Macrophages-derived high-mobility group box-1 protein induces endothelial progenitor cells pyroptosis.

Endothelial dysfunction is an important factor in the progress of sepsis. Endothelial progenitor cells (EPCs) are the precursor cells of endothelial cells and play a crucial role in the prognosis and treatment of sepsis. EPCs in the peripheral blood of patients with sepsis undergo pyroptosis, but the mechanism remains much of unknown. Serum high-mobility group box-1 (HMGB1) is significantly elevated in patients with sepsis, but whether it is related to EPCs pyroptosis is unknown. We used a cell model of sepsis in vitro to isolate EPCs for better observation. By detecting the pyroptosis-related indicators of EPCs and the level of release and acetylation of HMGB1 in inflammatory macrophages, it was found that HMGB1 released by inflammatory macrophages combined with receptor for advanced glycation end products (RAGE) is a key pathway to induce pyroptosis of EPCs.

Endothelial progenitor cells systemic administration alleviates multi-organ senescence by down-regulating USP7/p300 pathway in chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) has impacted approximately 390 million people worldwide and the morbidity is increasing every year. However, due to the poor treatment efficacy of COPD, exploring novel treatment has become the hotpot of study on COPD. Endothelial progenitor cells (EPCs) aging is a possible molecular way for COPD development. We aimed to explore the effector whether intravenous administration of EPCs has therapeutic effects in COPD mice. METHODS: COPD mice model was induced by cigarette smoke exposure and EPCs were injected intravenously to investigate their effects on COPD mice. At day 127, heart, liver, spleen, lung and kidney tissues of mice were harvested. The histological effects of EPCs intervention on multiple organs of COPD mice were detected by morphology assay. Quantitative real-time PCR and Western blotting were used to detect the effect of EPCs intervention on the expression of multi-organ senescence-related indicators. And we explored the effect of EPCs systematically intervening on senescence-related USP7/p300 pathway. RESULTS: Compared with COPD group, senescence-associated ß-galactosidase activity was decreased, protein and mRNA expression of p16 was down-regulated, while protein and mRNA expression of cyclin D1 and TERT were up-regulated of multiple organs, including lung, heart, liver, spleen and kidney in COPD mice after EPCs system intervention. But the morphological alterations of the tissues described above in COPD mice failed to be reversed. Mechanistically, EPCs systemic administration inhibited the expression of mRNA and protein of USP7 and p300 in multiple organs of COPD mice, exerting therapeutic effects. CONCLUSIONS: EPCs administration significantly inhibited the senescence of multiple organs in COPD mice via down-regulating USP7/p300 pathway, which presents a possibility of EPCs therapy for COPD.

Cigarette smoke extract induces the senescence of endothelial progenitor cells by upregulating p300.

INTRODUCTION: Endothelial progenitor cells (EPCs) are the main source of endothelial cells. The senescence of EPCs is involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). Cigarette smoke extract (CSE) can directly induce the dysfunction and increased expression of senescence-related markers in EPCs cultured in vitro. Histone acetyltransferase p300 is a transcriptional activator, and its changes can lead to cell senescence. The present study investigated whether CSE can induce the senescence of EPCs by upregulating p300. METHODS: EPCs were isolated from bone marrow of C57BL/6J mice by density gradient centrifugation. The p300 inhibitor C646 and agonist CTPB were used to interfere with EPCs, cell cycle and apoptosis were detected by flow cytometry, the proportion of senile cells was counted by ß-galactosidase staining, the protein expression of p300, H4K12, Cyclin D1, TERT and Ki67 were detected by western blot. RESULTS: Compared with the control group, the cell cycle of CSE group and CTPB group were blocked, the apoptosis rate and early apoptosis rate were increased, the proportion of senile cells counted by ß-galactosidase staining was increased, the expression of p300 and H4K12 protein were increased, the expression of Cyclin D1, TERT and Ki67 protein were decreased. C646 could partly alleviate the damages caused by CSE. CONCLUSIONS: CSE may promote the apoptosis and senescence of EPCs by upregulating the expression of p300 and H4K12 protein, thus preventing the transition of EPCs from G1 phase to S phase, affecting telomerase synthesis, and reducing EPCs proliferation.

Sepsis associated with acute lung injury over the period 2012-2021: a bibliometric analysis.

Background: Sepsis associated with acute lung injury (ALI) is a common acute and severe disease with severe socioeconomic burden. The aim of this study is to explore the literatures of sepsis associated with ALI from a bibliometric perspective. Methods: Articles and reviews related to sepsis associated with ALI published from 2012 to 2021 in the Web of Science Core Collection were retrieved. Countries, affiliations, journals, authors, references, co-citation and keyword analysis in this field were visually analyzed using WOS citation reports, bibliometric.com, CtieSpace and VOSviewer software. Results: Over the last decade (2012-2021), marked progress has been made in the area of sepsis associated with ALI research. 836 papers were enrolled in this study. China accounts for the most contributors. Articles from the United States has the highest average cited. Shanghai Jiao Tong University, University of California System and Huazhong University of Science Technology were the main contributing institutions. Articles in International Immunopharmacology, Inflammation, Shock and Critical Care were cited the most. Matthay MA and Ware LB were the main contributors to this field. Inflammation and NF-κB have always been the focus of sepsis associated with ALI related research, and programmed cell death (including apoptosis, necroptosis and pyroptosis) may be the important direction of future research. Conclusion: Research on the sepsis associated with ALI is flourishing. The research on programmed cell death is a hot spot and may be a promising research field in the coming years.

Screening of Sepsis Biomarkers Based on Bioinformatics Data Analysis.

Methods: Gene expression profiles of GSE13904, GSE26378, GSE26440, GSE65682, and GSE69528 were obtained from the National Center for Biotechnology Information (NCBI). The differentially expressed genes (DEGs) were searched using limma software package. Gene Ontology (GO) functional analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and protein-protein interaction (PPI) network analysis were performed to elucidate molecular mechanisms of DEGs and screen hub genes. Results: A total of 108 DEGs were identified in the study, of which 67 were upregulated and 41 were downregulated. 15 superlative diagnostic biomarkers (CCL5, CCR7, CD2, CD27, CD274, CD3D, GNLY, GZMA, GZMH, GZMK, IL2RB, IL7R, ITK, KLRB1, and PRF1) for sepsis were identified by bioinformatics analysis. Conclusion: 15 hub genes (CCL5, CCR7, CD2, CD27, CD274, CD3D, GNLY, GZMA, GZMH, GZMK, IL2RB, IL7R, ITK, KLRB1, and PRF1) have been elucidated in this study, and these biomarkers may be helpful in the diagnosis and therapy of patients with sepsis.

Ursolic acid-piperazine-dithiocarbamate ruthenium(II) polypyridyl complexes induced necroptosis in MGC-803 cells.

Three ursolic acid-piperazine-dithiocarbamate ruthenium(II) polypyridyl complexes Ru1-Ru3 were designed and synthesized for evaluating antitumor activity. All the complexes exhibited high in vitro cytotoxicity against MGC-803, T24, HepG2, CNE2, MDA-MB-231, MCF-7, A549, and A549/DDP cell lines. Ru1, Ru2, and Ru3 were 11, 8 and 10 times, respectively, more active than cisplatin against A549/DDP. An in vivo study on MGC-803 xenograft mouse models demonstrated that representative Ru2 exhibited an effective inhibitory effect on tumor growth, showing stronger antitumor activity than cisplatin. Biological investigations suggested that Ru2 entered MGC-803 cells by a clathrin-mediated endocytic pathway, initially localizing in the lysosomes and subsequently escaping and localizing in the mitochondria. Mitochondrial swelling resulted in vacuolization, which induced vacuolation-associated cell death and necroptosis with the formation of necrosomes (RIP1-RIP3) and the uptake of propidium iodide. These results demonstrate that the potential of Ru2 as a chemotherapeutic agent to kill cancer cells via a dual mechanism represents an alternative way to eradicate apoptosis-resistant forms of cancer.

High Mobility Group Proteins in Sepsis.

Sepsis, a systemic inflammatory response disease, is the most severe complication of infection and a deadly disease. High mobility group proteins (HMGs) are non-histone nuclear proteins binding nucleosomes and regulate chromosome architecture and gene transcription, which act as a potent pro-inflammatory cytokine involved in the delayed endotoxin lethality and systemic inflammatory response. HMGs increase in serum and tissues during infection, especially in sepsis. A growing number of studies have demonstrated HMGs are not only cytokines which can mediate inflammation, but also potential therapeutic targets in sepsis. To reduce sepsis-related mortality, a better understanding of HMGs is essential. In this review, we described the structure and function of HMGs, summarized the definition, epidemiology and pathophysiology of sepsis, and discussed the HMGs-related mechanisms in sepsis from the perspectives of non-coding RNAs (microRNA, long non-coding RNA, circular RNA), programmed cell death (apoptosis, necroptosis and pyroptosis), drugs and other pathophysiological aspects to provide new targets and ideas for the diagnosis and treatment of sepsis.

Cigarette smoke extract mediates cell premature senescence in chronic obstructive pulmonary disease patients by up-regulating USP7 to activate p300-p53/p21 pathway.

OBJECTIVES: Tobacco hazard is one of the most severe public health issues in the world. It is believed that smoking is the most important factor leading to chronic obstructive pulmonary disease (COPD). Endothelial progenitor cells (EPCs) originate from the bone marrow and can effectively repair vascular endothelial damage and improve vascular endothelial function. Current studies suggest that EPCs senescence and EPCs depletion exist in smoking-related COPD, but the molecular mechanism remains unclear. METHODS: Co-immunoprecipitation was used to detect the interaction between USP7 and p300. EPCs from smoking COPD patients were isolated, and the expressions of USP7 and p300 were detected by RT-PCR and Western Blot. Different concentrations of cigarette smoke extract (CSE) and USP7 or p300 inhibitors were used to treat EPCs, then the expression of p53, p53 target genes and aging-related genes were detected. Cell Counting Kit - 8 (CCK8) was used to detect cell proliferation, flow cytometry was used to detect cell cycle distribution, ß-galactosidase (ß-gal) staining and Lamp1 immunofluorescence was used to detect the proportion of aging cells. COPD mouse models were used to confirm the molecular mechanism. RESULTS: USP7 and p300 interacted with each other, and USP7 affected the protein stability of p300 by regulating the ubiquitination of p300. There existed high expressions of USP7 and p300 proteins in EPCs of smoking COPD patients and COPD mouse model. CSE promoted the high expressions of USP7 and p300 in EPCs. Further studies showed that CSE mediated the USP7/p300-dependent high expression of p53 and activated the expression of p53 target genes especially p21. Activation of p53 - p21 pathway finally inhibited cell activity, led to cell cycle arrest and premature senescence of EPCs. CONCLUSION: CSE mediated up-regulation of USP7 and p300 activated p53 - p21 pathway was a molecular mechanism that might lead to COPD.

Existence of multiple organ aging in animal model of emphysema induced by cigarette smoke extract.

INTRODUCTION: It is commonly considered that COPD or at least emphysema represents accelerated lung aging induced in part by oxidative damage from cigarette smoke components. However, the issue if there are any aging signs in other organs in patients with COPD or emphysema remains unclear. The aim of this study is to explore whether there is multiple organ aging in the animal model of emphysema induced by cigarette smoke extract (CSE), and to ascertain the possible mechanisms, if any. METHODS: The animal model of emphysema was induced by CSE. Histomorphological changes in lung, heart, liver, kidney and spleen tissues were measured after staining with hematoxylin and eosin (H&E). The concentrations of stem cell factor (SCF), CyclinD1 and superoxide dismutase (SOD) in serum were determined by ELISA kit. The expressions of p16 (INK4a), Sca-1, eNOS proteins and mRNA in lung, heart, liver, kidney and spleen tissues were detected by Western blotting and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), respectively. Decitabine (Dec) was applied to examine whether it could alter the changes caused by CSE. RESULTS: The histomorphology of lung tissue was significantly changed, while other organs exhibited normal structure and histomorphology. The concentrations of SCF, CyclinD1 and SOD in serum were lower in the CSE group than in the control group. The expression levels of p16(INK4a) protein and mRNA in lung, heart, liver, kidney and spleen tissues were higher in the CSE group than in the control group, while the expression levels of Sca-1 and eNOS proteins and mRNA were lower in the CSE group than in the control group, in the tissues described above. Dec could partly alleviate the damages caused by CSE and the degree of alleviation resulted by Dec varied from organ to organ. CONCLUSIONS: In addition to the aging of the lung tissue in the emphysema animal model induced by CSE, the tissues of the heart, liver, kidney and spleen were also in the progress of aging, but the sensibility and affinity of lung to CSE were higher than those of the other organs. Multiple organ aging may also exist in the animal model of emphysema induced by CSE. DEC can partly alleviate the multiple organ aging caused by CSE.

lncRNA IGF2-AS Regulates Nucleotide Metabolism by Mediating HMGA1 to Promote Pyroptosis of Endothelial Progenitor Cells in Sepsis Patients.

BACKGROUND: Sepsis is one of the major causes of death worldwide, and its high mortality and pathological complexity hinder early accurate diagnosis. We aimed to investigate lncRNA IGF2-AS and HMGA1 effects on pyroptosis of endothelial progenitor cells (EPCs) in sepsis patients and the mechanisms involved. METHODS: Blood samples from sepsis patients and healthy subjects were collected, and EPCs were isolated and identified. We constructed cell lines that knocked down lncRNA IGF2-AS, HMGA1, and TYMS. Furthermore, lncRNA IGF2-AS was overexpressed. Subsequently, dNTP treatment with different concentrations was performed to investigate lncRNA IGF2-AS and HMGA1 effects on pyroptosis of EPCs in sepsis patients. Finally, exosomes were isolated from bone marrow mesenchymal stem cells (MSCs) to detect lncRNA IGF2-AS expression, and the influence of MSC-derived exosomal lncRNA IGF2-AS on sepsis was preliminarily discussed. RESULTS: Compared with Healthy group, lncRNA IGF2-AS, HMGA1, and TYMS were highly expressed in Sepsis group. Compared with si-NC group, si-lncRNA IGF2-AS group had increased proliferation ability, decreased pyroptosis, decreased HMGA1, RRM2, TK1, and TYMS expressions. lncRNA IGF2-AS played a regulatory role by binding HMGA1. Compared with si-NC group, the proliferation ability of si-HMGA1 group increased, pyroptosis decreased, and RRM2, TK1, and TYMS expressions also decreased. Compared with si-NC group, pyroptosis in si-TYMS group was reduced. In addition, HMGA1 was related and bound to TYMS. After overexpressing lncRNA IGF2-AS, dNTP level decreased, while the proliferation increased and pyroptosis decreased with higher concentration of dNTP. In addition, we found that EPCs took up MSC-exosomes. Compared with supernatant group, lncRNA IGF2-AS was expressed in exosomes group. Compared with EPCs group, EPCs+exosomes group had increased lncRNA IGF2-AS expression and increased pyroptosis. CONCLUSIONS: lncRNA IGF2-AS regulated nucleotide metabolism by mediating HMGA1 to promote pyroptosis of EPCs in sepsis patients. This study provided important clues for finding new therapeutic targets for sepsis.

p300/Sp1-Mediated High Expression of p16 Promotes Endothelial Progenitor Cell Senescence Leading to the Occurrence of Chronic Obstructive Pulmonary Disease.

OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is a common chronic disease and develops rapidly into a grave public health problem worldwide. However, what exactly causes the occurrence of COPD remains largely unclear. Here, we are trying to explore whether the high expression of p16 mediated by p300/Sp1 can cause chronic obstructive pulmonary disease through promoting the senescence of endothelial progenitor cells (EPCs). METHODS: Peripheral blood EPCs were isolated from nonsmoking non-COPD, smoking non-COPD, and smoking COPD patients. The expressions of p16, p300, and senescence-related genes were detected by RT-PCR and Western Blot. Then, we knocked down or overexpressed Sp1 and p300 and used the ChIP assay to detect the histone H4 acetylation level in the promoter region of p16, CCK8 to detect cell proliferation, flow cytometry to detect the cell cycle, and ß-galactosidase staining to count the proportion of senescent cells. RESULTS: The high expression of p16 was found in peripheral blood EPCs of COPD patients; the cigarette smoke extract (CSE) led to the increase of p16. The high expression of p16 in EPCs promoted cell cycle arrest and apoptosis. The CSE-mediated high expression of p16 promoted cell senescence. The expression of p300 was increased in peripheral blood EPCs of COPD patients. Moreover, p300/Sp1 enhanced the histone H4 acetylation level in the promoter region of p16, thereby mediating the senescence of EPCs. And knockdown of p300/Sp1 could rescue CSE-mediated cell senescence. CONCLUSION: p300/Sp1 enhanced the histone H4 acetylation level in the p16 promoter region to mediate the senescence of EPCs.

Cigarette smoke extract affects methylation status and attenuates Sca-1 expression of mouse endothelial progenitor cell in vitro.

INTRODUCTION: Endothelial dysfunction appears in many smoking-related diseases, it is also an important pathophysiological feature. Endothelial progenitor cells (EPCs) are precursors of endothelial cells and have a crucial effect on the repair and maintenance of endothelial integrity. Sca-1 is not only common in bone marrow-derived hematopoietic stem cells (HSCs), but it is also expressed in nonhematopoietic organs by tissue-resident stem and progenitor cells. The aim of this study is to investigate the impact of cigarette smoke extract (CSE) on the function of bone marrow-derived EPCs and the expression level of Sca-1 in EPCs, and also whether the methylation of Sca-1 is involved in EPC dysfunction. METHODS: We measured EPC capacities including adhesion, secretion and proliferation, the concentration of endothelial nitric oxide synthase (eNOS) and apoptosis-inducing factor (AIF) in cell culture supernatant, and also Sca-1 expression and promoter methylation in EPCs induced by CSE. Decitabine (Dec) was applied to test whether it could alter the impact caused by CSE. RESULTS: The adhesion, proliferation and secretion ability of EPCs can be induced to be decreased by CSE in vitro, accompanied by decreased concentrations of AIF and eNOS in cell culture supernatant and decreased Sca-1 expression in EPCs. In addition, Dec could partly attenuate the impact described above. There were no significant differences in the quantitative analysis of Sca-1 promoter methylation among different groups. CONCLUSIONS: The decreased Sca-1 expression was related to EPC dysfunction induced by CSE. EPC dysfunction resulting from CSE may be related to methylation mechanism, but not the methylation of Sca-1 promoter.

Design, synthesis and antitumor evaluation of new 1,8-naphthalimide derivatives targeting nuclear DNA.

Four series of new 3-nitro naphthalimides derivatives, 4(4a‒4f), 5(5a‒5i), 6(6a‒6e) and 7 (7a‒7j), were designed and synthesized as antitumor agents. Methyl thiazolyl tetrazolium (MTT) screening assay results revealed that some compounds displayed effective in vitro antiproliferative activity on SMMC-7721, T24, SKOV-3, A549 and MGC-803 cancer cell lines in comparison with 5-fluorouracil (5-FU), mitonafide and amonafide. Nude mouse xenotransplantation model assay results indicated that compounds 6b and 7b exhibited good in vivo antiproliferative activity in MGC-803 xenografts in comparison with amonafide and cisplatin, suggesting that compounds 6b and 7b could be good candidates for antitumor agents. Gel electrophoresis assay indicated that DNA and Topo I were the potential targets of compounds 6b and 7b, and comet assay confirmed that compounds 6b and 7b could induce DNA damage, while the further study showed that the 6b- and 7b-induced DNA damage was accompanied by the upregulation of p-ATM, P-Chk2, Cdc25A and p-H2AX. Cell cycle arrest studies demonstrated that compounds 6b and 7b arrested the cell cycle at the S phase, accompanied by the upregulation of the expression levels of the antioncogene p21 and the down-regulation of the expression levels of cyclin E. Apoptosis assays indicated that compounds 6b and 7b caused the apoptosis of tumor cells along with the upregulation of the expression of Bax, caspase-3, caspase-9 and PARP and the downregulation of Bcl-2. These mechanistic studies suggested that compounds 6b and 7b exerted their antitumor activity by targeting to DNA, thereby inducing DNA damage and Topo I inhibition, and consequently causing S stage arrest and the induction of apoptosis.

Design, synthesis and biological evaluation of 3-nitro-1,8-naphthalimides as potential antitumor agents.

A series of 3-nitro-naphthalimides 1(1a-1h) were designed and synthesized as antitumor agents. MTT assay results showed that all these compounds exhibited obvious antiproliferative activity against SKOV3, HepG2, A549, T-24 and SMMC-7721 cancer cell lines, while compound 1a displayed the best antiproliferative activity against HepG2 and T-24 cell lines in comparison with mitonafide, with IC50 of 9.2 ± 1.8 and 4.133 ± 0.9 µM, respectively. In vivo antiproliferative activity assay results showed that compound 1a exhibited good antiproliferative activity in the HepG2 and T-24 models, compared with mitonafide. Action mechanism results showed that compound 1a could induced the damage of DNA and the inhibition topo I, accompanying by inducing the G2-stage arresting and the apoptosis of T-24 cancer cells through up-regulating expression levels of cyclin B1, cdc 2-pTy, Wee1, γH2AX, p21, Bax and cytochrome c and down-regulating expression of Bcl-2.

Bifunctional Naphthoquinone Aromatic Amide-Oxime Derivatives Exert Combined Immunotherapeutic and Antitumor Effects through Simultaneous Targeting of Indoleamine-2,3-dioxygenase and Signal Transducer and Activator of Transcription 3.

Indoleamine-2,3-dioxygenase 1 (IDO1) and signal transducer and activator of transcription 3 (STAT3) are important targets in the tumor microenvironment for cancer therapy. In the present study, a set of naphthoquinone aromatic amide-oxime derivatives were designed, which stimulated the immune response via IDO1 inhibition and simultaneously displayed powerful antitumor activity against three selected cancer cell lines through suppressing STAT3 signaling. The representative compound 8u bound effectively to IDO1, with greater inhibitory activity relative to the commercial IDO1 inhibitor 4-amino-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1,2,5-oxadiazole-3-carboximidamide (IDO5L) in addition to the efficient suppression of nuclear translocation of STAT3. Consistently, in vivo assays demonstrated a higher antiproliferative activity of compound 8u in both wild-type B16-F10 isograft tumors and an athymic HepG2 xenograft model relative to 1-methyl-l-tryptophan (1-MT) and doxorubicin (DOX). This bifunctional compound with dual immunotherapeutic and anticancer efficacy may represent a new generation of highly efficacious drug candidates for cancer therapy.

Design, synthesis and biological evaluation of naphthalenebenzimidizole platinum (II) complexes as potential antitumor agents.

A serial of naphthalenebenzimidizole-Pt complexes 1-6 were designed and synthesized as antitumor agents. In vitro antitumor assay results showed that complexes 1-6 exhibited moderate to high antiproliferative activity against Hela, HepG2, SKOV-3, NCI-H460, BEL-7404 and A549 cancer cell lines, while they displayed obvious sensitivity and selectivity against SMMC-7721 and U251 cell lines and low toxicity against normal HL-7702 cells, in comparison with cisplatin. In vivo antitumor assay results indicated that complex 1 and 5 exhibited important in vivo antiproliferative activity in the NCI-460 and SMMC-7721 models, in comparison with cisplatin, respectively. Complexes 1 and 5 exhibited better antiproliferative activity against A549CDDP and SKOV3CDDP cell lines than cisplatin, with IC50 values of 6.98 ± 0.47 µM, 5.62 ± 0.88 µM and 13.13 ± 2.11 µM, 5.30 ± 0.33 µM, respectively, while they displayed potential antiproliferation against A549 and SKOV3 cell lines, with IC50 values of 7.32 ± 0.51 µM, 5.19 ± 0.49 µM and 14.92 ± 0.11 µM, 12.19 ± 0.92 µM, indicating the introduction of naphthalenebenzimidizole into platinum-metal system may overcome the resistance. Mechanistic studies showed that the representative complexes 1 and 5 exerted the antitumor effect mainly by the obvious covalent binding with DNA and the upregulation of the expression level of intracellular topo I, showing different action mechanism from cisplatin.

Animal models of emphysema.

OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is a common chronic respiratory disease of human beings characterized by not fully reversible airflow limitation. Emphysema is the main pathological feature of COPD which causes high mortality worldwide every year and consumes a large amount of medical expenses. This paper was to review the establishment and evaluation methods of animal models of emphysema or COPD, and put forward some new ideas on animal selection, method of modeling, and model evaluation. DATA SOURCES: The author retrieved information from the PubMed database up to July 2019, using various combinations of search terms, including emphysema, model, and animal. STUDY SELECTION: Original articles, reviews, and other articles were searched and reviewed for animal models of emphysema. RESULTS: This review summarized animal models of emphysema from the perspectives of animal selection, emphysema mechanism, modeling method and model evaluation, and found that passive smoking is the classic method for developing animal model of emphysema, mice are more suitable for experimental study on emphysema. Compared with pulmonary function indicators, airway inflammation indicators and oxidative stress indicators, pathomorphological indicators of lung tissue are the most important parameters for evaluating the establishment of the animal model of emphysema. CONCLUSIONS: Mice model induced by passive smoking is the classic animal model of emphysema. Pathomorphological indicators are the most important parameters for evaluating the establishment of the animal model of emphysema.

Synthesis and discovery of asiatic acid based 1,2,3-triazole derivatives as antitumor agents blocking NF-κB activation and cell migration.

A series of asiatic acid (AA) based 1,2,3-triazole derivatives were designed, synthesized and subjected to a cell-based NF-κB inhibition screening assay. Among the tested compounds, compound 6k displayed impressive NF-κB inhibitory activity with an IC50 value in the low micromolar range. A molecular docking study was performed to reveal key interactions between 6k and NF-κB in which the 1,2,3-triazole moiety and the hydroxyl groups of the AA skeleton were important for improving the inhibitory activity. Subsequently, surface plasmon resonance analysis validated the high affinity between compound 6k and NF-κB protein with an equilibrium dissociation constant (KD) value of 0.36 µM. Further studies showed that compound 6k observably inhibited the NF-κB DNA binding, nuclear translocation and IκBα phosphorylation. Moreover, in vitro antitumor activity screening showed that compound 6k (IC50 = 2.67 ± 0.06 µM) exhibited the best anticancer activity against A549 cells, at least partly, by inhibition of the activity of NF-κB. Additionally, the treatment of A549 cells with compound 6k resulted in apoptosis induction potency and in vitro cell migration inhibition. Thus, we conclude that AA based 1,2,3-triazole derivatives may be potential NF-κB inhibitors with the ability to induce apoptosis and suppress cell migration.

Design, synthesis and pharmacological evaluation of novel 2-chloro-3-(1H-benzo[d]imidazol-2-yl)quinoline derivatives as antitumor agents: in vitro and in vivo antitumor activity, cell cycle arrest and apoptotic response.

A series of novel 2-chloro-3-(1H-benzo[d]imidazol-2-yl)quinoline derivatives (3a1-3d6) were designed and synthesized as antitumor agents. In vitro antitumor assay results showed that some compounds exhibited moderate to high inhibitory activities against HepG2, SK-OV-3, NCI-H460 and BEL-7404 tumor cell lines, and most compounds exhibited much lower cytotoxicities against HL-7702 normal cell line compared to 5-FU and cisplatin. In vivo antitumor assay results showed that the representative compound 3a1 exhibited effective inhibition on tumor growth in the HepG2 xenograft mouse model. Mechanistic studies suggested that 3a1 may exert antitumor activity by the up-regulation of Bax, intracellular Ca2+ release, ROS generation, p21, p27 and p53, downregulation of Bcl-2, activation of caspase-9 and caspase-3 and subsequent cleavage of PARP, and inhibition of CDK activity.

Discovery of dehydroabietic acid sulfonamide based derivatives as selective matrix metalloproteinases inactivators that inhibit cell migration and proliferation.

A series of dehydroabietic acid (DHAA) dipeptide derivatives containing the sulfonamide moiety were designed, synthesized and evaluated for inhibition of MMPs as well as the effects of in vitro cell migration. These compounds exhibited relatively good inhibition activity against MMPs with IC50 values in low micromolar range. A docking study of the most active compound 8k revealed key interactions between 8k and MMP-3 in which the sulfonamide moiety and the dipeptide group were important for improving activity. It is noteworthy that further antitumor activity screening revealed that some compounds exhibited better inhibitory activity than the commercial anticancer drug 5-FU. In particular, compound 8k appeared to be the most potent compound against the HepG2 cell line, at least partly, by inhibition of the activity of MMP-3 and apoptosis induction. The treatment of HepG2 cells with compound 8k resulted in inhibition of in vitro cell migration through wound healing assay and G1 phase of cell cycle arrested. In addition, 8k-induced apoptosis was significantly facilitated in HepG2 cells. Thus, we conclude that DHAA dipeptide derivatives containing the sulfonamide moiety may be the potential MMPs inhibitors with the ability to suppress cells migration.