ABSTRACT
The nuclear transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) plays a crucial role in maintaining cellular redox homeostasis. The aberrant NRF2 signaling confers enhanced antioxidant capacity, which is linked to tumor progression and therapeutic resistance. The current study investigates the biological effects and molecular mechanism of tribbles homolog 3 (TRIB3), a stress-induced protein, in regulating cell survival and apoptosis in lung cancer. This study first performed the RNA sequencing data analysis with 576 lung adenocarcinoma patients from the cancer genome atlas (TCGA) database. The NRF2- antioxidant response element (ARE) signature was enriched in patients with high TRIB3 expression. Dual-luciferase reporter assay and real-time quantitative polymerase chain reaction (PCR) were used to confirm the effect of TRIB3 on the kelch-like ECH-associated protein-1 (KEAP1)-NRF2 pathway. Abrogation of TRIB3 impaired NRF2 transcriptional activity and reduced the expression of its target genes. Moreover, TRIB3 enhanced NRF2 stability via blocking KEAP1-NRF2 interaction. TRIB3-depletion promoted reactive oxygen species (ROS) production, restrained cell proliferation, and enhanced carboplatin-induced apoptosis. In addition, NRF2 overexpression recovered the tumor inhibition effect of TRIB3-depletion. Consistently, TRIB3 failed to modulate apoptosis in NRF2 depletion cells. In summary, this study shows that TRIB3 inhibits the KEAP1-NRF2 interaction and upregulates the transcriptional activity of NRF2, thereby promoting lung cancer cell proliferation and reducing the sensitivity to chemotherapy. Targeting the TRIB3-NRF2 signal axis may become a new strategy for ROS homeostasis and lung cancer treatment.
ABSTRACT
Chemokines are small cytokines with chemotactic activity, they are involved in regulating immune responses and inflammatory responses. In the development of tumors, chemokines are multi-functional mediators that not only affect the infiltration of immune cells into the tumor, but also have an important impact on tumor growth, angiogenesis, invasion, and metastasis. Besides, they are important targets of tumor therapy. Here we review chemokines involved in the regulation of signaling pathways, analyze the mechanism of chemokines in the development of breast cancer, summarize the chemokines targeted drugs for breast cancer in recent years and make a prospect about the role of chemokines in anti-breast cancer therapy.
ABSTRACT
Philadelphia chromosome (Ph) positive (Ph+) B cell acute lymphoblastic leukemia (B-ALL) is the most common genetic abnormality associated with B-ALL and has been shown to confer the worst prognosis to both children and adults. Increasing evidence has revealed that high tribbles homologue 3 (TRIB3) expression contributes to multi-cancer development and progression, but the underlying role and molecular mechanisms of TRIB3 in Ph+ B-ALL remain unclear. Here, we report that TRIB3 expression was enhanced in Ph+ B-ALL patient samples and positively associated with the expression of breakpoint cluster region-Abelson tyrosine kinase (BCR-ABL). We further demonstrated that deletion of TRIB3 attenuated the progression of Ph+ B-ALL by reducing BCR-ABL expression. Mechanistically, TRIB3 interacted with lysosomal cysteine proteinase cathepsin Z (CTSZ) to suppress CTSZ-mediated BCR-ABL degradation, which enhanced BCR-ABL activity, causing high proliferation of Ph+ B-ALL cells. Thus, our study indicated that inhibiting the expression of TRIB3 to regulate BCR-ABL kinase activity may be exploited as an additional target therapy for Ph+ ALL. Procedures for animal study were performed with approval of the Animal Care and Use Committee of the Chinese Academy of Medical Sciences and Peking Union Medical College. The procedure of human leukemia sample was approved by the Ethics Committee of Chinese Academy of Medical Sciences and Peking Union Medical College (KT2019055-EC-1).
ABSTRACT
The aim of this study was to determine whether the anti-fibrotic effects of pirfenidone (Pirf) and nintedanib (Nint) associated with the regulation of the alveolar epithelial type 2 cell (AEC II)-mediated lung alveolar regeneration in single- and multiple-dosage animal models of bleomycin-induced pulmonary fibrosis. All procedures involving animal treatment were approved according to the Committee on the Ethics of Animal Experiments of the Institute of Materia Medica, Chinese Academy of Medical Sciences. We found that the Pirf and Nint treatment of mice decreased the lung weight index, inflammation level, and the content of hydroxyproline compared with nontreated fibrotic mice in the single dosage model. Also, Pirf and Nint increased the oxygen saturation level and improved the lung functions in fibrotic mice, indicating that both drugs have anti-fibrotic effects in this model. However, the anti-fibrotic effects of Pirf and Nint were not observed in the multiple-dosage model. Further studies showed that Pirf and Nint decreased the expression of β-catenin, Axin2, c-Myc, Cyclin D1, and inhibited the Wnt/β-catenin signaling pathway, suggesting that Pirf and Nint did not produce anti-fibrotic effects in the multiple-dosage model due to their inhibiting the Wnt/β-catenin pathway and suppressing the stemness of AEC II, namely, suppressing AEC II-mediated lung alveolar regeneration.
ABSTRACT
Protein acetylation is a process of adding an acetyl group to a protein lysine residue with the help of acetyltransferase, which is a pivotal protein post-translational modification linking acetyl-CoA metabolism and cell signal transduction. Recently, the development of mass spectrometry has deepened our understanding of lysine acetylation. Lysine acetylation is involved in many processes such as gene transcription, protein degradation, cellular metabolism, and stress response, which affects biological processes by regulating protein interactions, activity, stability and localization. Protein acetylation is widely happened and plays important regulatory roles in a diversity of human diseases such as metabolic diseases, tumors and cardiovascular diseases. Besides, deacetylase inhibitors have displayed a great potential in the treatment of various diseases especially tumors and metabolic associated diseases. In this review, we summarized the advances and application of acetylation, and discussed the remaining problems in this area.
ABSTRACT
italic>Akkermansia muciniphila (A. muciniphila) is an intestinal bacterium that was isolated from human feces in 2004. Its specialization in mucin degradation makes it a key organism that maintains the intestinal mucosal barrier function. A. muciniphila, which is the only representative of the Verrucomicrobia that can be cultured, is relatively easy to be detected in metagenomic analysis. For the past few years, A. muciniphila has quickly attracted the attention of researchers and become a medical and biological hotspot due to the close correlation between its intestinal colonization and the development and progression of various metabolic diseases. This review introduces the biological characteristics and colonization environment of A. muciniphila, and reviews its relationship with host health and disease, especially focusing on the metabolic disease and related mechanism, as well as the factors affecting its colonization in the host, expecting to provide evidence and clues for drug development targeting A. muciniphila.
ABSTRACT
Mutation and amplification of epidermal growth factor receptor (EGFR), one of the most important driver gene, are both reported to participate in the regulation of lung cancer development and progression. Here we investigated the effect and molecular mechanism of tripartite motif 25 (TRIM25) in the regulation of development of lung cancer. CCK-8 and Transwell assays were used to explore the tumor-promoting effect of TRIM25. Results showed that knockdown of TRIM25 significantly inhibited cell proliferation (34% inhibition rate) and invasion (42% inhibition rate). Gene set enrichment analysis (GSEA), Western blot and immunohistochemistry were adopted to detect the effect of TRIM25 on EGFR expression and its downstream signal activity. The results explained that TRIM25 not only up-regulated the expression level of EGFR, but also promoted EGFR signal activation. Co-immunoprecipitation, real-time PCR and cycloheximide (CHX) inhibit protein degradation assays were employed to explore the molecular mechanism of TRIM25 in regulating EGFR stability. Preliminary exploration results indicate that TRIM25 increases the expression level of EGFR and activates its downstream signaling activity through promoting K63-linked ubiquitination of EGFR. Restoration of EGFR expression rescues the phenotype of TRIM25 depletion. In A549 cells, overexpression of EGFR increased cell proliferation rate 1.5-fold and invasion rate 1.6-fold compared with knockdown of TRIM25 cells. Similarly, in H1975 cells, cell proliferation rate was enhanced 2-fold and invasion rate was improved 1.7-fold. These data suggest that TRIM25 promotes lung cancer development via maintaining EGFR stability and continuous EGFR signaling activation. The human lung cancer tissues were obtained from lung cancer patients at Cancer Hospital Chinese Academy of Medical Sciences. Informed consent was obtained from all participants in accordance with the Declaration of Helsinki. The study was approved by the Ethics Committee of the Cancer Hospital Chinese Academy of Medical Sciences.
ABSTRACT
Macrophage migration inhibitory factor (MIF) is a classical pro-inflammatory cytokine that plays an important role in the innate and adaptive immune regulation. In recent years, a large number of studies have demonstrated that the expression level of MIF is significantly increased in a variety of tumor tissues and MIF promotes the occurrence and development of tumors. MIF participates in the regulation of tumor growth, metastasis, angiogenesis, as well as induces and maintains the tumor microenvironment. Targeting MIF has been considered as a candidate strategy against cancer. In this review, the structural features, the signaling pathway, the biological functions of MIF are briefly outlined. Moreover, approaches that target MIF in the treatment of cancer are also summarized.
ABSTRACT
Phage display technology utilizes filamentous phage display proteins and polypeptides to extract a desired polypeptide or protein from a large number of variants. The antibody fragments screened and obtained by phage display library technology play an important role in disease diagnosis and treatment. This article briefly introduces the principles of phage display technology, summarizes the development of monoclonal antibodies, the development of antigenic microbial vaccines, and the application of peptide drugs. This review highlights the importance of phage display technology in the diagnosis and treatment of various human diseases such as cancer and autoimmune diseases etc.
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Over the past four decades, monoclonal antibodies (MAbs) have evolved from bioscience research tools to powerful biopharmaceutical MAbs products for multiple diseases treatment. More than 50 therapeutic MAbs have been approved by FDA, widely used in cancer, autoimmune diseases and other diseases in current market. This article reviews the current progress of MAbs development technology, key molecules for cancer-targeted therapy and immunotherapy, and emphasizes the importance of MAbs for disease diagnosis and treatment.
ABSTRACT
Diabetes and cancer are two major chronic diseases with tremendous impact on human health worldwide. Clinical and basic studies demonstrate that diabetes can promote carcinogenesis and tumor progression. High insulin and high insulin-like growth factor are considered to be the major risk factors for cancer. Chronic inflammation and aberrant metabolism also participate in cancer development. It is noteworthy that therapies used for treatment of diabetes may increase or decrease the risk of cancer. Revealing the mechanisms that connect diabetes to cancer will be crucial for prevention and treatment of diabetes-related cancers.
ABSTRACT
Autophagy is an active research area in the biomedical field as its role has been identified in many physiological and pathological processes. Accordingly, there is a growing demand to identify, quantify and manipulate the process accurately. Meanwhile, there is great interest in identifying compounds that modulate autophagy because they may have applications in the treatment of a variety of autophagy-related diseases. In this review, we summarize the current status of autophagy screening systems to facilitate identification of autophagy modulators.
ABSTRACT
Autophagy is a crucial biological process of eukaryotes, which is involved in cell growth, survival and energy metabolism, while the premise of the autophagy function is activated autophagic flux. It has been confirmed that impaired autophagic flux promotes pathogenesis of many chronic inflammatory diseases, especially cancer, neurodegenerative disease and tissue fibrosis, therefore the analysis of autophagic flux state is important for revealing autophagy function and the mechanism of autophagy related diseases. Given that autophagy is a dynamic process with multiple steps, it is very hard to observe the real state of autophagic flux. Summarized here is the novel concept and current approach to detect autophagic flux. This knowledge is crucial for the researching of the biological function of autophagy, and may provide some strategies for developing autophagy-related drug.
ABSTRACT
Autophagy is an important homeostatic cellular recycling mechanism responsible for degrading injured or dysfunctional subcellular organelles and proteins in all living cells. The process of autophagy can be divided into three relatively independent steps: the initiation of phagophore, the formation of autophagosome and the maturation/degradation stage. Different morphological characteristics and molecular marker changes can be observed at these stages. Morphological approaches are useful to produce novel knowledge that would not be achieved through other experimental methods. Here we summarize the morphological methods in monitoring autophagy, the principles in data interpretation and the cautions that should be considered in the study of autophagy.
ABSTRACT
Autophagy is an important homeostatic cellular recycling mechanism responsible for degrading injured or dysfunctional subcellular organelles and proteins in all living cells. The process of autophagy can be divided into three relatively independent steps: the initiation of phagophore, the formation of autophagosome and the maturation/degradation stage. Different morphological characteristics and molecular marker changes can be observed at these stages. Morphological approaches are useful to produce novel knowledge that would not be achieved through other experimental methods. Here we summarize the morphological methods in monitoring autophagy, the principles in data interpretation and the cautions that should be considered in the study of autophagy.
Subject(s)
Humans , Autophagy , Homeostasis , Organelles , PhagosomesABSTRACT
Autophagy is a crucial biological process of eukaryotes, which is involved in cell growth, survival and energy metabolism, while the premise of the autophagy function is activated autophagic flux. It has been confirmed that impaired autophagic flux promotes pathogenesis of many chronic inflammatory diseases, especially cancer, neurodegenerative disease and tissue fibrosis, therefore the analysis of autophagic flux state is important for revealing autophagy function and the mechanism of autophagy related diseases. Given that autophagy is a dynamic process with multiple steps, it is very hard to observe the real state of autophagic flux. Summarized here is the novel concept and current approach to detect autophagic flux. This knowledge is crucial for the researching of the biological function of autophagy, and may provide some strategies for developing autophagy-related drug.
Subject(s)
Humans , Autophagy , Fibrosis , Inflammation , Pathology , Neoplasms , Pathology , Neurodegenerative Diseases , PathologyABSTRACT
Autophagy is an active research area in the biomedical field as its role has been identified in many physiological and pathological processes. Accordingly, there is a growing demand to identify, quantify and manipulate the process accurately. Meanwhile, there is great interest in identifying compounds that modulate autophagy because they may have applications in the treatment of a variety of autophagy-related diseases. In this review, we summarize the current status of autophagy screening systems to facilitate identification of autophagy modulators.
Subject(s)
Humans , AutophagyABSTRACT
To investigate the protective effects and possible mechanism of Mycelium of Hirsutella hepiali Chen et Shen (MHCS) on metabolic syndromes, free fatty acid and MHCS-treated hepatocytes were used for detecting autophagy-related LC3, p62 and lipid accumulation. Moreover, high fat diet fed mice were used to establish metabolic syndromes model. 50-weeks age mice were randomly divided into: control group, model group and MHCS group. At 80-weeks age, 15 mice were randomly chosen from each group separately for examining oral glucose tolerance, serum insulin, insulin-like growth factor 1 (IGF-1), hepatic LC3, p62, p-NF-kappaB p65, NF-kappaB p65, IL-6 and CXCL-8. Moreover, insulin resistance index (IRI) was calculated. Hepatic pathological changes, including vacuoles, lipids accumulation and fibrosis were observed. Remaining mice were fed with diet separately to 110 weeks-age for statistics of mortality. MHCS promoted autophagy of free fatty acid treated hepatocytes. Mice fed with high fat plus MHCS diet exhibited improved oral glucose tolerance, insulin resistance, hepatic pathology, inflammation, mortality and activated autophagy. The protective effects of MHCS against metabolic syndroms might be through the activation of hepatic autophagy.
Subject(s)
Animals , Male , Mice , Autophagy , Diet, High-Fat , Glucose Tolerance Test , Hepatocytes , Metabolism , Pathology , Hypocreales , Insulin , Blood , Insulin Resistance , Insulin-Like Growth Factor I , Metabolism , Interleukin-6 , Metabolism , Interleukin-8 , Metabolism , Liver , Metabolism , Pathology , Metabolic Syndrome , Metabolism , Pathology , Mice, Inbred C57BL , Microtubule-Associated Proteins , Metabolism , Mycelium , Physiology , Random Allocation , Transcription Factor RelA , Metabolism , Transcription Factors , MetabolismABSTRACT
Autophagy is an important homeostatic cellular recycling mechanism responsible for degrading injured or dysfunctional cellular organelles and proteins in all living cells. Aging is a universal phenomenon characterized by progressive deterioration of cells and organs due to accumulation of macromolecular and organelle damage. Growing evidences indicate that the rate of autophagosome formation and maturation and the efficiency of autophagosome/lysosome fusion decline with age. Dysfunctional autophagy has also been observed in age-related diseases. Autophagy disruption resulted accumulation of mutated or misfolded proteins is the essential feature of neurodegenerative disorders. However, in cancers, fibroproliferative diseases or cardiovascular diseases, autophagy can play either a protective or destructive role in different types of disease, and even in different stages of the same disease. The review will discuss the cellular and molecular mechanisms of autophagy and its important role in the pathogenesis of aging and age-related diseases, and the ongoing drug discovery strategies for therapeutic intervention.
Subject(s)
Humans , Aging , Autophagy , Drug Discovery , Lysosomes , Metabolism , Neurodegenerative Diseases , Phagosomes , Metabolism , Protein FoldingABSTRACT
To prepare large naive phage antibody library, the host bacteria with high transformation efficiency is used in the Cre-LoxP recombination system. The variable regions of immunoglobulin light and heavy genes were amplified from lymphocytes collected from adult peripheral blood and newborn cord blood. The genes were spliced to form the single-chain variable fragments (scFv) by overlap PCR, cloned into pDAN5a vector and then transformed into XL2-blue MRF' with the Hte gene. Compared with XL1-blue strain, the size of the primary library was increased by 3.9 times. The primary library infected Cre recombinase-expressing bacteria, and the genes between phagemids created many new VH/VL combinations. The library was calculated to have a diversity of 1.7 x 10(11) and validated by the selection of antibodies against six different protein antigens. This library provides the basis for further selection of antibody-based drugs. It is the first time to report that XL2-blue MRF' can be used to improve the diversity of the library in the recombination system.