eRNAbase: a comprehensive database for decoding the regulatory eRNAs in human and mouse.

Enhancer RNAs (eRNAs) transcribed from distal active enhancers serve as key regulators in gene transcriptional regulation. The accumulation of eRNAs from multiple sequencing assays has led to an urgent need to comprehensively collect and process these data to illustrate the regulatory landscape of eRNAs. To address this need, we developed the eRNAbase (http://bio.liclab.net/eRNAbase/index.php) to store the massive available resources of human and mouse eRNAs and provide comprehensive annotation and analyses for eRNAs. The current version of eRNAbase cataloged 10 399 928 eRNAs from 1012 samples, including 858 human samples and 154 mouse samples. These eRNAs were first identified and uniformly processed from 14 eRNA-related experiment types manually collected from GEO/SRA and ENCODE. Importantly, the eRNAbase provides detailed and abundant (epi)genetic annotations in eRNA regions, such as super enhancers, enhancers, common single nucleotide polymorphisms, expression quantitative trait loci, transcription factor binding sites, CRISPR/Cas9 target sites, DNase I hypersensitivity sites, chromatin accessibility regions, methylation sites, chromatin interactions regions, topologically associating domains and RNA spatial interactions. Furthermore, the eRNAbase provides users with three novel analyses including eRNA-mediated pathway regulatory analysis, eRNA-based variation interpretation analysis and eRNA-mediated TF-target gene analysis. Hence, eRNAbase is a powerful platform to query, browse and visualize regulatory cues associated with eRNAs.

scATAC-Ref: a reference of scATAC-seq with known cell labels in multiple species.

Chromatin accessibility profiles at single cell resolution can reveal cell type-specific regulatory programs, help dissect highly specialized cell functions and trace cell origin and evolution. Accurate cell type assignment is critical for effectively gaining biological and pathological insights, but is difficult in scATAC-seq. Hence, by extensively reviewing the literature, we designed scATAC-Ref (https://bio.liclab.net/scATAC-Ref/), a manually curated scATAC-seq database aimed at providing a comprehensive, high-quality source of chromatin accessibility profiles with known cell labels across broad cell types. Currently, scATAC-Ref comprises 1 694 372 cells with known cell labels, across various biological conditions, >400 cell/tissue types and five species. We used uniform system environment and software parameters to perform comprehensive downstream analysis on these chromatin accessibility profiles with known labels, including gene activity score, TF enrichment score, differential chromatin accessibility regions, pathway/GO term enrichment analysis and co-accessibility interactions. The scATAC-Ref also provided a user-friendly interface to query, browse and visualize cell types of interest, thereby providing a valuable resource for exploring epigenetic regulation in different tissues and cell types.

Role of transcriptional cofactors in cardiovascular diseases.

Cardiovascular disease is a main cause of mortality in the world and the highest incidence of all diseases. However, the mechanism of the pathogenesis of cardiovascular disease is still unclear, and we need to continue to explore its mechanism of action. The occurrence and development of cardiovascular disease is significantly associated with genetic abnormalities, and gene expression is affected by transcriptional regulation. In this complex process, the protein-protein interaction promotes the RNA polymerase II to the initiation site. And in this process of transcriptional regulation, transcriptional cofactors are responsible for passing cues from enhancers to promoters and promoting the binding of RNA polymerases to promoters, so transcription cofactors playing a key role in gene expression regulation. There is growing evidence that transcriptional cofactors play a critical role in cardiovascular disease. Transcriptional cofactors can promote or inhibit transcription by affecting the function of transcription factors. It can affect the initiation and elongation process of transcription by forming complexes with transcription factors, which are important for the stabilization of DNA rings. It can also act as a protein that interacts with other proteins to affect the expression of other genes. Therefore, the aim of this overview is to summarize the effect of some transcriptional cofactors such as BRD4, EP300, MED1, EZH2, YAP, SIRT6 in cardiovascular disease and to provide a promising therapeutic strategy for the treatment of cardiovascular disease.

GREAP: a comprehensive enrichment analysis software for human genomic regions.

The rapid development of genomic high-throughput sequencing has identified a large number of DNA regulatory elements with abundant epigenetics markers, which promotes the rapid accumulation of functional genomic region data. The comprehensively understanding and research of human functional genomic regions is still a relatively urgent work at present. However, the existing analysis tools lack extensive annotation and enrichment analytical abilities for these regions. Here, we designed a novel software, Genomic Region sets Enrichment Analysis Platform (GREAP), which provides comprehensive region annotation and enrichment analysis capabilities. Currently, GREAP supports 85 370 genomic region reference sets, which cover 634 681 107 regions across 11 different data types, including super enhancers, transcription factors, accessible chromatins, etc. GREAP provides widespread annotation and enrichment analysis of genomic regions. To reflect the significance of enrichment analysis, we used the hypergeometric test and also provided a Locus Overlap Analysis. In summary, GREAP is a powerful platform that provides many types of genomic region sets for users and supports genomic region annotations and enrichment analyses. In addition, we developed a customizable genome browser containing >400 000 000 customizable tracks for visualization. The platform is freely available at http://www.liclab.net/Greap/view/index.

Atg5 deficiency in macrophages protects against kidney fibrosis via the CCR6-CCL20 axis.

BACKGROUND: Autophagy is a lysosome-dependent degradation pathway that regulates macrophage activation, differentiation, and polarization. Autophagy related 5 (Atg5) is a key protein involved in phagocytic membrane elongation in autophagic vesicles that forms a complex with Atg12 and Atg16L1. Alterations in Atg5 are related to both acute and chronic kidney diseases in experimental models. However, the role of macrophage-expressed Atg5 in acute kidney injury remains unclear. METHODS: Using a myeloid cell-specific Atg5 knockout (MΦ atg5-/-) mouse, we established renal ischemia/reperfusion and unilateral ureteral obstruction models to evaluate the role of macrophage Atg5 in renal macrophage migration and fibrosis. RESULTS: Based on changes in the serum urea nitrogen and creatinine levels, Atg5 deletion had a minimal effect on renal function in the early stages after mild injury; however, MΦ atg5-/- mice had reduced renal fibrosis and reduced macrophage recruitment after 4 weeks of ischemia/reperfusion injury and 2 weeks of unilateral ureteral obstruction injury. Atg5 deficiency impaired the CCL20-CCR6 axis after severe ischemic kidneys. Chemotactic responses of bone marrow-derived monocytes (BMDMs) from MΦ atg5-/- mice to CCL20 were significantly attenuated compared with those of wild-type BMDMs, and this might be caused by the inhibition of PI3K, AKT, and ERK1/2 activation. CONCLUSIONS: Our data indicate that Atg5 deficiency decreased macrophage migration by impairing the CCL20-CCR6 axis and inhibited M2 polarization, thereby improving kidney fibrosis.

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Phosphodiesterase (PDE) hydrolyze cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), and involve in the regulation of cellular physiological processes and neurological functions, including neuronal plasticity, synaptogenesis, synaptic transmission, memory formation and cognitive function by catalyzing the hydrolysis of intracellular cAMP and cGMP. A large number of basic and clinical studies have shown that PDE4 inhibitors block or ameliorate the occurrence and development of central nervous system (CNS) diseases by inhibiting cAMP hydrolysis, increasing cAMP content and enhancing its downstream effects. PDE4 inhibitors have long-term potentiation effect, which can enhance phosphorylation of cAMP response element binding protein (CREB) and upregulate expression of memory related Arc genes in hippocampal neurons, thereby improving cognitive impairment and Alzheimer's disease-like symptoms; and also resist the occurrence and development of Parkinson's disease by reducing the cytotoxicity induced by α-syn and increasing the effect of miR-124-3p on cell activity. Alteration of PDE4 activity is the molecular basis of psychosis and cognitive disorders, therefore it is considered as one of the therapeutic targets for schizophrenia. PDE4 inhibitors play a role in depression; Autism spectrum and Huntington's disease by inhibiting the advanced glycation end product receptor (RAGE), TLR4 and NLRP3 pathways in the hippocampus, reducing the activation of microglia and the production of interleukin-1ß, down-regulating HMGB1/RAGE signaling pathway and inhibiting inflammatory factors and Increase the nociception threshold. PDE4 inhibitors might be used in treatment of fragile X syndrome by regulating the level of cAMP and affecting the expression of fragile X mental retardation protein (FMRP). PDE4 inhibitors can also promote the differentiation of oligodendrocyte progenitor cells and enhance myelination, which has potential in the treatment of multiple sclerosis. PDE4 also related to Bipolar disorder which may be one of the therapeutic targets. At present, several PDE4 inhibitors are on clinical trials for treatment of CNS diseases. This article reviews and discusses the progress on basic researches and clinical trials of PDE4 inhibitors in CNS diseases, providing reference for the prevention and treatment of CNS diseases and the development of new drugs.

Acquired Resistance to Clinical Cancer Therapy: A Twist in Physiological Signaling.

Although modern therapeutic strategies have brought significant progress to cancer care in the last 30 years, drug resistance to targeted monotherapies has emerged as a major challenge. Aberrant regulation of multiple physiological signaling pathways indispensable for developmental and metabolic homeostasis, such as hyperactivation of pro-survival signaling axes, loss of suppressive regulations, and impaired functionalities of the immune system, have been extensively investigated aiming to understand the diversity of molecular mechanisms that underlie cancer development and progression. In this review, we intend to discuss the molecular mechanisms of how conventional physiological signal transduction confers to acquired drug resistance in cancer patients. We will particularly focus on protooncogenic receptor kinase inhibition-elicited tumor cell adaptation through two major core downstream signaling cascades, the PI3K/Akt and MAPK pathways. These pathways are crucial for cell growth and differentiation and are frequently hyperactivated during tumorigenesis. In addition, we also emphasize the emerging roles of the deregulated host immune system that may actively promote cancer progression and attenuate immunosurveillance in cancer therapies. Understanding these mechanisms may help to develop more effective therapeutic strategies that are able to keep the tumor in check and even possibly turn cancer into a chronic disease.

The emerging roles of SUMOylation in pulmonary diseases.

Small ubiquitin-like modifier mediated modification (SUMOylation) is a critical post-translational modification that has a broad spectrum of biological functions, including genome replication and repair, transcriptional regulation, protein stability, and cell cycle progression. Perturbation or deregulation of a SUMOylation and deSUMOylation status has emerged as a new pathophysiological feature of lung diseases. In this review, we highlighted the link between SUMO pathway and lung diseases, especially the sumoylated substrate such as C/EBPα in bronchopulmonary dysplasia (BDP), PPARγ in pneumonia, TFII-I in asthma, HDAC2 in chronic obstructive pulmonary disease (COPD), KLF15 in hypoxic pulmonary hypertension (HPH), SMAD3 in idiopathic pulmonary fibrosis (IPF), and YTHDF2 in cancer. By exploring the impact of SUMOylation in pulmonary diseases, we intend to shed light on its potential to inspire the development of innovative diagnostic and therapeutic strategies, holding promise for improving patient outcomes and overall respiratory health.

Distinct Associations Between Postdischarge Cognitive Change Patterns and 1-year Outcomes in Patients Hospitalized for Heart Failure.

BACKGROUND: The patterns of patients' cognitive function after hospital discharge for heart failure (HF), their prognostic implication and the predictors for new-onset cognitive impairment remain unknown. METHODS AND RESULTS: We included 2307 patients (64 ± 14 years, 36.4% female sex) hospitalized for HF from a cohort who completed cognitive testing before discharge and after 1 month. Among 1658 patients with normal cognition before discharge, 229 (13.8%) and 1429 (86.2%) had new-onset cognitive impairment and normal cognition at 1 month, respectively. Of the 649 with cognitive impairment, 315 (48.5%) and 334 (51.5%) had transient and persistent cognitive impairment, respectively. Multivariable analyses showed that, compared with normal cognition, patients with new-onset cognitive impairment had an increased risk of cardiovascular death or HF rehospitalization (hazard ratio 1.35, 95% confidence interval 1.07-1.70); patients with persistent cognitive impairment showed an increased risk, but it was not statistically significant (hazard ratio 1.17, 95% confidence interval 0.95-1.44); patients with transient cognitive impairment had a similar risk (hazard ratio 0.91, 95% confidence interval 0.73-1.13). Older age, females, lower education level, prior atherosclerotic cardiovascular diseases, lower health status, and lower Mini-Cog score before discharge predicted new-onset cognitive impairment. CONCLUSIONS: Acute HF substantially affects short-term cognition. Patients who have developed new-onset cognitive impairment have an increased risk of adverse outcomes. Monitoring cognition is necessary, particularly in high-risk patients.

Synergistic effect of biotic and abiotic factors drives microbiota succession and assembly in medium-temperature Daqu.

BACKGROUND: The feasibility of fortification techniques to improve the quality of medium-temperature Daqu (MTD) by inoculation functional isolates has been demonstrated. However, it is unclear what is the effect of inoculation on the controllability during the MTD fermentation process. Here, inoculated a single strain of Bacillus licheniformis, and the microbiota composed of Bacillus velezensis and Bacillus subtilis, were used to investigate the synergistic effect of biotic and abiotic factors on the succession and assembly of the MTD microbiota during the process. RESULTS: The biotic factors promoted the proliferation of microorganisms that arrived early at the MTD. Subsequently, this alteration might inhibit microorganisms that colonized later in the MTD microecosystem, thereby assembling a different but more stable microbial community. Moreover, the biotic factors making bacterial community assembly were dominated by variable selection earlier, whereas the fungal community assembly was dominated mainly by extreme abiotic factors rather than biotic factors. Interestingly, fermentation temperature and moisture were significantly associated with the succession and assembly of the fortified MTD community. Meanwhile, the effect of the environmental variables on endogenous variables was also significant. Thus, changes in endogenous variables could be mitigated by adjusting environmental variables to regulate the process of MTD fermentation. CONCLUSION: Biotic factors cause rapid changes of the microbiota during the MTD fermentation process, which could be controlled indirectly by regulating environmental variables. Meanwhile, a more stable MTD ecological network might be beneficial for enhancing the stability of MTD quality. © 2023 Society of Chemical Industry.

Animal models of drug-induced pulmonary fibrosis: an overview of molecular mechanisms and characteristics.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by progressive loss of pulmonary function. Drug-induced interstitial lung disease has been reported as a severe adverse effect of some drugs, such as bleomycin, amiodarone, and methotrexate. Based on good characteristics, drug-induced pulmonary fibrosis (PF) animal model has played a key role in our understanding of the molecular mechanisms of PF pathogenesis and recapitulates the specific pathology in patients and helps develop therapeutic strategies. Here, we summarize the mechanisms and characteristics of given fibrotic drug-induced animal models for PFs. Together with the key publications describing these models, this brief but detailed overview would be helpful for the pharmacological research with animal models of PFs. Potential mechanisms underlying drug induced lung toxicity.

circYap inhibits oral squamous cell carcinoma by arresting cell cycle.

OBJECTIVE: Circular RNAs (circRNAs) involve in the development and progression of tumour. The mechanism of circRNAs in oral squamous cell carcinoma (OSCC) has remained unclear. This study aimed to investigate the role of circular Yes-associated protein (circYap) in OSCC. METHODS: Quantification reverse transcription-polymerase chain reaction (qRT-PCR) was applied to measure circYap expression in patients with OSCC tissues and cells. Flow cytometry was performed to evaluate cell cycle. circYap interaction with CDK4 was detected by RNA immunoprecipitation (RIP) and RNA pull-down. The interaction of Cyclin D1 and CDK4 was determined using co-immunoprecipitation (co-IP). RESULTS: We showed that circYap expression was downregulated in OSCC tissues. Using small interfering circular (Si-circYap) and overexpression plasmid, we found that circYap overexpression inhibited proliferation and arrested cell cycle in OSCC cells, while, circYap knockdown yielded the opposite result. Cyclin D1/CDK4 complexes and nuclear translocation is essential for cell cycle progression. We found that CDK4 interacted with circYap was increased when circYap overexpression, meanwhile, Cyclin D1/CDK4 complexes and of nuclear distribution were decreased. CONCLUSIONS: Our findings suggest that circYap impedes progression of OSCC. Overexpression of circYap suppresses proliferation and cell cycle through binding to CDK4 to block formation and nuclear translocation of Cyclin D1/CDK4 complexes. Thus, circYap may serves as a valuable therapeutic target for OSCC.

High-density lipoprotein-mediated cardioprotection in heart failure.

The prevalence of heart failure (HF), including reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF), has increased significantly worldwide. However, the prognosis and treatment of HF are still not good. Recent studies have demonstrated that high-density lipoprotein (HDL) plays an important role in cardiac repair during HF. The exact role and mechanism of HDL in the regulation of HF remain unexplained. Here, we discuss recent findings regarding HDL in the progression of HF, such as the regulation of excitation-contraction coupling, energy homeostasis, inflammation, neurohormone activation, and microvascular dysfunction. The effects of HDL on the regulation of cardiac-related cells, such as endothelial cells (ECs), cardiomyocytes (CMs), and on cardiac resident immune cell dysfunction in HF are also explained. An in-depth understanding of HDL function in the heart may provide new strategies for the prevention and treatment of HF.

Huanglianjiedu Decoction as an effective treatment for oral squamous cell carcinoma based on network pharmacology and experimental validation.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is one of malignant tumors in oral and maxillofacial region with high fatality. Huanglianjiedu Decoction (HLJDD) is a well-known traditional Chinese medicinal prescription, which consists of Coptis chinensis Franch, Scutellaria baicalensis Georgi, Phellodendron amurense Rupr and Gardenia jasminoides J.Ellis. Some clinical studies showed HLJDD had good effectiveness on OSCC, but the mechanism is unclear. METHODS: In this study, potential components of HLJDD and putative targets were screened by Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Combining with potential targets of OSCC searched from Therapeutic Target Database (TTD) and Online Mendelian Inheritance in Man (OMIM), we drew protein-protein interaction (PPI) network by Cytoscape v3.2.0 software. After topological analysis we got core targets and further did Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Then we did the in vitro experiments to verify the major biological processes (cell cycle, apoptosis and proliferation) and signaling pathways (mitogen-activated protein kinase (MAPK), nuclear factor-kappa B (NF-κB), protein kinase B (AKT)) on OSCC cell lines, SCC-25 and CAL-27. RESULTS: The potential component targets number of Coptis chinensis Franch, Scutellaria baicalensis Georgi, Phellodendron amurense Rupr and Gardenia jasminoides J.Ellis were 39, 93, 81and 88, respectively. Then we got 52 core targets which enriched in cell cycle, apoptosis, proliferation, MAPK activation etc. and obtained TOP30 pathways. On SCC-25 and CAL-27, HLJDD suppressed cell proliferation, induced late apoptosis and inhibited cell invasion and migration which were consistent with the results from network pharmacology analysis. Additionally, in cell cycle, we confirmed HLJDD inhibited G1 phase and arrested in S phase to reduce cell proliferation on SCC-25. In signaling pathways, HLJDD inhibited the phosphorylation of extracellular regulatory protein kinase 1/2 (ERK1/2) and NF-κB p65 (S468) on SCC-25 and CAL-27. CONCLUSIONS: HLJDD played a potential therapeutic role on OSCC via inhibiting p-ERK1/2 and p-NF-κB p65 (S468).

Declines in PDE4B activity promote myopia progression through downregulation of scleral collagen expression.

Myopia is the most common cause of a visual refractive error worldwide. Cyclic adenosine monophosphate (cAMP)-linked signaling pathways contribute to the regulation of myopia development, and increases in cAMP accumulation promote myopia progression. To pinpoint the underlying mechanisms by which cAMP modulates myopia progression, we performed scleral transcriptome sequencing analysis in form-deprived mice, a well-established model of myopia development. Form deprivation significantly inhibited the expression levels of genes in the cAMP catabolic pathway. Quantitative real-time polymerase chain reaction analysis validated that the gene expression level of phosphodiesterase 4B (PDE4B), a cAMP hydrolase, was downregulated in form-deprived mouse eyes. Under visually unobstructed conditions, loss of PDE4B function in Pde4b-knockout mice increased the myopic shift in refraction, -3.661 ± 1.071 diopters, more than that in the Pde4b-wildtype littermates (P < 0.05). This suggests that downregulation and inhibition of PDE4B gives rise to myopia. In guinea pigs, subconjunctival injection of rolipram, a selective inhibitor of PDE4, led to myopia in normal eyes, and it also enhanced form-deprivation myopia (FDM). Subconjunctival injection of dibutyryl-cyclic adenosine monophosphate, a cAMP analog, induced only a myopic shift in the normal visually unobstructed eyes, but it did not enhance FDM. As myopia developed, axial elongation occurred during scleral remodeling that was correlated with changes in collagen fibril thickness and distribution. The median collagen fibril diameter in the FDM + rolipram group, 55.09 ± 1.83 nm, was thinner than in the FDM + vehicle group, 59.33 ± 2.06 nm (P = 0.011). Thus, inhibition of PDE4 activity with rolipram thinned the collagen fibril diameter relative to the vehicle treatment in form-deprived eyes. Rolipram also inhibited increases in collagen synthesis induced by TGF-ß2 in cultured human scleral fibroblasts. The current results further support a role for PDE enzymes such as PDE4B in the regulation of normal refractive development and myopia because either loss or inhibition of PDE4B function increased myopia and FDM development through declines in the scleral collagen fibril diameter.

Research progress of phosphodiesterase inhibitors in inflammatory bowel disease treatment.

Inflammatory bowel disease is a recurrent chronic intestinal inflammatory disease with unknown etiology and no effective treatment. Phosphodiesterase (PDE) regulates a variety of physiological and pathophysiological processes by mediating the hydrolysis of intracellular second messengers cyclic adenosine monophosphate and cyclic guanosine monophosphate. In recent years, a series of researches suggest that PDE inhibitors such as several PDE4 inhibitors, PDE5 inhibitors (sildenafil, tadalafil and vardenafil), PDE3 inhibitors (cilostazol), PDE9 inhibitor (PF-04447943) and PDE3/PDE4 double inhibitor (pumafentrine) have ameliorating effect on experimental colitis in animals. In clinical trials, PDE4 inhibitor apremilast showed more therapeutic advantage than tetomilast. This article reviews the recent research progress of PDE inhibitors in treatment of inflammatory bowel disease.

Microbiological analysis of endotracheal aspirate and endotracheal tube cultures in mechanically ventilated patients.

BACKGROUND: To compare the microbiological culture within endotracheal aspirate specimens (ETAs) and endotracheal tube specimens (ETTs) in patients undergoing mechanical ventilation (MV) by statistical tools. METHOD: ETAs and ETTs from a total number of 81 patients, who were undergoing MV at the intensive care unit (ICU) of Jiading Central Hospital Affiliated Shanghai University of Medicine & Health Sciences from September 1st, 2017 to August 31st, 2018, were collected for microbiological culture analysis. Correlation of ETAs and ETTs cultures were obtained by Spear-men correlation analysis, while the consistency of the two specimens was determined by Kappa analysis and principal component analysis (PCA). RESULTS: Microbiological culture from both ETAs and ETTs showed that Acinetobacter baumannii, Pseudomonas aeruginosa, Staphylococcus aureus, and Klebsiella pneumoniae were the main pathogens, with Spear-man correlation coefficients of 0.676, 0.951, 0.730 and 0.687 respectively (all P < 0.01), and the overall Spear-man correlation coefficient is 0.757 (P < 0.01). This result shows that two samples were positively correlated. Kappa analysis also revealed high consistency of the microbial culture results from the ETAs and the ETTs (overall κ = 0.751, P < 0.01). The κ values for the four bacteria detected were 0.670, 0.949, 0.723, and 0.687, respectively (all P < 0.001). PCA also revealed high similarity. CONCLUSION: Combining microbiological culture and statistical analysis of samples collected from 81 patients who were undergoing MV in ICU, we showed that microbe found in the ETAs had high similarity with that found in the ETTs which collected at the end of the catheters. In clinical practice, ETAs analysis is easily accessible meanwhile provides a valuable information for MV patients.

Major Physiological Signaling Pathways in the Regulation of Cell Proliferation and Survival.

Multiple signaling pathways regulate cell proliferation and survival and are therefore important for maintaining homeostasis of development. The balance between cell growth and death is achieved through orchestrated signal transduction pathways mediated by complex functional interactions between signaling axes, among which, PI3K/Akt and Ras/MAPK as well as JAK/STAT play a dominant role in promoting cell proliferation, differentiation, and survival. In clinical cancer therapies, drug resistance is the major challenge that occurs in almost all targeted therapeutic strategies. Recent advances in research have suggested that the intrinsic pro-survival signaling crosstalk is the driving force in acquired resistance to a targeted therapy, which may be abolished by interfering with the cross-reacting network.

[Research progress on composite animal models of inflammatory bowel disease based on gene knockout].

Establishing a suitable animal model is important for studying the mechanism of inflammatory bowel disease (IBD) and exploring new therapeutic approaches. Although a large number of IBD single gene knockout animal models have been established, single knockout of certain genes associated with human IBD susceptibility does not manifest symptoms of IBD or manifest extremely milder symptoms, while composite animal models based on other modeling factors can better simulate the clinical features of IBD. This article mainly introduces three novel composite animal models and elaborates the possible pathogenesis of each composite model:animal models established by gene double knockout have more obvious and earlier symptoms than single-knockout models; single gene knockout model with Helicobacter infection can help to study the role of microbial infections in the pathogenesis of IBD; on the basis of gene knockout, specific deletion of certain immune cells can be used to study the role of the immune cells in the development of IBD. Among the above composite animal models, Muc2/IL-10 double knockout mice may be important animal models for IBD study.

Protective actions of aspirin-triggered (17R) resolvin D1 and its analogue, 17R-hydroxy-19-para-fluorophenoxy-resolvin D1 methyl ester, in C5a-dependent IgG immune complex-induced inflammation and lung injury.

Increasing evidence suggests that the novel anti-inflammatory and proresolving mediators such as the resolvins play an important role during inflammation. However, the functions of these lipid mediators in immune complex-induced lung injury remain unknown. In this study, we determined the role of aspirin-triggered resolvin D1 (AT-RvD1) and its metabolically stable analog, 17R-hydroxy-19-para-fluorophenoxy-resolvin D1 methyl ester (p-RvD1), in IgG immune complex-induced inflammatory responses in myeloid cells and injury in the lung. We show that lung vascular permeability in the AT-RvD1- or p-RvD1-treated mice was significantly reduced when compared with values in mice receiving control vesicle during the injury. Furthermore, i.v. administration of either AT-RvD1 or p-RvD1 caused significant decreases in the bronchoalveolar lavage fluid contents of neutrophils, inflammatory cytokines, and chemokines. Of interest, AT-RvD1 or p-RvD1 significantly reduced bronchoalveolar lavage fluid complement C5a level. By EMSA, we demonstrate that IgG immune complex-induced activation of NF-κB and C/EBPß transcription factors in the lung was significantly inhibited by AT-RvD1 and p-RvD1. Moreover, AT-RvD1 dramatically mitigates IgG immune complex-induced NF-κB and C/EBP activity in alveolar macrophages. Also, secretion of TNF-α, IL-6, keratinocyte cell-derived chemokine, and MIP-1α from IgG immune complex-stimulated alveolar macrophages or neutrophils was significantly decreased by AT-RvD1. These results suggest a new approach to the blocking of immune complex-induced inflammation.