is an emerging target for PC prevention and therapy. Indeed, Nrf2 plays an either tumor-suppressive or promoting function in PC, which depends on the developmental stages of the disease and the cellular context. Several natural-product Nrf2 activators have been developed to prevent pancreatic carcinogenesis, while the Nrf2 inhibitors have been examined for their efficacy in inhibiting PC growth and metastasis and reversing chemoresistance. However, further preclinical and clinical studies for determining the effectiveness and safety of targeting the Keap1-Nrf2 pathway for PC prevention and therapy are warranted. In this review, we comprehensively discuss the dual roles of the Keap1-Nrf2 signaling pathway in PC as well as the current targeting strategies and known activators and inhibitors of Nrf2. We also propose new strategies that may be used to address the current issues and develop more specific and more effective Nrf2 activator/inhibitors for PC prevention and therapy.

Since accurate grading of gliomas has important clinical value, the aim of this study is to evaluate the diagnostic efficacy of perfusion values derived from arterial spin labeling (ASL) to grade gliomas. In addition, the correlation between perfusion and isocitrate dehydrogenase 1 (IDH1) genotypes and chromosome arms 1p and 19q (1p/19q) status of gliomas was assessed. A total of 52 cases of supratentorial gliomas in adults who received ASL imaging were enrolled in this retrospective study. The cerebral blood flow (CBF) images derived from ASL and anatomical maps were normalized to the Montreal Neurological Institute coordinate system and matched. The mean CBF (meanCBF), the maximum CBF (maxCBF), and their relative values (rmeanCBF and rmaxCBF, respectively) were assessed in each case. The tumor grades, IDH1 genotypes, and 1p/19q status were diagnosed according to the 2016 WHO criteria. Receiver operating characteristic curves were performed to assess the efficacy of perfusion parameters for grading. Qualitatively, all gliomas were divided into high- and low-perfusion groups. The crosstabs chi-square test of independence was performed to calculate contingency coefficient (C) and Cramer V coefficient to assess the correlation between perfusion and IDH1 genotypes and 1p/19q status of gliomas. The rmaxCBF showed the best diagnostic efficacy; meanwhile, rmeanCBF had the best specificity for grade discrimination. In astrocytoma, there was a mild correlation between IDH1 genotypes and tumor perfusion with the Cramer's V coefficient of 0.378. There was no significant association between 1p/19q codeletion and perfusion in grade II and III gliomas.

Abstract Triple negative breast cancer (TNBC), which is typically lack of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), represents the most aggressive and mortal subtype of breast cancer. Currently, only a few treatment options are available for TNBC due to the absence of molecular targets, which underscores the need for developing novel therapeutic and preventive approaches for this disease. Recent evidence from clinical trials and preclinical studies has demonstrated a pivotal role of signal transducer and activator of transcription 3 (STAT3) in the initiation, progression, metastasis, and immune evasion of TNBC. STAT3 is overexpressed and constitutively activated in TNBC cells and contributes to cell survival, proliferation, cell cycle progression, anti-apoptosis, migration, invasion, angiogenesis, chemoresistance, immunosuppression, and stem cells self-renewal and differentiation by regulating the expression of its downstream target genes. STAT3 small molecule inhibitors have been developed and shown excellent anticancer activities in in vitro and in vivo models of TNBC. This review discusses the recent advances in the understanding of STAT3, with a focus on STAT3’s oncogenic role in TNBC. The current targeting strategies and representative small molecule inhibitors of STAT3 are highlighted. We also propose potential strategies that can be further examined for developing more specific and effective inhibitors for TNBC prevention and therapy.

Primary plant metabolites can be used for artificial preparation of natural deep eutectic solvents (NADESs), which have strong dissolving capacity, good biocompatibility, and biodegradability. In this study, for the first time, we verified that NADESs were present in Coptidis Rhizoma extract and systematically investigated its effects and mechanisms on the pharmacokinetics of oral berberine hydrochloride (BBR), a co-existing bioactive constituent. First, three LC-MS/MS based methods were established and fully validated to determine the levels of 11 primary metabolites in Coptidis Rhizoma extract. According to the weight ratio of four major primary metabolites in the Coptidis Rhizoma extract, a stable “endogenous” NADES was prepared using the heating method by the addition of 350 μl of water to 1,307.8 mg of the mixture of malic acid (490.5 mg), glucose (280.6 mg), sucrose (517.7 mg), and choline chloride (19.0 mg). The prepared NADES showed significant acute toxicity in mice and cytotoxicity in MDCK-MDR1 cells. However, after being diluted 10 times or 100 times, the NADES had no significant acute toxicity or cytotoxicity, respectively. The dilutions of the NADES significantly increased the water solubility of BBR, reduced its efflux in gut sacs and MDCK-MDR1 cell monolayer, and improved its metabolic stability in intestinal S9. In addition, the NADES dilutions reversibly opened the tight junctions between the enterocytes in the gut sacs. Moreover, the NADES dilutions significantly improved the exposure levels of BBR in the portal vein and livers of mice that were administered oral BBR. Malic acid was identified as a major component in the NADES in terms of solubility, acute toxicity, cytotoxicity, and pharmacokinetic-improving effects on oral BBR. In conclusion, the primary metabolites of Coptidis Rhizoma extract could form “endogenous” NADES, and its dilutions improve the pharmacokinetics of oral BBR. This study demonstrates the synergistic interaction of the constituents of Coptidis Rhizoma extract and the potential use of the NADES dilutions in oral BBR delivery.

Proteolysis targeting chimeric (PROTAC) technology is an effective endogenous protein degradation tool developed in recent years that can ubiquitinate the target proteins through the ubiquitin-proteasome system (UPS) to achieve an effect on tumor growth. A number of literature studies on PROTAC technology have proved an insight into the feasibility of PROTAC technology to degrade target proteins. Additionally, the first oral PROTACs (ARV-110 and ARV-471) have shown encouraging results in clinical trials for prostate and breast cancer treatment, which inspires a greater enthusiasm for PROTAC research. Here we focus on the structures and mechanisms of PROTACs and describe several classes of effective PROTAC degraders based on E3 ligases.

Despite the dramatic advances in cancer research in the past few years, effective therapeutic strategies are urgently needed. Endothelial cell-specific molecule 1 (ESM-1), a soluble dermatan sulfate proteoglycan, also known as endocan, serves as a diagnostic and prognostic indicator due to its aberrant expression under pathological conditions, including cancer, sepsis, kidney diseases, and cardiovascular disease. Significantly, ESM-1 can promote cancer progression and metastasis through the regulation of tumor cell proliferation, migration, invasion, and drug resistant. In addition, ESM-1 is involved in the tumor microenvironment, containing inflammation, angiogenesis, and lymph angiogenesis. This article reviews the molecular and biological characteristics of ESM-1 in cancer, the underlying mechanisms, the currently clinical and pre-clinical applications, and potential therapeutic strategies. Herein, we propose that ESM-1 is a new therapeutic target for cancer therapy.

The p53 tumor suppressor protein and its major negative regulators MDM2 and MDMX oncoproteins form the MDM2/MDMX-p53 circuitry, which plays critical roles in regulating cancer cell growth, proliferation, cell cycle progression, apoptosis, senescence, angiogenesis, and immune response. Recent studies have shown that the stabilities of p53, MDM2, and MDMX are tightly controlled by the ubiquitin-proteasome system. Ubiquitin specific protease 7 (USP7), one of the most studied deubiquitinating enzymes plays a crucial role in protecting MDM2 and MDMX from ubiquitination-mediated proteasomal degradation. USP7 is overexpressed in human cancers and contributes to cancer initiation and progression. USP7 inhibition promotes the degradation of MDM2 and MDMX, activates the p53 signaling, and causes cell cycle arrest and apoptosis, making USP7 a potential target for cancer therapy. Several small-molecule inhibitors of USP7 have been developed and shown promising efficacy in preclinical settings. In the present review, we focus on recent advances in the understanding of the USP7-MDM2/MDMX-p53 network in human cancers as well as the discovery and development of USP7 inhibitors for cancer therapy.

ZG0Cr26Ni5Mo3Cu3 Duplex Stainless Steel (DSS) was solution treated at 1,060 ìC for 3 h,followed by water cooling. Tempering treatments were conducted at 720, 750 and 780 ìC, respectively, for 16 h, followed by air cooling. The microstructures of ZG0Cr26Ni5Mo3Cu3 duplex stainless steel samples treated at different tempering temperatures were observed by scanning electron microscope (SEM) and energy dispersal spectroscopy (EDS), and the phase consitutions were analyzed using X-ray diffraction (XRD). The effects of the precipitation of sigma (σ) phase on the duplex phase percentage, hardness, impact toughness and corrosion resistance of the DSS were studied. Results showed that microstructures of ZG0Cr26Ni5Mo3Cu3 after solution treatment consists of ferrite (α) phase and austenite (γ) phase; after being tempered at different temperatures, σ phase appeared due to a eutectoid-type reaction of α—σ+γ2 during tempering treatment. It was observed that σ phase distributed along the grain boundary. The volume fraction of σ and γ phases increased with increasing tempering temperature in the range of 720 to 780 °C, whereas the volume fraction of α phase showed the opposite trend. When the percentage of σ phase increased, the hardness of steel also increased. In the solution treated steel, hardness was measured to be only 244.0 HB, because σ phase did not appear. However, it increased to 391.8 HB when the DSS was tempered at 780 ìC because a great of deal of σ phase appeared. The impact toughness and corrosion resistance of DSS decreased when the percentage of σ phase increased.

Objective: To investigate the network pharmacology of Shexiang Baoxin pill (SBP) and systematically analyze the mechanisms of SBP. Methods: In this study, we excavated all the targets of 26 constituents of SBP which were identified in rat plasma though literature mining and target calculation (reverse docking and similarity search) and analyzed the multiple pharmacology actions of SBP comprehensively through a network pharmacology approach. Results: In the end, a total of 330 Homo sapiens targets were identified for 26 blood constituents of SBP. Moreover, the pathway enrichment analysis found that these targets mapped into 171 KEGG pathways and 31 of which were more enriched. Among these identified pathways, 3 pathways were selected for analyzing the mechanisms of SBP for treating coronary heart disease. Conclusion: This study systematically illustrated the mechanisms of the SBP by analyzing the corresponding “drug-target-pathway-disease” interaction network.

PURPOSE: To evaluate whether intravoxel incoherent motion (IVIM)–related parameters could be used to differentiate malignant from benign focal liver lesions (FLLs) and to improve diagnostic efficiency. METHODS: Seventy-four patients with 75 lesions, including 51 malignant FLLs and 24 benign FLLs, underwent liver 3.0-T magnetic resonance imaging for routine examination sequences. IVIM diffusion-weighted imaging (DWI) with 11 b values (0-800 s/mm2) was also acquired concurrently. Apparent diffusion coefficient (ADCtotal) and IVIM-derived parameters, such as the pure diffusion coefficient (D), the pseudodiffusion coefficient (D⁎), and the perfusion fraction (f), were calculated and compared between the two groups. A receiver operating characteristic curve analysis was performed to assess their diagnostic value. RESULTS: ADCtotal, D, and f were significantly lower in the malignant group than in the benign group, whereas D⁎ did not show a statistical difference. D had a larger area under the curve value (0.968) and higher sensitivity (92.30%) for differentiation. CONCLUSION: IVIM is a useful method to differentiate malignant and benign FLLs. The D value showed higher efficacy to detect hepatic solid lesions.

PURPOSE:We aimed to explore whether intravoxel incoherent motion (IVIM)-related parameters of hepatocellular carcinoma (HCC) and focal nodular hyperplasia (FNH) demonstrate differences that could be used to differentiate and improve diagnostic efficiency.METHODS:A total of 27 patients, including 22 with HCC and 5 with FNH, underwent liver 3.0 T magnetic resonance imaging for routine sequences. They were concurrently examined by IVIM diffusion-weighted imaging (DWI) scanning with 11 different b values (0–800 s/mm2). IVIM-derived parameters, such as pure diffusion coefficient (D), pseudo-diffusion coefficient (D*), perfusion fraction (f), and apparent diffusion coefficient (ADCtotal), were quantified automatically by post-processing software and compared between HCC and FNH groups. A receiver operating characteristic (ROC) curve was then created to predict their diagnostic value.RESULTS:D* was weak in terms of reproducibility among the other parameters. ADCtotal, D, and D* were significantly lower in the HCC group than in the FNH group, while f did not show a significant difference. ADCtotal and D had the largest area under the curve values (AUC; 0.915 and 0.897, respectively) and similarly high efficacy to differentiate the two conditions.CONCLUSION:IVIM provides a new modality to differentiate the HCC and FNH. ADCtotal and D demonstrated outstanding and comparable diagnosing utility.

The systematic separation strategy has long and widely been applied in the research and development of herbal medicines. However, the pharmacological effects of many bioactive constituents are much weaker than those of the corresponding herbal extracts. Thus, there is a consensus that purer herbal extracts are sometimes less effective. Pharmacological loss of purified constituents is closely associated with their significantly reduced intestinal absorption after oral administration. In this review, pharmacokinetic synergies among constituents in herbal extracts during intestinal absorption were systematically summarized to broaden the general understanding of the pharmaceutical nature of herbal medicines. Briefly, some coexisting constituents including plant-produced primary and secondary metabolites, promote the intestinal absorption of active constituents by improving solubility, inhibiting first-pass elimination mediated by drug-metabolizing enzymes or drug transporters, increasing the membrane permeability of enterocytes, and reversibly opening the paracellular tight junction between enterocytes. Moreover, some coexisting constituents change the forms of bioactive constituents via mechanisms including the formation of natural nanoparticles. This review will focus on explaining this new synergistic mechanism. Thus, herbal extracts can be considered mixtures of bioactive compounds and pharmacokinetic synergists. This review may provide ideas and strategies for further research and development of herbal medicines.

The purpose of this study was to detect changes in urine of mice and to clarify the toxicity induced by bupleurotoxin (BETX) using liquid chromatography/quadrupole time-of-flight mass spectrometry (LC-Q-TOF-MS). A procedure for urine analysis using pattern recognition was proposed to evaluate the toxicity induced by BETX in male BALB/c mice. BETX at 2.5 mg/kg was administrated intraperitoneally (i.p.), and urine samples for the metabolomic study were collected from control and BETX experimental groups. Changes in the concentrations of some urine metabolites were detected exclusively in the experimental group. All results suggested that exposure to BETX might cause a disturbance in fatty acid metabolism and the oxidative stress system. These results may not only clarify the underlying mechanism of diverse intoxication effects of BETX but also provide the guidance in preclinical toxicity screening for new drugs.

Human carboxylesterase 1 (hCE1), one of the most important serine hydrolases distributed in liver and adipocytes, plays key roles in endobiotic homeostasis and xenobiotic metabolism. This study aimed to find potent and selective inhibitors against hCE1 from phytochemicals and their derivatives. To this end, a series of natural triterpenoids were collected and their inhibitory effects against human carboxylesterases (hCEs) were assayed using D-Luciferin methyl ester (DME) and 6,8-dichloro-9,9-dimethyl-7-oxo-7,9-dihydroacridin-2-yl benzoate (DDAB) as specific optical substrate for hCE1, and hCE2, respectively. Following screening of a series of natural triterpenoids, oleanolic acid (OA), and ursolic acid (UA) were found with strong inhibitory effects on hCE1 and relative high selectivity over hCE2. In order to get the highly selective and potent inhibitors of hCE1, a series of OA and UA derivatives were synthesized from OA and UA by chemical modifications including oxidation, reduction, esterification, and amidation. The inhibitory effects of these derivatives on hCEs were assayed and the structure-activity relationships of tested triterpenoids as hCE1 inhibitors were carefully investigated. The results demonstrated that the carbonyl group at the C-28 site is essential for hCE1 inhibition, the modifications of OA or UA at this site including esters, amides and alcohols are unbeneficial for hCE1 inhibition. In contrast, the structural modifications on OA and UA at other sites, such as converting the C-3 hydroxy group to 3-O-β-carboxypropionyl (compounds 20 and 22), led to a dramatically increase of the inhibitory effects against hCE1 and very high selectivity over hCE2. 3D-QSAR analysis of all tested triterpenoids including OA and UA derivatives provide new insights into the fine relationships linking between the inhibitory effects on hCE1 and the steric-electrostatic properties of triterpenoids. Furthermore, both inhibition kinetic analyses and docking simulations demonstrated that compound 22 was a potent competitive inhibitor against hCE1-mediated DME hydrolysis. All these findings are very helpful for medicinal chemists to design and develop highly selective and more potent hCE1 inhibitors for biomedical applications.

Purpose: Recently, high-resolution magnetic resonance imaging (HR-MRI) has been used to depict the wall characteristics of the intracranial arteries. The aim of this study was to explain the relationship between the remodeling patterns and acute ischemic stroke in patients with atherosclerotic middle cerebral artery (MCA) stenosis using HR-MRI.Materials and Methods: From August 2015 to May 2016, we prospectively screened 33 consecutive patients with unilateral MCA stenosis using time-to-flight MR angiography, including 15 patients with symptomatic MCA stenosis and 18 patients with asymptomatic MCA stenosis. Among them, 14 patients were diagnosed as positive remodeling (PR) and 19 as negative remodeling or non-remodeling. The cross-sectional images of the stenotic MCA wall on HR-MRI including T1WI, T2WI, and PDWI were compared between the symptomatic group and the asymptomatic group as well as the PR group and the non-PR group, based on the vessel area, lumen area, wall area, plaque area, degree of stenosis, remodeling index, and NIHSS score.Results: The symptomatic group had larger wall area (P = 0.040), plaque area (P

Zinc oxide (ZnO) nanoparticles (NPs) have been applied in numerous industrial products and personal care products like sunscreens and cosmetics. The released ZnO NPs from consumer and household products into the environment might pose potential health issues for animals and humans. In this study the expression of microRNAs and the correlations of microRNAs and their targeted genes in ZnO NPs treated chicken ovarian granulosa cells were investigated. ZnSO4 was used as the sole Zn2+ provider to differentiate the effects of NPs from Zn2+. It was found that ZnO-NP-5 μg/ml specifically regulated the expression of microRNAs involved in embryonic development although ZnO-NP-5 μg/ml and ZnSO4-10 μg/ml treatments produced the same intracellular Zn concentrations and resulted in similar cell growth inhibition. And ZnO-NP-5 μg/ml also specifically regulated the correlations of microRNAs and their targeted genes. This is the first investigation that intact NPs in ZnO-NP-5 μg/ml treatment specifically regulated the expression of microRNAs, and the correlations of microRNAs and their targeted genes compared to that by Zn2+. This expands our knowledge for biological effects of ZnO NPs and at the same time it raises the health concerns that ZnO NPs might adversely affect our biological systems, even the reproductive systems through regulation of specific signaling pathways.

A novel and sensitive HPLC-UV method has been developed for the simultaneous determination of twelve major compounds in Longdan Xiegan Pill. The chemical profile of the twelve compounds, including geniposidic acid (1), geniposide(2), gentiopicroside(3), liquiritin(4), crocin(5), baicalin(6), wogonoside(7), baicalein(8), glycyrrhizic acid (9), wogonin (10), oroxylin A (11) and aristolochic acid A (12), was acquired using high-performance liquid chromatography-diode array detector coupled with an electrospray tandem mass spectrometer (HPLC-DAD-ESI-MS). The analysis was performed on a Dikma Platisil ODS C18 column (250 mm à 4. 6 mm, 5 μm) with a gradient solvent system of acetonitrile-0. 1% aqueous formic acid. The validation was carried out and the linearities (r > 0. 9996), repeatability (RSD

Abieslactone is a triterpenoid lactone isolated from Abies plants. Previous studies have demonstrated that its derivative abiesenonic acid methyl ester possesses anti-tumor-promoting activity in vitro and in vivo. In the present study, cell viability assay demonstrated that abieslactone had selective cytotoxicity against human hepatoma cell lines. Immunostaining experiments revealed that abieslactone induced HepG2 and SMMC7721 cell apoptosis. Flow cytometry and western blot analysis showed that the apoptosis was associated with cell cycle arrest during the G1 phase, up-regulation of p53 and p21, and down-regulation of CDK2 and cyclin D1. Furthermore, our results revealed that induction of apoptosis through a mitochondrial pathway led to upregulation of Bax, down-regulation of Bcl-2, mitochondrial release of cytochrome c, reduction of mitochondrial membrane potential (MMP), and activation of caspase cascades (Casp-9 and -3). Activation of caspase cascades also resulted in the cleavage of PARP fragment. Involvement of the caspase apoptosis pathway was confirmed using caspase inhibitor Z-VAD-FMK pretreatment. Recent studies have shown that ROS is upstream of Akt signal in mitochondria-mediated hepatoma cell apoptosis. Our results showed that the accumulation of ROS was detected in HepG2 cells when treated with abieslactone, and ROS scavenger partly blocked the effects of abieslactone-induced HepG2 cell death. In addition, inactivation of total and phosphorylated Akt activities was found to be involved in abieslactone-induced HepG2 cell apoptosis. Therefore, our findings suggested that abieslactone induced G1 cell cycle arrest and caspase-dependent apoptosis via the mitochondrial pathway and the ROS/Akt pathway in HepG2 cells.