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  1. Article ; Online: Modulation of secretory factors by lipofundin contributes to its anti‑neuroinflammatory effects.

    Chen, Ming-Shan / Hu, Chia-Lin / Jiang, Shin-Kuang / Chong, Zhi-Yong / Chen, Jui-Chieh

    Experimental and therapeutic medicine

    2024  Volume 27, Issue 4, Page(s) 169

    Abstract: As the global population ages, the prevalence of neuroinflammatory diseases such as Alzheimer's disease, Parkinson's disease and stroke continues to increase. Therefore, it is necessary to develop preventive and therapeutic methods against ... ...

    Abstract As the global population ages, the prevalence of neuroinflammatory diseases such as Alzheimer's disease, Parkinson's disease and stroke continues to increase. Therefore, it is necessary to develop preventive and therapeutic methods against neuroinflammatory diseases. Lipofundin is a lipid emulsion commonly used in clinical anesthetic solvents and nutritional supplements. Lipid emulsions have been shown to possess anti-inflammatory properties. However, the potential beneficial effect of lipofundin against neuroinflammation requires elucidation. In the present study, two cell models were used to investigate the efficacy of lipofundin against neuroinflammation. In the first model, BV2 mouse microglial cells were treated with lipopolysaccharide (LPS) to induce nitric oxide (NO) production as a model of neuroinflammation. In the second model, HMC3 human microglial were activated by LPS, and changes in the secretion of factors associated with inflammation were analyzed using Luminex xMAP
    Language English
    Publishing date 2024-02-27
    Publishing country Greece
    Document type Journal Article
    ZDB-ID 2683844-8
    ISSN 1792-1015 ; 1792-0981
    ISSN (online) 1792-1015
    ISSN 1792-0981
    DOI 10.3892/etm.2024.12456
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Lidocaine attenuates TMZ resistance and inhibits cell migration by modulating the MET pathway in glioblastoma cells.

    Chen, Ming-Shan / Chong, Zhi-Yong / Huang, Cheng / Huang, Hsiu-Chen / Su, Pin-Hsuan / Chen, Jui-Chieh

    Oncology reports

    2024  Volume 51, Issue 5

    Abstract: Glioblastoma multiforme (GBM) is the most aggressive type of malignant brain tumor. Currently, the predominant clinical treatment is the combination of surgical resection with concurrent radiotherapy and chemotherapy, using temozolomide (TMZ) as the ... ...

    Abstract Glioblastoma multiforme (GBM) is the most aggressive type of malignant brain tumor. Currently, the predominant clinical treatment is the combination of surgical resection with concurrent radiotherapy and chemotherapy, using temozolomide (TMZ) as the primary chemotherapy drug. Lidocaine, a widely used amide‑based local anesthetic, has been found to have a significant anticancer effect. It has been reported that aberrant hepatocyte growth factor (HGF)/mesenchymal‑epithelial transition factor (MET) signaling plays a role in the progression of brain tumors. However, it remains unclear whether lidocaine can regulate the MET pathway in GBM. In the present study, the clinical importance of the HGF/MET pathway was analyzed using bioinformatics. By establishing TMZ‑resistant cell lines, the impact of combined treatment with lidocaine and TMZ was investigated. Additionally, the effects of lidocaine on cellular function were also examined and confirmed using knockdown techniques. The current findings revealed that the HGF/MET pathway played a key role in brain cancer, and its activation in GBM was associated with increased malignancy and poorer patient outcomes. Elevated HGF levels and activation of its receptor were found to be associated with TMZ resistance in GBM cells. Lidocaine effectively suppressed the HGF/MET pathway, thereby restoring TMZ sensitivity in TMZ‑resistant cells. Furthermore, lidocaine also inhibited cell migration. Overall, these results indicated that inhibiting the HGF/MET pathway using lidocaine can enhance the sensitivity of GBM cells to TMZ and reduce cell migration, providing a potential basis for developing novel therapeutic strategies for GBM.
    MeSH term(s) Humans ; Antineoplastic Agents, Alkylating/pharmacology ; Brain Neoplasms/drug therapy ; Brain Neoplasms/genetics ; Brain Neoplasms/metabolism ; Cell Line, Tumor ; Cell Movement ; Drug Resistance, Neoplasm ; Glioblastoma/drug therapy ; Glioblastoma/genetics ; Glioblastoma/metabolism ; Lidocaine/pharmacology ; Lidocaine/therapeutic use ; Signal Transduction ; Temozolomide/therapeutic use
    Chemical Substances Antineoplastic Agents, Alkylating ; Lidocaine (98PI200987) ; Temozolomide (YF1K15M17Y)
    Language English
    Publishing date 2024-04-12
    Publishing country Greece
    Document type Journal Article
    ZDB-ID 1222484-4
    ISSN 1791-2431 ; 1021-335X
    ISSN (online) 1791-2431
    ISSN 1021-335X
    DOI 10.3892/or.2024.8731
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: α-Viniferin-Induced Apoptosis through Downregulation of SIRT1 in Non-Small Cell Lung Cancer Cells.

    Huang, Cheng / Lin, Zi-Jun / Chen, Jui-Chieh / Zheng, Hao-Jun / Lai, Yu-Heng / Huang, Hsiu-Chen

    Pharmaceuticals (Basel, Switzerland)

    2023  Volume 16, Issue 5

    Abstract: α-Viniferin, a natural stilbene compound found in plants and a polymer of resveratrol, had demonstrated potential anti-cancer and anti-inflammatory effects. However, the specific mechanisms underlying its anti-cancer activity were not yet fully ... ...

    Abstract α-Viniferin, a natural stilbene compound found in plants and a polymer of resveratrol, had demonstrated potential anti-cancer and anti-inflammatory effects. However, the specific mechanisms underlying its anti-cancer activity were not yet fully understood and required further investigation. This study evaluated the effectiveness of α-viniferin and ε-viniferin using MTT assay. Results showed that α-viniferin was more effective than ε-viniferin in reducing the viability of NCI-H460 cells, a type of non-small cell lung cancer. Annexin V/7AAD assay results provided further evidence that the decrease in cell viability observed in response to α-viniferin treatment was due to the induction of apoptosis in NCI-H460 cells. The present findings indicated that treatment with α-viniferin could stimulate apoptosis in cells by cleaving caspase 3 and PARP. Moreover, the treatment reduced the expression of SIRT1, vimentin, and phosphorylated AKT, and also induced AIF nuclear translocation. Furthermore, this research provided additional evidence for the effectiveness of α-viniferin as an anti-tumor agent in nude mice with NCI-H460 cell xenografts. As demonstrated by the TUNEL assay results, α-viniferin promoted apoptosis in NCI-H460 cells in nude mice.
    Language English
    Publishing date 2023-05-10
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2193542-7
    ISSN 1424-8247
    ISSN 1424-8247
    DOI 10.3390/ph16050727
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: ADAM17 Confers Temozolomide Resistance in Human Glioblastoma Cells and miR-145 Regulates Its Expression.

    Yang, Jen-Tsung / Lee, I-Neng / Huang, Cheng / Huang, Hsiu-Chen / Wu, Yu-Ping / Chong, Zhi-Yong / Chen, Jui-Chieh

    International journal of molecular sciences

    2023  Volume 24, Issue 9

    Abstract: Glioblastoma (GBM) is a malignant brain tumor, commonly treated with temozolomide (TMZ). Upregulation of A disintegrin and metalloproteinases (ADAMs) is correlated to malignancy; however, whether ADAMs modulate TMZ sensitivity in GBM cells remains ... ...

    Abstract Glioblastoma (GBM) is a malignant brain tumor, commonly treated with temozolomide (TMZ). Upregulation of A disintegrin and metalloproteinases (ADAMs) is correlated to malignancy; however, whether ADAMs modulate TMZ sensitivity in GBM cells remains unclear. To explore the role of ADAMs in TMZ resistance, we analyzed changes in ADAM expression following TMZ treatment using RNA sequencing and noted that ADAM17 was markedly upregulated. Hence, we established TMZ-resistant cell lines to elucidate the role of ADAM17. Furthermore, we evaluated the impact of ADAM17 knockdown on TMZ sensitivity in vitro and in vivo. Moreover, we predicted microRNAs upstream of ADAM17 and transfected miRNA mimics into cells to verify their effects on TMZ sensitivity. Additionally, the clinical significance of ADAM17 and miRNAs in GBM was analyzed. ADAM17 was upregulated in GBM cells under serum starvation and TMZ treatment and was overexpressed in TMZ-resistant cells. In in vitro and in vivo models, ADAM17 knockdown conferred greater TMZ sensitivity. miR-145 overexpression suppressed ADAM17 and sensitized cells to TMZ. ADAM17 upregulation and miR-145 downregulation in clinical specimens are associated with disease progression and poor prognosis. Thus, miR-145 enhances TMZ sensitivity by inhibiting ADAM17. These findings offer insights into the development of therapeutic approaches to overcome TMZ resistance.
    MeSH term(s) Humans ; Temozolomide/pharmacology ; Temozolomide/therapeutic use ; Glioblastoma/drug therapy ; Glioblastoma/genetics ; Glioblastoma/pathology ; Cell Line, Tumor ; MicroRNAs/metabolism ; Down-Regulation ; Brain Neoplasms/pathology ; Drug Resistance, Neoplasm/genetics ; Gene Expression Regulation, Neoplastic ; Antineoplastic Agents, Alkylating/pharmacology ; Antineoplastic Agents, Alkylating/therapeutic use ; ADAM17 Protein/genetics ; ADAM17 Protein/metabolism
    Chemical Substances Temozolomide (YF1K15M17Y) ; MicroRNAs ; Antineoplastic Agents, Alkylating ; ADAM17 protein, human (EC 3.4.24.86) ; ADAM17 Protein (EC 3.4.24.86) ; MIRN145 microRNA, human
    Language English
    Publishing date 2023-04-22
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms24097703
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: MicroRNA-631 Resensitizes Doxorubicin-Resistant Chondrosarcoma Cells by Targeting Apelin.

    Chen, Jui-Chieh / Shih, Hsun-Chang / Lin, Chih-Yang / Guo, Jeng-Hung / Huang, Cheng / Huang, Hsiu-Chen / Chong, Zhi-Yong / Tang, Chih-Hsin

    International journal of molecular sciences

    2023  Volume 24, Issue 1

    Abstract: Chondrosarcoma is the second most common type of bone cancer. Surgical resection is the best choice for clinical treatment. High-grade chondrosarcoma is destructive and is more possible to metastasis, which is difficult to remove using surgery. ... ...

    Abstract Chondrosarcoma is the second most common type of bone cancer. Surgical resection is the best choice for clinical treatment. High-grade chondrosarcoma is destructive and is more possible to metastasis, which is difficult to remove using surgery. Doxorubicin (Dox) is the most commonly used chemotherapy drug in the clinical setting; however, drug resistance is a major obstacle to effective treatment. In the present study, we compared Dox-resistant SW1353 cells to their parental cells using RNA sequencing (RNA-Seq). We found that the apelin (APLN) pathway was highly activated in resistant cells. In addition, tissue array analysis also showed that APLN was higher in high-grade tissues compared to low-grade tissues. APLN is a member of the adipokine family, which is a novel secreted peptide with multifunctional and biological activities. Previously, studies have shown that inhibition of the APLN axis may have a therapeutic benefit in cancers. However, the role of APLN in chondrosarcoma is completely unclear, and no related studies have been reported. During in vitro experiments, APLN was also observed to be highly expressed and secreted in Dox-resistant cells. Once APLN was knocked down, it could effectively improve its sensitivity to Dox. We also explored possible upstream regulatory microRNAs (miRNAs) of APLN through bioinformatics tools and the results disclosed that miR-631 was the most likely regulator of APLN. Furthermore, the expression of miR-631 was lower in the resistant cells, but overexpression of miR-631 in the Dox-resistant cell lines significantly increased the Dox sensitivity. These results were also observed in another chondrosarcoma cell line, JJ012 cells. Taken together, these findings will provide rationale for the development of drug resistance biomarkers and therapeutic strategies for APLN pathway inhibitors to improve the survival of patients with chondrosarcoma.
    MeSH term(s) Humans ; Apelin/genetics ; Apelin/metabolism ; Bone Neoplasms/drug therapy ; Bone Neoplasms/genetics ; Bone Neoplasms/metabolism ; Chondrosarcoma/drug therapy ; Chondrosarcoma/genetics ; Chondrosarcoma/metabolism ; Doxorubicin/pharmacology ; Doxorubicin/therapeutic use ; MicroRNAs/genetics ; MicroRNAs/therapeutic use ; Drug Resistance, Neoplasm
    Chemical Substances Apelin ; Doxorubicin (80168379AG) ; MicroRNAs ; MIRN631 microRNA, human
    Language English
    Publishing date 2023-01-03
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms24010839
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Ergosterol peroxide blocks HDV infection as a novel entry inhibitor by targeting human NTCP receptor.

    Chiou, Wei-Chung / Lyu, Yi-Syuan / Hsia, Tzu-Lan / Chen, Jui-Chieh / Lin, Lie-Chwen / Chang, Ming-Fu / Hsu, Meng-Shiuan / Huang, Cheng

    Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

    2023  Volume 170, Page(s) 116077

    Abstract: Hepatitis D virus (HDV), which co-infects or superinfects patients with hepatitis B virus, is estimated to affect 74 million people worldwide. Chronic hepatitis D is the most severe form of viral hepatitis and can result in liver cirrhosis, liver failure, ...

    Abstract Hepatitis D virus (HDV), which co-infects or superinfects patients with hepatitis B virus, is estimated to affect 74 million people worldwide. Chronic hepatitis D is the most severe form of viral hepatitis and can result in liver cirrhosis, liver failure, and hepatocellular carcinoma (HCC). Currently, there are no efficient HDV-specific drugs. Therefore, there is an urgent need for novel HDV therapies that can achieve a functional cure or even eliminate the viral infection. In the HDV life cycle, agents targeting the entry step of HDV infection preemptively reduce the intrahepatic viral RNA. Human sodium taurocholate co-transporting polypeptide (hNTCP), a transporter of bile acids on the plasma membrane of hepatocytes, is an essential entry receptor of HDV and is a promising molecular target against HDV infection. Here, we investigated the effect of ergosterol peroxide (EP) on HDV infection in vitro and in vivo. EP inhibited HDV infection of hNTCP-expressing dHuS-E/2 hepatocytes by interrupting the early fusion/endocytosis step of HDV entry. Furthermore, molecular modeling suggested that EP hinders LHBsAg binding to hNTCP by blocking access to S267 and V263. In addition, we generated hNTCP-expressing transgenic (Tg) C57BL/6 mice using the Cre/loxP system for in vivo study. EP reduced the liver HDV RNA level of HDV-challenged hNTCP-Cre Tg mice. Intriguingly, EP downregulated the mRNA level of liver IFN-γ. We demonstrate that EP is a bona fide HDV entry inhibitor that acts on hNTCP and has the potential for use in HDV therapies.
    MeSH term(s) Mice ; Animals ; Humans ; Hepatitis Delta Virus/genetics ; Hepatitis Delta Virus/metabolism ; Carcinoma, Hepatocellular/drug therapy ; Carcinoma, Hepatocellular/metabolism ; Liver Neoplasms/metabolism ; Mice, Inbred C57BL ; Hepatitis D/drug therapy ; Hepatitis D/pathology ; Hepatitis B virus/physiology ; Hepatocytes ; Mice, Transgenic ; Symporters/metabolism
    Chemical Substances ergosterol-5,8-peroxide (UG9TN81TGH) ; Symporters
    Language English
    Publishing date 2023-12-28
    Publishing country France
    Document type Journal Article
    ZDB-ID 392415-4
    ISSN 1950-6007 ; 0753-3322 ; 0300-0893
    ISSN (online) 1950-6007
    ISSN 0753-3322 ; 0300-0893
    DOI 10.1016/j.biopha.2023.116077
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Significant Changes of Corneal Astigmatism After Levator Muscle Surgery for Acquired Blepharoptosis.

    Chen, Po-Jui / Lee, Yu-Kuei / Lai, Chun-Chieh

    Ophthalmic plastic and reconstructive surgery

    2024  

    Abstract: Purpose: To investigate the change of corneal astigmatism after the correction of blepharoptosis.: Methods: This was a single-center retrospective cohort study conducted in Taiwan from 2017 to 2021. The medical records of patients with acquired ... ...

    Abstract Purpose: To investigate the change of corneal astigmatism after the correction of blepharoptosis.
    Methods: This was a single-center retrospective cohort study conducted in Taiwan from 2017 to 2021. The medical records of patients with acquired blepharoptosis who had received levator muscle surgeries were collected. The differences in corneal astigmatism between the measurements before and at least 1 month after surgeries were investigated. Subgroup analysis of various severities of blepharoptosis and different types of corneal astigmatism was performed to determine their impacts on the axial changes after blepharoptosis surgeries.
    Results: A total of 120 eyes of 68 patients were enrolled in this study. The mean axial change of corneal astigmatism was 17.4° after blepharoptosis surgeries, and 55 eyes (45.8%) had a change of at least 10°. In the subgroup analysis, the eyes with against-the-rule, with-the-rule, and oblique astigmatism had 42.9%, 68.4%, and 91.7% with an axial change of at least 10° after surgeries, respectively. The averaged axial change of corneal astigmatism after surgeries was 22.7° in eyes with severe blepharoptosis (margin to reflex distance1 < 1 mm), whereas it was 12.0° in eyes with mild-to-moderate blepharoptosis (margin to reflex distance1 ≥ 1 mm).
    Conclusions: A high proportion of eyes had a crucial axial change in corneal astigmatism after blepharoptosis surgeries, especially in those with oblique astigmatism and severe blepharoptosis. For blepharoptosis patients needing refractive surgeries or astigmatism correction with toric intraocular lens implantation, a surgical correction of blepharoptosis may be considered beforehand.
    Language English
    Publishing date 2024-03-21
    Publishing country United States
    Document type Journal Article
    ZDB-ID 632830-1
    ISSN 1537-2677 ; 0740-9303
    ISSN (online) 1537-2677
    ISSN 0740-9303
    DOI 10.1097/IOP.0000000000002663
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: MicroRNA-631 Resensitizes Doxorubicin-Resistant Chondrosarcoma Cells by Targeting Apelin

    Jui-Chieh Chen / Hsun-Chang Shih / Chih-Yang Lin / Jeng-Hung Guo / Cheng Huang / Hsiu-Chen Huang / Zhi-Yong Chong / Chih-Hsin Tang

    International Journal of Molecular Sciences, Vol 24, Iss 1, p

    2023  Volume 839

    Abstract: Chondrosarcoma is the second most common type of bone cancer. Surgical resection is the best choice for clinical treatment. High-grade chondrosarcoma is destructive and is more possible to metastasis, which is difficult to remove using surgery. ... ...

    Abstract Chondrosarcoma is the second most common type of bone cancer. Surgical resection is the best choice for clinical treatment. High-grade chondrosarcoma is destructive and is more possible to metastasis, which is difficult to remove using surgery. Doxorubicin (Dox) is the most commonly used chemotherapy drug in the clinical setting; however, drug resistance is a major obstacle to effective treatment. In the present study, we compared Dox-resistant SW1353 cells to their parental cells using RNA sequencing (RNA-Seq). We found that the apelin (APLN) pathway was highly activated in resistant cells. In addition, tissue array analysis also showed that APLN was higher in high-grade tissues compared to low-grade tissues. APLN is a member of the adipokine family, which is a novel secreted peptide with multifunctional and biological activities. Previously, studies have shown that inhibition of the APLN axis may have a therapeutic benefit in cancers. However, the role of APLN in chondrosarcoma is completely unclear, and no related studies have been reported. During in vitro experiments, APLN was also observed to be highly expressed and secreted in Dox-resistant cells. Once APLN was knocked down, it could effectively improve its sensitivity to Dox. We also explored possible upstream regulatory microRNAs (miRNAs) of APLN through bioinformatics tools and the results disclosed that miR-631 was the most likely regulator of APLN. Furthermore, the expression of miR-631 was lower in the resistant cells, but overexpression of miR-631 in the Dox-resistant cell lines significantly increased the Dox sensitivity. These results were also observed in another chondrosarcoma cell line, JJ012 cells. Taken together, these findings will provide rationale for the development of drug resistance biomarkers and therapeutic strategies for APLN pathway inhibitors to improve the survival of patients with chondrosarcoma.
    Keywords chondrosarcoma ; doxorubicin ; apelin ; microRNA ; drug resistance ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 616
    Language English
    Publishing date 2023-01-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: α-Viniferin and ε-Viniferin Inhibited TGF-β1-Induced Epithelial-Mesenchymal Transition, Migration and Invasion in Lung Cancer Cells through Downregulation of Vimentin Expression.

    Chiou, Wei-Chung / Huang, Cheng / Lin, Zi-Jun / Hong, Lian-Sheng / Lai, Yu-Heng / Chen, Jui-Chieh / Huang, Hsiu-Chen

    Nutrients

    2022  Volume 14, Issue 11

    Abstract: Resveratrol has well-known anticancer properties; however, its oligomers, including α-viniferin, ε-viniferin, and kobophenol A, have not yet been well investigated. This is the first study examining the anti-epithelial-mesenchymal transition (EMT) ... ...

    Abstract Resveratrol has well-known anticancer properties; however, its oligomers, including α-viniferin, ε-viniferin, and kobophenol A, have not yet been well investigated. This is the first study examining the anti-epithelial-mesenchymal transition (EMT) effects of α-viniferin and ε-viniferin on A549, NCI-H460, NCI-H520, MCF-7, HOS, and U2OS cells. The results showed that α-viniferin and ε-viniferin significantly inhibited EMT, invasion and migration in TGF-β1- or IL-1β-induced non-small cell lung cancer. α-Viniferin and ε-viniferin also reversed TGF-β1-induced reactive oxygen species (ROS), MMP2, vimentin, Zeb1, Snail,
    MeSH term(s) Animals ; Benzofurans ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Cell Line, Tumor ; Cell Movement ; Down-Regulation ; Epithelial-Mesenchymal Transition ; Humans ; Lung Neoplasms/pathology ; Mice ; Stilbenes ; Transforming Growth Factor beta1/metabolism ; Vimentin/genetics ; Vimentin/metabolism
    Chemical Substances Benzofurans ; Stilbenes ; Transforming Growth Factor beta1 ; Vimentin ; epsilon-viniferin (62218-08-0) ; alpha-viniferin (62218-13-7)
    Language English
    Publishing date 2022-05-30
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2518386-2
    ISSN 2072-6643 ; 2072-6643
    ISSN (online) 2072-6643
    ISSN 2072-6643
    DOI 10.3390/nu14112294
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Identification of a novel interaction site between the large hepatitis delta antigen and clathrin that regulates the assembly of genotype III hepatitis delta virus.

    Chiou, Wei-Chung / Lu, Hsu-Feng / Chen, Jui-Chieh / Lai, Yu-Heng / Chang, Ming-Fu / Huang, Yuan-Li / Tien, Ni / Huang, Cheng

    Virology journal

    2022  Volume 19, Issue 1, Page(s) 163

    Abstract: Background: Hepatitis delta virus (HDV), a satellite virus of hepatitis B virus (HBV), is a small, defective RNA virus strongly associated with the most severe form of hepatitis and progressive chronic liver disease and cirrhosis. Chronic hepatitis D, ... ...

    Abstract Background: Hepatitis delta virus (HDV), a satellite virus of hepatitis B virus (HBV), is a small, defective RNA virus strongly associated with the most severe form of hepatitis and progressive chronic liver disease and cirrhosis. Chronic hepatitis D, resulting from HBV/HDV coinfection, is considered to be the most severe form of viral hepatitis and affects 12-20 million people worldwide. Involved in the endocytosis and exocytosis of cellular and viral proteins, clathrin contributes to the pathogenesis and morphogenesis of HDV. Previously, we demonstrated that HDV-I and -II large hepatitis delta antigens (HDAg-L) possess a putative clathrin box that interacts with clathrin heavy chain (CHC) and supports HDV assembly.
    Methods: Virus assembly and vesicular trafficking of HDV virus-like particles (VLPs) were evaluated in Huh7 cells expressing HDV-I, -II and -III HDAg-L and hepatitis B surface antigen (HBsAg). To elucidate the interaction motif between HDAg-L and CHC, site-directed mutagenesis was performed to introduce mutations into HDAg-L and CHC and analyzed using coimmunoprecipitation or pull-down assays.
    Results: Comparable to HDV-I virus-like particles (VLPs), HDV-III VLPs were produced at a similar level and secreted into the medium via clathrin-mediated post-Golgi vesicular trafficking. Mutation at F27 or E33 of CHC abolished the binding of CHC to the C-terminus of HDV-III HDAg-L. Mutation at W207 of HDV-III HDAg-L inhibited its association with CHC and interfered with HDV-III VLP formation. We elucidated mechanism of the binding of HDV-III HDAg-L to CHC and confirmed the pivotal role of clathrin binding in the assembly of genotype III HDV.
    Conclusions: A novel W box which was identified at the C terminus of HDV-III HDAg-L is known to differ from the conventional clathrin box but also interacts with CHC. The novel W box of HDAg-L constitutes a new molecular target for anti-HDV-III therapeutics.
    MeSH term(s) Clathrin/metabolism ; Clathrin Heavy Chains/genetics ; Clathrin Heavy Chains/metabolism ; Genotype ; Hepatitis B Surface Antigens/metabolism ; Hepatitis B virus/genetics ; Hepatitis Delta Virus/genetics ; Hepatitis delta Antigens/chemistry ; Hepatitis delta Antigens/genetics ; Hepatitis delta Antigens/metabolism ; Humans ; RNA, Viral/metabolism ; Viral Proteins/genetics ; Virus Replication
    Chemical Substances Clathrin ; Hepatitis B Surface Antigens ; Hepatitis delta Antigens ; RNA, Viral ; Viral Proteins ; hepatitis delta virus large antigen ; Clathrin Heavy Chains (114899-12-6)
    Language English
    Publishing date 2022-10-17
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2160640-7
    ISSN 1743-422X ; 1743-422X
    ISSN (online) 1743-422X
    ISSN 1743-422X
    DOI 10.1186/s12985-022-01866-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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