ABSTRACT
Centralized Training with Decentralized Execution (CTDE) is a prevalent paradigm in the field of fully cooperative Multi-Agent Reinforcement Learning (MARL). Existing algorithms often encounter two major problems: independent strategies tend to underestimate the potential value of actions, leading to the convergence on sub-optimal Nash Equilibria (NE); some communication paradigms introduce added complexity to the learning process, complicating the focus on the essential elements of the messages. To address these challenges, we propose a novel method called Optimistic Sequential Soft Actor Critic with Motivational Communication (OSSMC). The key idea of OSSMC is to utilize a greedy-driven approach to explore the potential value of individual policies, named optimistic Q-values, which serve as an upper bound for the Q-value of the current policy. We then integrate a sequential update mechanism with optimistic Q-value for agents, aiming to ensure monotonic improvement in the joint policy optimization process. Moreover, we establish motivational communication modules for each agent to disseminate motivational messages to promote cooperative behaviors. Finally, we employ a value regularization strategy from the Soft Actor Critic (SAC) method to maximize entropy and improve exploration capabilities. The performance of OSSMC was rigorously evaluated against a series of challenging benchmark sets. Empirical results demonstrate that OSSMC not only surpasses current baseline algorithms but also exhibits a more rapid convergence rate.
ABSTRACT
Antimicrobial peptides (AMPs) are vital components of the nonspecific immune system that represent a promising broad-spectrum alternative to conventional antibiotics. Several short cationic antimicrobial peptides show highly effective antibacterial activity and low hemolytic activity, which are based on the action of a few critical amino acids, such as phenylalanine (F) and lysine (K). Previous studies have reported that Fmoc-based phenylalanine peptides possess appreciable antibacterial potency against Gram-positive bacteria, but their ability to kill Gram-negative bacteria was suboptimal. In this study, we designed and prepared a series of Fmoc-KnF peptide (n = 1-3) series by adding lysine motifs to strengthen their broad-spectrum antibacterial activity. The effect was investigated that the amount of lysine in Fmoc-F peptides on their antibacterial properties and hemolytic activities. Our results showed that the Fmoc-KKF peptide holds the strongest antimicrobial activity against both Gram-positive and negative bacteria among all designed peptides, as well as low hemolytic activity. These results provide support for the general strategy of enhancing the broad-spectrum antibacterial activity of AMPs through increased lysine content.
Subject(s)
Antimicrobial Cationic Peptides , Lysine , Antimicrobial Cationic Peptides/pharmacology , Antimicrobial Cationic Peptides/chemistry , Lysine/chemistry , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Bacteria , Gram-Negative Bacteria , Phenylalanine/chemistry , Microbial Sensitivity TestsABSTRACT
In this study, we recruited chitosan (CS) both for selenium nanoparticles (SeNPs) synthesis and for the development of a thermoresponsive nanocomposite hydrogel with the addition of glycerol phosphate (GP). Considering that SeNPs are toxic at high concentrations, five different ingredients of the nanocomposite hydrogel system with low concentrations of SeNPs (1.25-20 µg/mL) were prepared. The gelation conditions, structural characteristics, and mechanical properties of SeNPs-loaded thermosensitive CS/GP hydrogels were investigated. We also evaluated their antioxidizing activities and biocompatibility of the CS/GP/SeNPs hydrogels. Our study demonstrated that the incorporation of SeNPs in the hydrogel improved its mechanical properties, antioxidant activity, and degree of swelling. According to the properties of SeNPs and CS/GP thermosensitive hydrogels, the combination of these two technologies in an appropriate manner would be a promising antioxidant system for drug delivery and tissue engineering.
Subject(s)
Chitosan , Nanoparticles , Selenium , Antioxidants , Hydrogels , Materials TestingABSTRACT
Over half a million US residents are suffering with bladder cancer (BC), which costs a total $4 billion in treatment annually. Although recent studies report that autophagy-related gene 7 (ATG7) is overexpressed in BCs, the regulatory effects of ATG7 on cancer stem-like phenotypes and invasion have not been explored yet. Current studies demonstrated that the deficiency of ATG7 by its shRNA dramatically reduced sphere formation and invasion in vitro, as well as lung metastasis in vivo in human invasive BC cells. Further studies indicated that the knockdown of ATG7 attenuated the expression of CD44 standard (CD44s), while ectopic introduction of CD44s, was capable of completely restoring sphere formation, invasion, and lung metastasis in T24T(shATG7) cells. Mechanistic studies revealed that ATG7 overexpression stabilized CD44s proteins accompanied with upregulating USP28 proteins. Upregulated USP28 was able to bind to CD44s and remove the ubiquitin group from CD44s' protein, resulting in the stabilization of CD44s protein. Moreover, ATG7 inhibition stabilized AUF1 protein and thereby reduced tet1 mRNA stability and expression, which was able to demethylate usp28 promoter, reduced USP28 expression, finally promoting CD44s degradation. In addition, CD44s was defined to inhibit degradation of RhoGDIß, which in turn promotes BC invasion. Our results demonstrate that CD44s is a key ATG7 downstream regulator of the sphere formation, invasion, and lung metastasis of BCs, providing significant insight into understanding the BC invasions, metastasis, and stem-like properties.
Subject(s)
Autophagy-Related Protein 7/genetics , Hyaluronan Receptors/genetics , Lung Neoplasms/secondary , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/pathology , Autophagy-Related Protein 7/metabolism , Cell Line, Tumor , Humans , Hyaluronan Receptors/metabolism , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mixed Function Oxygenases/genetics , Mixed Function Oxygenases/metabolism , Neoplasm Metastasis , Promoter Regions, Genetic , RNA, Small Interfering/genetics , Ubiquitin Thiolesterase/genetics , Ubiquitin Thiolesterase/metabolism , Up-Regulation , Urinary Bladder Neoplasms/metabolismABSTRACT
AhR is an environmental response gene that mediates cellular responses to a variety of xenobiotic compounds that frequently function as AhR ligands. Many AhR ligands are classified as carcinogens or pro-carcinogens. Thus, AhR itself acts as a major mediator of the carcinogenic effect of many xenobiotics in vivo. In this concise review, mechanisms by which AhR trans-activates downstream target gene expression, modulates immune responses, and mediates malignant transformation and tumor development are discussed. Moreover, activation of AhR by post-translational modifications and crosstalk with other transcription factors or signaling pathways are also summarized.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , Carcinogenesis/metabolism , Cell Transformation, Neoplastic/metabolism , Receptors, Aryl Hydrocarbon/genetics , Receptors, Aryl Hydrocarbon/metabolism , Animals , Carcinogenesis/genetics , Cell Transformation, Neoplastic/genetics , Gene Expression Regulation, Neoplastic , Humans , Ligands , Phosphorylation , Protein Processing, Post-Translational , Signal Transduction , Transcriptional Activation , Xenobiotics/toxicityABSTRACT
Cheliensisin A (Chel A), a styryl-lactone compound extracted from Goniothalamus cheliensis, is reported to have significant anti-cancer effects in various cancer cells. Here we demonstrated that Chel A treatment resulted in apoptosis and an inhibition of anchorage-independent growth in human bladder cancer T24, T24T and U5637 cells. Mechanistic studies showed that such effect is mediated by PH domain and Leucine rich repeat Protein Phosphatases (PHLPP2) protein. Chel A treatment led to PHLPP2 degradation and subsequently increased in c-Jun phosphorylation. Moreover PHLPP2 degradation could be attenuated by inhibition of autophagy, which was mediated by Beclin 1. Collectively, we discover that Chel A treatment induces Beclin-dependent autophagy, consequently mediates PHLPP2 degradation and JNK/C-Jun phosphorylation and activation, further in turn contributing to apoptosis in human bladder cancer cells. Current studies provide a significant insight into understanding of anticancer effect of Chel A in treatment of human bladder cancer.
Subject(s)
Apoptosis/drug effects , Epoxy Compounds/pharmacology , Phosphoprotein Phosphatases/metabolism , Pyrones/pharmacology , 3' Untranslated Regions/genetics , Autophagy/drug effects , Base Sequence , Beclin-1/metabolism , Cell Line, Tumor , Gene Expression Regulation, Neoplastic/drug effects , Humans , JNK Mitogen-Activated Protein Kinases/metabolism , MicroRNAs/genetics , Phosphoprotein Phosphatases/genetics , Phosphorylation/drug effects , Proteolysis/drug effects , Sequence Homology, Nucleic Acid , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/metabolism , Urinary Bladder Neoplasms/pathologyABSTRACT
Chronic lung inflammation is accepted as being associated with the development of lung cancer caused by nickel exposure. Therefore, identifying the molecular mechanisms that lead to a nickel-induced sustained inflammatory microenvironment that causes transformation of human bronchial epithelial cells is of high significance. In the current studies, we identified SQSTM1/p62 as a novel nickel-upregulated protein that is important for nickel-induced inflammatory TNF expression, subsequently resulting in transformation of human bronchial epithelial cells. We found that nickel exposure induced SQSTM1 protein upregulation in human lung epithelial cells in vitro and in mouse lung tissues in vivo. The SQSTM1 upregulation was also observed in human lung squamous cell carcinoma. Further studies revealed that the knockdown of SQSTM1 expression dramatically inhibited transformation of human lung epithelial cells upon chronic nickel exposure, whereas ectopic expression of SQSTM1 promoted such transformation. Mechanistic studies showed that the SQSTM1 upregulation by nickel was the compromised result of upregulating SQSTM1 mRNA transcription and promoting SQSTM1 protein degradation. We demonstrated that nickel-initiated SQSTM1 protein degradation is mediated by macroautophagy/autophagy via an MTOR-ULK1-BECN1 axis, whereas RELA is important for SQSTM1 transcriptional upregulation following nickel exposure. Furthermore, SQSTM1 upregulation exhibited its promotion of nickel-induced cell transformation through exerting an impetus for nickel-induced inflammatory TNF mRNA stability. Consistently, the MTOR-ULK1-BECN1 autophagic cascade acted as an inhibitory effect on nickel-induced TNF expression and cell transformation. Collectively, our results demonstrate a novel SQSTM1 regulatory network that promotes a nickel-induced tumorigenic effect in human bronchial epithelial cells, which is negatively controlled by an autophagic cascade following nickel exposure.
Subject(s)
Bronchi/pathology , Cell Transformation, Neoplastic/pathology , Epithelial Cells/metabolism , Epithelial Cells/pathology , Nickel/adverse effects , Sequestosome-1 Protein/genetics , Up-Regulation/drug effects , Adenine/analogs & derivatives , Adenine/pharmacology , Animals , Autophagy/drug effects , Autophagy-Related Protein-1 Homolog/metabolism , Beclin-1/metabolism , Cell Line, Tumor , Humans , Inflammation/pathology , Intracellular Signaling Peptides and Proteins/metabolism , Lung Neoplasms/pathology , Macrolides/pharmacology , Male , Mice, Inbred C57BL , Sequestosome-1 Protein/metabolism , Signal Transduction/drug effects , TOR Serine-Threonine Kinases/metabolism , Transcription, Genetic/drug effects , Tumor Necrosis Factor-alpha/metabolismABSTRACT
BACKGROUND: Spliceosomal introns are a common feature of eukaryotic genomes. To approach a comprehensive understanding of intron evolution on Earth, studies should look beyond repeatedly studied groups such as animals, plants, and fungi. The slime mold Dictyostelium belongs to a supergroup of eukaryotes not covered in previous studies. RESULTS: We found 441 precise intron losses in Dictyostelium discoideum and 202 precise intron losses in Dictyostelium purpureum. Consistent with these observations, Dictyostelium discoideum was found to have significantly more copies of reverse transcriptase genes than Dictyostelium purpureum. We also found that the lost introns are significantly further from the 5' end of genes than the conserved introns. Adjacent introns were prone to be lost simultaneously in Dictyostelium discoideum. In both Dictyostelium species, the exonic sequences flanking lost introns were found to have a significantly higher GC content than those flanking conserved introns. Together, these observations support a reverse-transcription model of intron loss in which intron losses were caused by gene conversion between genomic DNA and cDNA reverse transcribed from mature mRNA. We also identified two imprecise intron losses in Dictyostelium discoideum that may have resulted from genomic deletions. Ninety-eight putative intron gains were also observed. Consistent with previous studies of other lineages, the source sequences were found in only a small number of cases, with only two instances of intron gain identified in Dictyostelium discoideum. CONCLUSIONS: Although they diverged very early from animals and fungi, Dictyostelium species have similar mechanisms of intron loss.
Subject(s)
Dictyostelium/classification , Dictyostelium/genetics , Genome, Protozoan , Introns , Base Composition , Base Sequence , Dictyostelium/enzymology , Dictyostelium/metabolism , Eukaryota/classification , Eukaryota/genetics , Exons , Gene Conversion , Molecular Sequence Data , RNA-Directed DNA Polymerase/genetics , RNA-Directed DNA Polymerase/metabolism , Retroelements , Sequence DeletionABSTRACT
WWP2 is a ubiquitin E3 ligase belonging to the Nedd4-like family. Given that WWP2 target proteins including PTEN that are crucial for regulating cell proliferation or suppressing tumorigenesis, we have asked whether WWP2 plays a role in controlling cell cycle progression. Here we report that WWP2 is necessary for normal cell cycle progression as its silencing significantly reduces the cell proliferation rate. We have identified that an isoform of WWP2 (WWP2-V4) is highly expressed in the M phase of the cell cycle. Silencing of WWP2 accelerates the turnover of cyclin E, which is accompanied by increased levels of phospho-histone H3 (p-H3) and cyclin B. Moreover, silencing of WWP2 results in compromised phosphorylation of Akt(S473), a residue whose phosphorylation is tightly associated with the activation of the kinase. Combined, these results strongly suggest that WWP2 is an important component in regulating the Akt signaling cascade, as well as cell cycle progression.
ABSTRACT
The ability to metastasize is a hallmark of malignant tumors, and metastasis is the principal cause of death of cancer patients. The High Mobility Group Box-1 (HMGB1) is a multifunction protein that serves as both a chromatin protein and an extracellular signaling molecule. Our current study demonstrated a novel mechanism of HMGB1 in the regulation of cancer cell actin polymerization, cell skeleton formation, cancer cell motility and metastasis. We found that knockdown of HMGB1 in human lung cancer A549 cells significantly increased cell ß-actin polymerization, cell skeleton formation, cancer cell migration and invasion in vitro, as well as metastasis in vivo. And this increase could be inhibited by treatment of HMGB1 knockdown cells with recombinant human HMGB1. Further studies discovered that HMGB1 suppressed phosphorylation, nuclear translocation, and activation of CREB, by inhibiting nuclear translocation of PKA catalytic subunit. This reduces nWASP mRNA transcription and expression, further impairing cancer cell motility. Our findings on the novel mechanism underlying the HMGB1 anti-metastatic effect on cancer provides significant insight into the understanding of the nature of HMGB1 in cancer invasion and metastasis, further serving as key information for utilization of HMGB1 and its regulated downstream components as new targets for cancer therapy.
Subject(s)
Adenocarcinoma/pathology , Cell Movement , Cyclic AMP Response Element-Binding Protein/biosynthesis , Gene Expression Regulation, Neoplastic/physiology , HMGB1 Protein/metabolism , Lung Neoplasms/pathology , Wiskott-Aldrich Syndrome Protein/biosynthesis , Adenocarcinoma/metabolism , Animals , Blotting, Western , Cell Line, Tumor , Cell Movement/physiology , Electrophoretic Mobility Shift Assay , Female , Fluorescent Antibody Technique , Heterografts , Humans , Lung Neoplasms/metabolism , Mice , Mice, Nude , Microscopy, Confocal , Neoplasm Invasiveness/pathology , Neoplasm Metastasis , Real-Time Polymerase Chain Reaction , TransfectionABSTRACT
p27 is a cyclin-dependent kinase (CDK) inhibitor that suppresses a cell's transition from G0 to S phase, therefore acting as a tumor suppressor. Our most recent studies demonstrate that upon arsenite exposure, p27 suppresses Hsp27 and Hsp70 expressions through the JNK2/c-Jun- and HSF-1-dependent pathways, suggesting a novel molecular mechanism underlying the tumor suppressive function of p27 in a CDK-independent manner. We found that p27-deficiency (p27-/-) resulted in the elevation of cyclooxygenase-2 (COX-2) expression at transcriptional level, whereas the introduction of p27 brought back COX-2 expression to a level similar to that of p27+/+ cells, suggesting that p27 exhibits an inhibitory effect on COX-2 expression. Further studies identified that p27 inhibition of COX-2 expression was specifically due to phosphorylation of transcription factor cAMP response element binding (CREB) phosphorylation mediated by p38ß and p38δ. These results demonstrate a novel mechanism underlying tumor suppression effect of p27 and will contribute to the understanding of the overall mechanism of p27 tumor suppression in a CDK-independent manner.
Subject(s)
Arsenites/pharmacology , Cyclic AMP Response Element-Binding Protein/metabolism , Cyclin-Dependent Kinase Inhibitor p27/metabolism , Cyclooxygenase 2/biosynthesis , Gene Expression Regulation, Enzymologic/drug effects , Mitogen-Activated Protein Kinase 11/metabolism , Mitogen-Activated Protein Kinase 13/metabolism , Teratogens/pharmacology , Animals , Cell Line , Cyclic AMP Response Element-Binding Protein/genetics , Cyclin-Dependent Kinase Inhibitor p27/genetics , Cyclooxygenase 2/genetics , Gene Expression Regulation, Enzymologic/genetics , Mice , Mice, Knockout , Mitogen-Activated Protein Kinase 11/genetics , Mitogen-Activated Protein Kinase 13/genetics , Phosphorylation/drug effects , Phosphorylation/genetics , Transcription, Genetic/drug effects , Transcription, Genetic/geneticsABSTRACT
microRNA(miRNA) is a kind of non-coding RNA that has a regulatory function on coding miRNA. miRNA can target the 3 UTR of mRNA and inhibit its gene expression by either inhibiting its translation or promoting its degradation. miRNAs are thus considered to be oncogenic or antineoplastic, depending on their downstream target mRNAs. Besides their clinical application in cancer treatment, diagnosis, and prognosis, miRNA has also recently been reported to be involved in cancer chemotherapy and chemoprevention. This review focuses on the implication of miRNA in cancer chemoprevention and cancer control as well as molecular mechanisms underlying those biological effects.
ABSTRACT
OBJECTIVE: To investigate the therapeutic effect of Dachaihutang on the development of atherosclerosis (AS) in rabbits and its possible mechanism by detecting the expression level of carnitine patmitoyl transferase-1 (CPT-1) in vascular smooth muscle layer of atherosclerotic rabbits, and search the new way and evidence for AS cures. METHOD: Thirty six male New Zealand white rabbits were divided randomly into control group, model control group, simvastatin group and Chinese traditional medicine dachaihutang group. After 9 weeks and 20 weeks of treatment, serum total cholesterol (TC) and triglyceride (TG) and low-density lipoprotein (LDL) levels were examined. At the end of 25 th weeks, histological changes in ascending aorta were studied by HE staining and histomorphometric analysis. The gene expression of CPT-1 in vascular smooth muscle layer of thoracic aorta was detected by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR). RESULT: Compared with model control group, in dachaihutang group serum TC and TG and LDL levels attenuated. Pathomorphology indicated that intima and media (I + M) became thinned, and the ratios of the thickness of intima to media(I/M) and the area of intima to media (SI/SM) were decreased (P < 0.05). Aortic intimal proliferation in Dachaihutang group was associated with a marked increase in CPT-1 expression in vascular smooth muscle layer of thoracic aorta. Compared to simvastatin group, except TG value, other values were higher in Dachaihutang group, however, there were no significant differences between the two groups. CONCLUSION: These findings suggest that early treatment with Dachaihutang not only induces a significant regression of arterial lesions of high cholesterol diet rabbits, but also has a crucial inhibited genesis and development of atherosclerosis effect by up-regulating CPT-1 expression in vascular smooth muscle layer.
Subject(s)
Atherosclerosis/enzymology , Carnitine O-Palmitoyltransferase/genetics , Drugs, Chinese Herbal/pharmacology , Gene Expression/drug effects , Myocytes, Smooth Muscle/enzymology , Animals , Aorta/cytology , Aorta/drug effects , Aorta/enzymology , Atherosclerosis/drug therapy , Atherosclerosis/genetics , Carnitine O-Palmitoyltransferase/metabolism , Disease Models, Animal , Humans , Male , Myocytes, Smooth Muscle/drug effects , Rabbits , Random AllocationABSTRACT
DNA molecular constitution is damaged to result in the inductive variation of base structure in female breast tissue under the influence of physical factors and chemical factors. The present research indicated that the FTIR spectra can reflect sensitively the change in the constitution. Our findings indicated that normal, benign and cancerous breast tissues are different in constitution and content of protein, nucleic acid and sugar, comparing the FTIR spectra, deconvolution spectra and date analysis. The result indicated that the content of collagen protein and nucleic acid increased obviously in cancerous tissue, while the content of glycoprotein increased gradually except mucinous carcinoma. After extracting nucleic acid of breast tissue, we further investigated the difference of constitution and content of base and phosphate by comparing normal, benign and cancerous breast tissues. The spectra and spectral data showed that the degree of hydrogen-bonding of base ring guanine (Gue) increased in cancerous tissue, base ring adenine (Ade) presented mostly in oxydic 8-OH-Ade via the attack of the *OH in cancerous breast, the peak position shifted to higher wave number with enhancing of C=N vibration, and the content of phosphate increased. After deconvolution, the ratio A1080/A1050 showed that the amount of PO2- relative to C-O increased from normal to cancerous breast tissues. It provided a important basis to study the mechanism of cancerization from molecular biology and molecular medicine.
Subject(s)
Breast Neoplasms/chemistry , Nucleic Acids/analysis , Spectroscopy, Fourier Transform Infrared/methods , Adenine/analysis , Breast Neoplasms/pathology , Female , Guanine/analysis , Humans , Spectrum Analysis/methodsABSTRACT
A portable laser-induced fluorescence detector, based on confocal configuration detection system has been developed. This is assembled from commercially available components. All the components of the detector are domestic, which makes it low cost. The routine alignment procedure is simplified by using a skillful and visual alignment system and requires minimal experience for operation. The module design makes it possible for high performance liquid chromatographic, capillary electrophoretic and microfluid chip applications. The performance of the detector, including the sensitivity, noise, linear range and detection limit, was evaluated by capillary electrophoresis and flow injection analytical technique using a red-absorbing cyanine derivative (Cy5) and Cy5 labeled tryptophan as test samples. The results show that the background signal is very low and the peak-to-peak noise level is 0.002 mV. The detection limit and the linear dynamic range are 3.7 nmol/L and 10(3), respectively.