• Herbal Formula Science
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• v.31 no.4
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• pp.295-313
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• 2023

Objectives : While treatments for cancer are advancing, the development of effective treatments for cancer metastasis, the main cause of cancer patient death, remains insufficient. Recent studies on Dichroae Radix have revealed that its active ingredients have the potential to inhibit cancer metastasis. This study aimed to investigate the cancer metastasis inhibitory effect of Dichroae Radix using network pharmacological analysis. Methods : The active compounds of Dichroae Radix have been identified using Traditional Chinese Medicine System Pharmacology Database and Analysis Platform. The UniProt database was used to collect each of information of all target proteins associated with the active compounds. To find the bio-metabolic processes associated with each target, the DAVID6.8 Gene Functional classifier tool was used. Compound-Target and Target-Pathway networks were analyzed via Cytoscape 3.40. Results : In total, 25 active compounds and their 62 non-redundant targets were selected through the TCMSP database and analysis platform. The target genes underwent gene ontology and pathway enrichment analysis. The gene list applied to the gene ontology analysis revealed associations with various biological processes, including signal transduction, chemical synaptic transmission, G-protein-coupled receptor signaling pathways, response to xenobiotic stimulus, and response to drugs, among others. A total of eleven genes, including HSP90AB1, CALM1, F2, AR, PAKACA, PTGS2, NOS2, RXRA, ESR1, ESR2, and NCOA1, were found to be associated with biological pathways related to cancer metastasis. Furthermore, nineteen of the active compounds from Dichroae Radix were confirmed to interact with these genes. Conclusions : The results provide valuable insights into the mechanism of action and molecular targets of Dichroae Radix. Notably, Berberine, the main active ingredient of Dichroae Radix, plays a significant role in degrading AR proteins in advanced prostate cancer. Further studies and validations can provide crucial data to advance cancer metastasis prevention and treatment strategies.

• ALGAE
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• v.39 no.1
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• pp.17-30
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• 2024

Red macroalga Pyropia yezoensis is a high valuable cultivated marine crop. Its acclimation to cold stress is especially important for long cultivation period across winter in coasts of warm temperate zone in East Asia. In this study, the response of P. yezoensis thalli to low temperature was analyzed on physiology and transcriptome level, to explore its acclimation mechanism to cold stress. The results showed that the practical photosynthesis activity (indicated by Φ_PSII and qP) was depressed and pigment allophycocyanin content was decreased during the cold stress of 48 h. However, the F_v/F_m and non-photochemical quenching increased significantly after 24 h, and the average growth rate of thalli also rebounded from 24 to 48 h, indicating a certain extent of acclimation to cold stress. On transcriptionally, the low temperature promoted the expression of differentially expressed genes (DEGs) related to carbohydrate metabolism and energy metabolism, while genes related to photosynthetic system were depressed. The increased expression of DEGs involved in ribosomal biogenesis and lipid metabolism which could accelerate protein synthesis and enhance the degree of fatty acid unsaturation, might help P. yezoensis thallus cells to cope with cold stress. Further co-expression network analysis revealed differential expression trends along with stress time, and corresponding hub genes play important roles in the systemic acquired acclimation to cold stress. This study provides basic mechanisms of P. yezoensis acclimation to cold temperature and may aid in exploration of functional genes for genetic breeding of economic macroalgae.

• Genomics & Informatics
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• v.21 no.4
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• pp.46.1-46.10
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• 2023

Colon adenocarcinoma (COAD) is the predominant type of colorectal cancer. Early diagnosis and treatment can significantly improve the prognosis of COAD patients. Anoctamin 7 (ANO7), an anion channel protein, has been implicated in prostate cancer and other types of cancer. In this study, we analyzed the expression of ANO7 and its correlation with clinicopathological characteristics among COAD patients using the Gene Expression Profiling Interactive Analysis 2 (GEPIA2) and the University of Alabama at Birmingham CANcer (UALCAN) databases. The GEPIA2, Kaplan-Meier plotter, and the Survival Genie platform were employed for survival analysis. The co-expression network and potential function of ANO7 in COAD were analyzed using GeneFriends, the Database for Annotation, Visualization and Integrated Discovery (DAVID), GeneMANIA, and Pathway Studio. Our data analysis revealed a significant reduction in ANO7 expression levels within COAD tissues compared to normal tissues. Additionally, ANO7 expression was found to be associated with race and histological subtype. The COAD patients exhibiting low ANO7 expression had lower survival rates compared to those with high ANO7 expression. The genes correlated with ANO7 were significantly enriched in proteolysis and mucin type O-glycan biosynthesis pathway. Furthermore, ANO7 demonstrated a direct interaction and a positive co-expression correlation with mucin 2 (MUC2). In conclusion, our findings suggest that ANO7 might serve as a potential prognostic biomarker and potentially plays a role in proteolysis and mucin biosynthesis in the context of COAD.

• IMMUNE NETWORK
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• v.23 no.5
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• pp.37.1-37.11
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• 2023

Forkhead box P3-positive (Foxp3⁺)-inducible Tregs (iTregs) are readily generated by TGF-β1 at low TCR signaling intensity. TGF-β1-mediated Foxp3 expression is further enhanced by retinoic acid (RA) and lactoferrin (LF). However, the intensity of TCR signaling required for induction of Foxp3 expression by TGF-β1 in combination with RA and LF is unknown. Here, we found that either RA or LF alone decreased TGF-β1-mediated Foxp3 expression at low TCR signaling intensity. In contrast, at high TCR signaling intensity, the addition of either RA or LF strongly increased TGF-β1-mediated Foxp3 expression. Moreover, decreased CD28 stimulation was more favorable for TGF-β1/LF-mediated Foxp3 expression. Lastly, we found that at high signaling intensities of both TCR and CD28, combined treatment with TGF-β1, RA, and LF induced robust expression of Foxp3, in parallel with powerful suppressive activity against responder T cell proliferation. Our findings that TGFβ/RA/LF strongly generate high affinity Ag-specific iTreg population would be useful for the control of unwanted hypersensitive immune reactions such as various autoimmune diseases.

• IMMUNE NETWORK
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• v.23 no.3
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• pp.22.1-22.15
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• 2023

Alcoholic liver cirrhosis (ALC) is caused by chronic alcohol overconsumption and might be linked to dysregulated immune responses in the gut-liver axis. However, there is a lack of comprehensive research on levels and functions of innate lymphocytes including mucosal-associated invariant T (MAIT) cells, NKT cells, and NK (NK) cells in ALC patients. Thus, the aim of this study was to examine the levels and function of these cells, evaluate their clinical relevance, and explore their immunologic roles in the pathogenesis of ALC. Peripheral blood samples from ALC patients (n = 31) and healthy controls (HCs, n = 31) were collected. MAIT cells, NKT cells, NK cells, cytokines, CD69, PD-1, and lymphocyte-activation gene 3 (LAG-3) levels were measured by flow cytometry. Percentages and numbers of circulating MAIT cells, NKT cells, and NK cells were significantly reduced in ALC patients than in HCs. MAIT cell exhibited increased production of IL-17 and expression levels of CD69, PD-1, and LAG-3. NKT cells displayed decreased production of IFN-γ and IL-4. NK cells showed elevated CD69 expression. Absolute MAIT cell levels were positively correlated with lymphocyte count but negatively correlated with C-reactive protein. In addition, NKT cell levels were negatively correlated with hemoglobin levels. Furthermore, log-transformed absolute MAIT cell levels were negatively correlated with the Age, Bilirubin, INR, and Creatinine score. This study demonstrates that circulating MAIT cells, NKT cells, and NK cells are numerically deficient in ALC patients, and the degree of cytokine production and activation status also changed. Besides, some of their deficiencies are related to several clinical parameters. These findings provide important information about immune responses of ALC patients.

• IMMUNE NETWORK
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• v.24 no.1
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• pp.9.1-9.21
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• 2024

The cytokine IL-7 plays critical and nonredundant roles in T cell immunity so that the abundance and availability of IL-7 act as key regulatory mechanisms in T cell immunity. Importantly, IL-7 is not produced by T cells themselves but primarily by non-lymphoid lineage stromal cells and epithelial cells that are limited in their numbers. Thus, T cells depend on cell extrinsic IL-7, and the amount of in vivo IL-7 is considered a major factor in maximizing and maintaining the number of T cells in peripheral tissues. Moreover, IL-7 provides metabolic cues and promotes the survival of both naïve and memory T cells. Thus, IL-7 is also essential for the functional fitness of T cells. In this regard, there has been an extensive effort trying to increase the protein abundance of IL-7 in vivo, with the aim to augment T cell immunity and harness T cell functions in anti-tumor responses. Such approaches started under experimental animal models, but they recently culminated into clinical studies, with striking effects in re-establishing T cell immunity in immunocompromised patients, as well as boosting anti-tumor effects. Depending on the design, glycosylation, and the structure of recombinantly engineered IL-7 proteins and their mimetics, recombinant IL-7 molecules have shown dramatic differences in their stability, efficacy, cellular effects, and overall immune functions. The current review is aimed to summarize the past and present efforts in the field that led to clinical trials, and to highlight the therapeutical significance of IL-7 biology as a master regulator of T cell immunity.

• IMMUNE NETWORK
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• v.22 no.6
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• pp.48.1-48.13
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• 2022

With the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, which are randomly mutated, the dominant strains in regions are changing globally. The development of preclinical animal models is imperative to validate vaccines and therapeutics against SARS-CoV-2 variants. The objective of this study was to develop a non-human primate (NHP) model for SARS-CoV-2 Delta variant infection. Cynomolgus macaques infected with Delta variants showed infectious viruses and viral RNA in the upper (nasal and throat) and lower respiratory (lung) tracts during the acute phase of infection. After 3 days of infection, lesions consistent with diffuse alveolar damage were observed in the lungs. For cellular immune responses, all macaques displayed transient lymphopenia and neutrophilia in the early stages of infection. SARS-CoV-2 Delta variant spike protein-specific IgM, IgG, and IgA levels were significantly increased in the plasma of these animals 14 days after infection. This new NHP Delta variant infection model can be used for comparative analysis of the difference in severity between SARS-CoV-2 variants of concern and may be useful in the efficacy evaluation of vaccines and universal therapeutic drugs for mutations.

• IMMUNE NETWORK
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• v.23 no.6
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• pp.47.1-47.16
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• 2023

Scrub typhus, a mite-borne infectious disease, is caused by Orientia tsutsugamushi. Despite many attempts to develop a protective strategy, an effective preventive vaccine has not been developed. The identification of appropriate Ags that cover diverse antigenic strains and provide long-lasting immunity is a fundamental challenge in the development of a scrub typhus vaccine. We investigated whether this limitation could be overcome by harnessing the nanoparticle-forming polysorbitol transporter (PST) for an O. tsutsugamushi vaccine strategy. Two target proteins, 56-kDa type-specific Ag (TSA56) and surface cell Ag A (ScaA) were used as vaccine candidates. PST formed stable nano-size complexes with TSA56 (TSA56-PST) and ScaA (ScaA-PST); neither exhibited cytotoxicity. The formation of Ag-specific IgG2a, IgG2b, and IgA in mice was enhanced by intranasal vaccination with TSA56-PST or ScaA-PST. The vaccines containing PST induced Ag-specific proliferation of CD8⁺ and CD4⁺ T cells. Furthermore, the vaccines containing PST improved the mouse survival against O. tsutsugamushi infection. Collectively, the present study indicated that PST could enhance both Ag-specific humoral immunity and T cell response, which are essential to effectively confer protective immunity against O. tsutsugamushi infection. These findings suggest that PST has potential for use in an intranasal vaccination strategy.

• IMMUNE NETWORK
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• v.23 no.4
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• pp.34.1-34.15
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• 2023

Lung cancer, particularly non-small cell lung cancer (NSCLC) which contributes more than 80% to totally lung cancer cases, remains the leading cause of cancer death and the 5-year survival is less than 20%. Continuous understanding on the mechanisms underlying the pathogenesis of this disease and identification of biomarkers for therapeutic application and response to treatment will help to improve patient survival. Here we found that a molecule known as DUSP10 (also known as MAPK phosphatase 5) is oncogenic in NSCLC. Overexpression of DUSP10 in NSCLC cells resulted in reduced activation of ERK and JNK, but increased activation of p38, which was associated with increased cellular growth and migration. When inoculated in immunodeficient mice, the DUSP10-overexpression NSCLC cells formed larger tumors compared to control cells. The increased growth of DUSP10-overexpression NSCLC cells was associated with increased expression of tumor-promoting cytokines including IL-6 and TGFβ. Importantly, higher DUSP10 expression was associated with poorer prognosis of NSCLC patients. Therefore, DUSP10 could severe as a biomarker for NSCLC prognosis and could be a target for development of therapeutic method for lung cancer treatment.

• IMMUNE NETWORK
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• v.23 no.3
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• pp.25.1-25.17
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• 2023

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces excessive pro-inflammatory cytokine release and cell death, leading to organ damage and mortality. High-mobility group box 1 (HMGB1) is one of the damage-associated molecular patterns that can be secreted by pro-inflammatory stimuli, including viral infections, and its excessive secretion levels are related to a variety of inflammatory diseases. Here, the aim of the study was to show that SARS-CoV-2 infection induced HMGB1 secretion via active and passive release. Active HMGB1 secretion was mediated by post-translational modifications, such as acetylation, phosphorylation, and oxidation in HEK293E/ACE2-C-GFP and Calu-3 cells during SARS-CoV-2 infection. Passive release of HMGB1 has been linked to various types of cell death; however, we demonstrated for the first time that PANoptosis, which integrates other cell death pathways, including pyroptosis, apoptosis, and necroptosis, is related to passive HMGB1 release during SARS-CoV-2 infection. In addition, cytoplasmic translocation and extracellular secretion or release of HMGB1 were confirmed via immunohistochemistry and immunofluorescence in the lung tissues of humans and angiotensin-converting enzyme 2-overexpressing mice infected with SARS-CoV-2.