|
1
|
Zhang R, Wu Z, Wang H, Ji M, Shen T, Yang L, Li Y, Yu J, Huang Y, Li L, Xu Z, Sheng Y, Li X, Wang F, Xiao W. Structural optimization and pharmacological evaluation of diphenyl amine esters as anti-hepatocellular carcinoma agents by targeting TAR RNA-binding protein 2. Eur J Med Chem 2025; 291:117676. [PMID: 40279767 DOI: 10.1016/j.ejmech.2025.117676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 04/21/2025] [Accepted: 04/22/2025] [Indexed: 04/29/2025]
Abstract
Hepatocellular Carcinoma (HCC), a leading cause of cancer-related death in the world, urgently requires novel therapeutic strategies and drug targets. The TRBP-Dicer complex plays a critical role in miRNA biosynthesis, which can be regulated by small molecules to exert anti-cancer effects. This study presented the structural modification of the natural product (-)-Gomisin M1(GM), resulting in the synthesis of 37 derivatives with a diphenyl amine ester scaffold. Several of these derivatives exhibited enhanced modulation of miRNA biogenesis compared to GM. Notably, derivative 13j displayed improved binding affinity to TRBP and greater efficacy in modulating miRNA biosynthesis, as well as anti-HCC activity in vitro and in vivo. Further investigation revealed that 13j induced apoptosis and pyroptosis while inhibiting the epithelial-to-mesenchymal transition process in HCC cells. In terms of druggability, 13j possesses favorable drug-likeness and a promising safety profile. These findings provide a promising scaffold with potent activity and low toxicity, offering a foundation for the development of miRNA-based therapeutic strategies for HCC.
Collapse
Affiliation(s)
- Ruihan Zhang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Characteristic Plant Extraction Laboratory; Yunnan Key Laboratory of Research and Development for Natural Products; School of Chemical Science and Technology; School of Pharmacy, Yunnan University, Kunming, 650500, China
| | - Zhao Wu
- Center for the Utilization of Biological Resources, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Hairong Wang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Characteristic Plant Extraction Laboratory; Yunnan Key Laboratory of Research and Development for Natural Products; School of Chemical Science and Technology; School of Pharmacy, Yunnan University, Kunming, 650500, China
| | - Minghui Ji
- Center for the Utilization of Biological Resources, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Tianze Shen
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Characteristic Plant Extraction Laboratory; Yunnan Key Laboratory of Research and Development for Natural Products; School of Chemical Science and Technology; School of Pharmacy, Yunnan University, Kunming, 650500, China
| | - Linhan Yang
- Center for the Utilization of Biological Resources, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yiming Li
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Characteristic Plant Extraction Laboratory; Yunnan Key Laboratory of Research and Development for Natural Products; School of Chemical Science and Technology; School of Pharmacy, Yunnan University, Kunming, 650500, China
| | - Jialing Yu
- Center for the Utilization of Biological Resources, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yinqiao Huang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Characteristic Plant Extraction Laboratory; Yunnan Key Laboratory of Research and Development for Natural Products; School of Chemical Science and Technology; School of Pharmacy, Yunnan University, Kunming, 650500, China
| | - Lingyu Li
- Center for the Utilization of Biological Resources, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Zihan Xu
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Characteristic Plant Extraction Laboratory; Yunnan Key Laboratory of Research and Development for Natural Products; School of Chemical Science and Technology; School of Pharmacy, Yunnan University, Kunming, 650500, China
| | - Yuwen Sheng
- Center for the Utilization of Biological Resources, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, China
| | - Xiaoli Li
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Characteristic Plant Extraction Laboratory; Yunnan Key Laboratory of Research and Development for Natural Products; School of Chemical Science and Technology; School of Pharmacy, Yunnan University, Kunming, 650500, China
| | - Fei Wang
- Center for the Utilization of Biological Resources, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, China.
| | - Weilie Xiao
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Characteristic Plant Extraction Laboratory; Yunnan Key Laboratory of Research and Development for Natural Products; School of Chemical Science and Technology; School of Pharmacy, Yunnan University, Kunming, 650500, China.
| |
Collapse
|
|
2
|
Benton A, Liu B, Gartenhaus LE, Hanna JA. Genomic landscape and preclinical models of angiosarcoma. Mol Oncol 2025; 19:965-983. [PMID: 39367667 PMCID: PMC11977660 DOI: 10.1002/1878-0261.13744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 09/03/2024] [Accepted: 09/24/2024] [Indexed: 10/06/2024] Open
Abstract
Angiosarcoma is a cancer that develops in blood or lymphatic vessels that presents a significant clinical challenge due to its rarity and aggressive features. Clinical outcomes have not improved in decades, highlighting a need for innovative therapeutic strategies to treat the disease. Genetically, angiosarcomas exhibit high heterogeneity and complexity with many recurrent mutations. However, recent studies have identified some common features within anatomic and molecular subgroups. To identify potential therapeutic vulnerabilities, it is essential to understand and integrate the mutational landscape of angiosarcoma with the models that exist to study the disease. In this review, we will summarize the insights gained from reported genomic alterations in molecular and anatomic subtypes of angiosarcoma, discuss several potential actionable targets, and highlight the preclinical disease models available in the field.
Collapse
Affiliation(s)
- Annaleigh Benton
- Department of Biological SciencesPurdue UniversityWest LafayetteINUSA
- Purdue University Institute for Cancer ResearchPurdue UniversityWest LafayetteINUSA
| | - Bozhi Liu
- Department of Biological SciencesPurdue UniversityWest LafayetteINUSA
- Purdue University Institute for Cancer ResearchPurdue UniversityWest LafayetteINUSA
| | - Lauren E. Gartenhaus
- Department of Biological SciencesPurdue UniversityWest LafayetteINUSA
- Purdue University Institute for Cancer ResearchPurdue UniversityWest LafayetteINUSA
| | - Jason A. Hanna
- Department of Biological SciencesPurdue UniversityWest LafayetteINUSA
- Purdue University Institute for Cancer ResearchPurdue UniversityWest LafayetteINUSA
| |
Collapse
|
|
3
|
Schlösser V, Lightfoot HL, Leemann C, Bejoy AM, Tiwari S, Schloßhauer JL, Vongrad V, Brunschweiger A, Hall J, Metzner KJ, Imig J. Anti-HIV-1 Effect of the Fluoroquinolone Enoxacin and Modulation of Pro-Viral hsa-miR-132 Processing in CEM-SS Cells. Noncoding RNA 2025; 11:8. [PMID: 39846686 PMCID: PMC11755467 DOI: 10.3390/ncrna11010008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Revised: 01/06/2025] [Accepted: 01/13/2025] [Indexed: 01/24/2025] Open
Abstract
BACKGROUND Despite tremendous advances in antiretroviral therapy (ART) against HIV-1 infections, no cure or vaccination is available. Therefore, discovering novel therapeutic strategies remains an urgent need. In that sense, miRNAs and miRNA therapeutics have moved intensively into the focus of recent HIV-1-related investigations. A strong reciprocal interdependence has been demonstrated between HIV-1 infection and changes of the intrinsic cellular miRNA milieu. This interrelationship may direct potential alterations of the host cells' environment beneficial for the virus or its suppression of replication. Whether this tightly balanced and controlled battle can be exploited therapeutically remains to be further addressed. In this context, the fluoroquinolone antibiotic Enoxacin has been demonstrated as a potent modulator of miRNA processing. Here, we test the hypothesis that this applies also to selected HIV-1-related miRNAs. METHODS We studied the effect of Enoxacin on HIV-1 replication coupled with miRNA qRT-PCR analysis of HIV-1-related miRNAs in CEM-SS and MT-4 T-cells. The effects of miRNA mimic transfections combined with Enoxacin treatment on HIV-1 replication were assessed. Finally, we employed an in vitro DICER1 cleavage assay to study the effects of Enoxacin on a pro-HIV-1 miRNA hsa-miR-132 processing. RESULTS We established that Enoxacin, but not the structurally similar compound nalidixic acid, exhibits strong anti-HIV-1 effects in the T-cell line CEM-SS, but not MT-4. We provide experimental data that this effect of Enoxacin is partly attributed to the specific downregulation of mature hsa-miR-132-3p, but not other tested pro- or anti-HIV-1 miRNAs, which is likely due to affecting DICER1 processing. CONCLUSIONS Our findings show an anti-retroviral activity of Enoxacin at least in part by downregulation of hsa-miR-132-3p, which may be relevant for future antiviral therapeutic applications by modulation of the RNA interference pathway.
Collapse
Affiliation(s)
- Verena Schlösser
- Institute of Pharmaceutical Sciences, ETH Zurich, 8093 Zurich, Switzerland
| | | | - Christine Leemann
- Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland
- Institute of Medical Virology, University of Zurich, 8057 Zurich, Switzerland
| | - Aathma Merin Bejoy
- Max Planck Institute of Molecular Physiology, Chemical Genomics Centre, 44227 Dortmund, Germany
| | - Shashank Tiwari
- Max Planck Institute of Molecular Physiology, Chemical Genomics Centre, 44227 Dortmund, Germany
| | - Jeffrey L. Schloßhauer
- Max Planck Institute of Molecular Physiology, Chemical Genomics Centre, 44227 Dortmund, Germany
| | - Valentina Vongrad
- Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland
- Institute of Medical Virology, University of Zurich, 8057 Zurich, Switzerland
| | - Andreas Brunschweiger
- Institute of Pharmaceutical Sciences, ETH Zurich, 8093 Zurich, Switzerland
- Department of Pharmaceutical and Medicinal Chemistry, University Würzburg, 97074 Würzburg, Germany
| | - Jonathan Hall
- Institute of Pharmaceutical Sciences, ETH Zurich, 8093 Zurich, Switzerland
| | - Karin J. Metzner
- Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland
- Institute of Medical Virology, University of Zurich, 8057 Zurich, Switzerland
| | - Jochen Imig
- Institute of Pharmaceutical Sciences, ETH Zurich, 8093 Zurich, Switzerland
- Max Planck Institute of Molecular Physiology, Chemical Genomics Centre, 44227 Dortmund, Germany
| |
Collapse
|
|
4
|
Sergi CM, Minervini F. DICER1: The Argonaute Endonuclease Family Member and Its Role in Pediatric and Youth Pathology. BIOLOGY 2025; 14:93. [PMID: 39857323 PMCID: PMC11761906 DOI: 10.3390/biology14010093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 01/06/2025] [Accepted: 01/15/2025] [Indexed: 01/27/2025]
Abstract
In 2001, two enzyme-encoding genes were recognized in the fruit fly Drosophila melanogaster. The genetic material, labeled Dicer-1 and Dicer-2, encodes ribonuclease-type enzymes with slightly diverse target substrates. The human orthologue is DICER1. It is a gene, which has been positioned on chromosome 14q32.13. It contains 27 exons, which are linking the two enzyme domains. DICER1 is found in all organ systems. It has been proved that it is paramount in human development. The protein determined by DICER1 is a ribonuclease (RNase). This RNase belongs to the RNase III superfamily, formally known as 'endoribonuclease'. It has been determined that the function of RNase III proteins is set to identify and degrade double-stranded molecules of RNA. DICER1 is a vital "housekeeping" gene. The multi-domain enzyme is key for small RNA processing. This enzyme functions in numerous pathways, including RNA interference paths, DNA damage renovation, and response to viruses. At the protein level, DICER is also involved in several human diseases, of which the pleuro-pulmonary blastoma is probably the most egregious entity. Numerous studies have determined the full range of DICER1 functions and the corresponding relationship to tumorigenic and non-neoplastic diseases. In fact, genetic mutations (somatic and germline) have been detected in DICER1 and are genetically associated with at least two clinical syndromes: DICER1 syndrome and GLOW syndrome. The ubiquity of this enzyme in the human body makes it an exquisite target for nanotechnology-supported therapies and repurposing drug approaches.
Collapse
Affiliation(s)
- Consolato M. Sergi
- Division of Anatomic Pathology, Children’s Hospital of Eastern Ontario, Ottawa, ON K1H 8L1, Canada
- Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, ON K1N 6N5, Canada
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB T6G 2B7, Canada
| | - Fabrizio Minervini
- Division of Thoracic Surgery, Cantonal Hospital Lucerne, 6000 Lucerne, Switzerland;
| |
Collapse
|
|
5
|
Shi H, Yu J, Li L, Ji M, Li R, Peng T, Cheng Y, Wang T, Yang L, Wu Z, Zhang G, Wang F, Lu X. Design, Synthesis, and Antitumor Activity Evaluation of 2-Phenylthiazole-5-Carboxylic Acid Derivatives Targeting Transactivation Response RNA-Binding Protein 2. J Med Chem 2025; 68:421-447. [PMID: 39722648 DOI: 10.1021/acs.jmedchem.4c02041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2024]
Abstract
Transactivation response (TAR) RNA-binding protein 2 (TRBP) plays a critical role in microRNA (miRNA) biosynthesis, with aberrant expression linked to various cancers. Previously, we identified CIB-3b, a phenyloxazole derivative that disrupts the TRBP-Dicer interaction in hepatocellular carcinoma (HCC). In this study, we optimized this scaffold and substituent, leading to the discovery of CIB-L43, a 2-phenylthiazole-5-carboxylic acid derivative with nanomolar inhibitory activity (EC50 = 0.66 nM). CIB-L43 demonstrated superior TRBP binding affinity (KD = 4.78 nM) and enhanced disruption of TRBP-Dicer interactions (IC50 = 2.34 μM). Mechanistically, CIB-L43 suppressed oncogenic miR-21 biosynthesis, increasing PTEN and Smad7 expression and inhibiting AKT and TGF-β signaling, thereby reducing HCC cell proliferation and migration. In vivo, CIB-L43 exhibited favorable pharmacokinetics, including 53.9% oral bioavailability, and comparable antitumor efficacy to first-line anticancer drug, sorafenib, with lower toxicity. CIB-L43 emerges as a promising HCC treatment candidate with potent TRBP inhibition and favorable drug-like properties.
Collapse
Affiliation(s)
- Hailong Shi
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jialing Yu
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Lingyu Li
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Minghui Ji
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Runze Li
- Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 611731, China
| | - Ting Peng
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
- Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu 610052, China
| | - Yao Cheng
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Tao Wang
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Linhan Yang
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Zhao Wu
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Guolin Zhang
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
| | - Fei Wang
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
| | - Xiaoxia Lu
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
| |
Collapse
|
|
6
|
Ji M, Li L, Yu J, Wu Z, Sheng Y, Wang F. New insights into the function and therapeutic potential of RNA-binding protein TRBP in viral infection, chronic metabolic diseases, brain disorders and cancer. Life Sci 2024; 358:123159. [PMID: 39447729 DOI: 10.1016/j.lfs.2024.123159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 10/12/2024] [Accepted: 10/16/2024] [Indexed: 10/26/2024]
Abstract
RNA-binding proteins (RBPs) and non-coding RNAs are crucial trans-acting factors that bind to specific cis-acting elements in mRNAs, thereby regulating their stability and translation. The trans-activation response (TAR) RNA-binding protein (TRBP) recognizes precursor microRNAs (pre-miRNAs), modulates miRNA maturation, and influences miRNA interference (mi-RNAi) mediated by the RNA-induced silencing complex (RISC). TRBP also directly binds and mediates the degradation of certain mRNAs. Thus, TRBP acts as a hub for regulating gene expression and influences a variety of biological processes, including immune evasion, metabolic abnormalities, stress response, angiogenesis, hypoxia, and metastasis. Aberrant TRBP expression has been proven to be closely related to the initiation and progression of diseases, such as viral infection, chronic metabolic diseases, brain disorders, and cancer. This review summarizes the roles of TRBP in cancer and other diseases, the therapeutic potential of TRBP inhibition, and the current status of drug discovery on TRBP.
Collapse
Affiliation(s)
- Minghui Ji
- Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Lingyu Li
- Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jialing Yu
- Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Zhao Wu
- Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yuwen Sheng
- Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
| | - Fei Wang
- Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.
| |
Collapse
|
|
7
|
Sarma S, Thakur N, Varshney N, Jha HC, Sarma TK. Chromatin inspired bio-condensation between biomass DNA and guanosine monophosphate produces all-nucleic hydrogel as a hydrotropic drug carrier. Commun Chem 2024; 7:261. [PMID: 39533097 PMCID: PMC11557961 DOI: 10.1038/s42004-024-01353-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 11/01/2024] [Indexed: 11/16/2024] Open
Abstract
The integration of biomolecules into supramolecular nanostructures forms the basis of the natural world. Naturally occurring liquid-liquid phase separation resulting in biomolecular condensates has inspired the formation of biomolecule-based smart materials with multi-dimensional applications. A non-covalent bio-condensation between biomass DNA and guanosine monophosphate (GMP) has been described, mimicking chromatin folding and creating a unique "all-nucleic" DNA-GMP condensates. These condensates initiate the formation of G-quadruplex-based superstructures, assembling into super-helical fibres driven by synergistic hydrogen bonding and stacking, which have been thoroughly investigated. This simple, one-step method for the bio-condensation of biomass DNA leads to an "all-nucleic" hydrogel with higher-order self-assembly and excellent mechanical properties. While most of the reported DNA based biomaterials, including hydrogels, require precisely sequenced and molecularly architectured DNA building blocks, we have developed a simple, universal, and facile bio-condensation method that utilizes biomass DNA acquired from any bio-resource to fabricate DNA hydrogels. The hydrogel efficiently encapsulates and sustains the release of both hydrophilic and hydrophobic drugs, demonstrating its competency as a drug carrier. We believe this energy-efficient and low-cost method represents a new technique for using biomass DNA as building blocks for the next generation of soft materials.
Collapse
Affiliation(s)
- Suryakamal Sarma
- Department of Chemistry, Indian Institute of Technology Indore, Indore, India
| | - Neha Thakur
- Developmental Bioengineering, TechMed Centre, University of Twente. Drienerlolaan 5, Enschede, The Netherlands
| | - Nidhi Varshney
- Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, India
| | - Hem Chandra Jha
- Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, India
| | - Tridib K Sarma
- Department of Chemistry, Indian Institute of Technology Indore, Indore, India.
| |
Collapse
|
|
8
|
Felicetti T, Di Iacovo N, Della Fazia MA, Piobbico D, Pieroni S, Pacetti M, Yu J, Sun Y, Massari S, Barreca ML, Sabatini S, Tabarrini O, Cecchetti V, Wang F, Pommier Y, Morlando M, Servillo G, Manfroni G. New anti-ovarian cancer quinolone derivatives acting by modulating microRNA processing machinery. RSC Med Chem 2024; 16:d4md00649f. [PMID: 39399313 PMCID: PMC11467779 DOI: 10.1039/d4md00649f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Accepted: 09/26/2024] [Indexed: 10/15/2024] Open
Abstract
MicroRNAs (miRNAs) play a crucial role in ovarian cancer (OC) pathogenesis and miRNA processing can be the object of pharmacological intervention. By exploiting our in-house quinolone library, we combined a cell-based screening with medicinal chemistry efforts, ultimately leading to derivative 33 with anti-OC activity against distinct cell lines (GI50 values 13.52-31.04 μM) and CC50 Wi-38 = 142.9 μM. Compound 33 retained anticancer activity against additional cancer cells and demonstrated a synergistic effect with cisplatin against cisplatin-resistant A2780 cells. Compound 33 bound TRBP by SPR (K D = 4.09 μM) and thermal shift assays and its activity was TRBP-dependent, leading to modulation of siRNA and miRNA maturation. Derivative 33 exhibited augmented potency against OC cells and a stronger binding affinity for TRBP compared to enoxacin, the sole quinolone identified as a modulator of miRNA maturation. Consequently, 33 represents a promising template for developing novel anti-OC agents with a distinctive mechanism of action.
Collapse
Affiliation(s)
- Tommaso Felicetti
- Department of Pharmaceutical Sciences, Section of Chemistry and Pharmaceutical Technology, University of Perugia Via Del Liceo 1-06123 Perugia Italy +39 06 4991 2341 +39 075 585 5126
| | - Nicola Di Iacovo
- Department of Medicine and Surgery, University of Perugia Piazza L. Severi 1/8-06132 Perugia Italy +39 075 585 8110
| | - Maria Agnese Della Fazia
- Department of Medicine and Surgery, University of Perugia Piazza L. Severi 1/8-06132 Perugia Italy +39 075 585 8110
| | - Danilo Piobbico
- Department of Medicine and Surgery, University of Perugia Piazza L. Severi 1/8-06132 Perugia Italy +39 075 585 8110
| | - Stefania Pieroni
- Department of Medicine and Surgery, University of Perugia Piazza L. Severi 1/8-06132 Perugia Italy +39 075 585 8110
| | - Martina Pacetti
- Department of Pharmaceutical Sciences, Section of Chemistry and Pharmaceutical Technology, University of Perugia Via Del Liceo 1-06123 Perugia Italy +39 06 4991 2341 +39 075 585 5126
| | - Jialing Yu
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences Chengdu 610041 China
| | - Yilun Sun
- Center for Cancer Research, Developmental Therapeutics Branch & Laboratory of Molecular Pharmacology, NCI 31 Center Drive Bethesda MD 20892-4255 USA
| | - Serena Massari
- Department of Pharmaceutical Sciences, Section of Chemistry and Pharmaceutical Technology, University of Perugia Via Del Liceo 1-06123 Perugia Italy +39 06 4991 2341 +39 075 585 5126
| | - Maria Letizia Barreca
- Department of Pharmaceutical Sciences, Section of Chemistry and Pharmaceutical Technology, University of Perugia Via Del Liceo 1-06123 Perugia Italy +39 06 4991 2341 +39 075 585 5126
| | - Stefano Sabatini
- Department of Pharmaceutical Sciences, Section of Chemistry and Pharmaceutical Technology, University of Perugia Via Del Liceo 1-06123 Perugia Italy +39 06 4991 2341 +39 075 585 5126
| | - Oriana Tabarrini
- Department of Pharmaceutical Sciences, Section of Chemistry and Pharmaceutical Technology, University of Perugia Via Del Liceo 1-06123 Perugia Italy +39 06 4991 2341 +39 075 585 5126
| | - Violetta Cecchetti
- Department of Pharmaceutical Sciences, Section of Chemistry and Pharmaceutical Technology, University of Perugia Via Del Liceo 1-06123 Perugia Italy +39 06 4991 2341 +39 075 585 5126
| | - Fei Wang
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences Chengdu 610041 China
| | - Yves Pommier
- Center for Cancer Research, Developmental Therapeutics Branch & Laboratory of Molecular Pharmacology, NCI 31 Center Drive Bethesda MD 20892-4255 USA
| | - Mariangela Morlando
- Department of Pharmaceutical Sciences, Section of Chemistry and Pharmaceutical Technology, University of Perugia Via Del Liceo 1-06123 Perugia Italy +39 06 4991 2341 +39 075 585 5126
| | - Giuseppe Servillo
- Department of Medicine and Surgery, University of Perugia Piazza L. Severi 1/8-06132 Perugia Italy +39 075 585 8110
| | - Giuseppe Manfroni
- Department of Pharmaceutical Sciences, Section of Chemistry and Pharmaceutical Technology, University of Perugia Via Del Liceo 1-06123 Perugia Italy +39 06 4991 2341 +39 075 585 5126
| |
Collapse
|
|
9
|
Jurj A, Fontana B, Varani G, Calin GA. Small molecules targeting microRNAs: new opportunities and challenges in precision cancer therapy. Trends Cancer 2024; 10:809-824. [PMID: 39107162 PMCID: PMC11961049 DOI: 10.1016/j.trecan.2024.06.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 06/17/2024] [Accepted: 06/20/2024] [Indexed: 08/09/2024]
Abstract
Noncoding RNAs, especially miRNAs, play a pivotal role in cancer initiation and metastasis, underscoring their susceptibility to precise modulation via small molecule inhibitors. This review examines the innovative strategy of targeting oncogenic miRNAs with small drug-like molecules, an approach that can reshape the cancer treatment landscape. We review the current understanding of the multifaceted roles of miRNAs in oncogenesis, highlighting emerging therapeutic paradigms that have the potential to expand cancer treatment options. As research on small molecule inhibitors of miRNA is still in its early stages, ongoing investigative efforts and the development of new technologies and chemical matter are essential to fulfill the significant potential of this innovative approach to cancer treatment.
Collapse
Affiliation(s)
- Ancuta Jurj
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Beatrice Fontana
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Gabriele Varani
- Department of Chemistry, University of Washington, Seattle, WA 98195, USA.
| | - George A Calin
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| |
Collapse
|
|
10
|
Fang Y, Wu Q, Wang F, Liu Y, Zhang H, Yang C, Zhu Z. Aptamer-RIBOTAC Strategy Enabling Tumor-Specific Targeted Degradation of MicroRNA for Precise Cancer Therapy. SMALL METHODS 2024:e2400349. [PMID: 38794853 DOI: 10.1002/smtd.202400349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 05/08/2024] [Indexed: 05/26/2024]
Abstract
MicroRNA (miRNA) molecules play crucial roles in a variety of diseases, making miRNA targeting a burgeoning field in medicinal chemistry. Ribonuclease targeting chimeras (RIBOTACs) present a compelling approach for RNA degradation. However, small molecule-based RIBOTAC requires an expensive and time-consuming screening process, and is difficult to directly target miRNA due to its short length lacking secondary structure. Antisense oligonucleotide (ASO)-based RIBOTAC is easy to design but with poor cell permeability. While both of them lack the specificity for tumor targeting. In this study, the first Aptamer-RIBOTAC (ARIBOTAC) chimera is designed based on ASO to achieve precise degradation of miRNA in a tumor cell-specific manner for precise cancer therapy. This chimera exhibits a remarkable ability to specifically identify and enter cancer cells, trigger localized activation of endogenous RNase L, and selectively cleave miRNAs that are complementary to ASO. The efficacy and universality of the ARIBOTAC strategy both in vitro and in vivo by degrading oncogenic miR-210-3p and miR-155-5p are validated. These findings underscore the potential of the ARIBOTAC strategy as a promising avenue for cancer therapy by precisely targeting cancer-associated miRNAs.
Collapse
Affiliation(s)
- Yuan Fang
- MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Key Laboratory for Chemical Biology of Fujian Province, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361000, China
| | - Qiuyue Wu
- MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Key Laboratory for Chemical Biology of Fujian Province, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361000, China
| | - Feiyu Wang
- MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Key Laboratory for Chemical Biology of Fujian Province, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361000, China
| | - Ye Liu
- MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Key Laboratory for Chemical Biology of Fujian Province, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361000, China
| | - Huimin Zhang
- Innovation Laboratory for Sciences, Technologies of Energy Materials of Fujian Province, Xiamen, 361000, China
| | - Chaoyong Yang
- MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Key Laboratory for Chemical Biology of Fujian Province, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361000, China
- Innovation Laboratory for Sciences, Technologies of Energy Materials of Fujian Province, Xiamen, 361000, China
| | - Zhi Zhu
- MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Key Laboratory for Chemical Biology of Fujian Province, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361000, China
| |
Collapse
|
|
11
|
Seo Y, Rhim J, Kim JH. RNA-binding proteins and exoribonucleases modulating miRNA in cancer: the enemy within. Exp Mol Med 2024; 56:1080-1106. [PMID: 38689093 PMCID: PMC11148060 DOI: 10.1038/s12276-024-01224-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 02/20/2024] [Accepted: 02/25/2024] [Indexed: 05/02/2024] Open
Abstract
Recent progress in the investigation of microRNA (miRNA) biogenesis and the miRNA processing machinery has revealed previously unknown roles of posttranscriptional regulation in gene expression. The molecular mechanistic interplay between miRNAs and their regulatory factors, RNA-binding proteins (RBPs) and exoribonucleases, has been revealed to play a critical role in tumorigenesis. Moreover, recent studies have shown that the proliferation of hepatocellular carcinoma (HCC)-causing hepatitis C virus (HCV) is also characterized by close crosstalk of a multitude of host RBPs and exoribonucleases with miR-122 and its RNA genome, suggesting the importance of the mechanistic interplay among these factors during the proliferation of HCV. This review primarily aims to comprehensively describe the well-established roles and discuss the recently discovered understanding of miRNA regulators, RBPs and exoribonucleases, in relation to various cancers and the proliferation of a representative cancer-causing RNA virus, HCV. These have also opened the door to the emerging potential for treating cancers as well as HCV infection by targeting miRNAs or their respective cellular modulators.
Collapse
Affiliation(s)
- Yoona Seo
- Cancer Molecular Biology Branch, Research Institute, National Cancer Center, Goyang, 10408, Korea
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, 10408, Korea
| | - Jiho Rhim
- Cancer Molecular Biology Branch, Research Institute, National Cancer Center, Goyang, 10408, Korea
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, 10408, Korea
| | - Jong Heon Kim
- Cancer Molecular Biology Branch, Research Institute, National Cancer Center, Goyang, 10408, Korea.
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, 10408, Korea.
| |
Collapse
|
|
12
|
To KKW, Huang Z, Zhang H, Ashby CR, Fu L. Utilizing non-coding RNA-mediated regulation of ATP binding cassette (ABC) transporters to overcome multidrug resistance to cancer chemotherapy. Drug Resist Updat 2024; 73:101058. [PMID: 38277757 DOI: 10.1016/j.drup.2024.101058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 12/27/2023] [Accepted: 01/16/2024] [Indexed: 01/28/2024]
Abstract
Multidrug resistance (MDR) is one of the primary factors that produces treatment failure in patients receiving cancer chemotherapy. MDR is a complex multifactorial phenomenon, characterized by a decrease or abrogation of the efficacy of a wide spectrum of anticancer drugs that are structurally and mechanistically distinct. The overexpression of the ATP-binding cassette (ABC) transporters, notably ABCG2 and ABCB1, are one of the primary mediators of MDR in cancer cells, which promotes the efflux of certain chemotherapeutic drugs from cancer cells, thereby decreasing or abolishing their therapeutic efficacy. A number of studies have suggested that non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), play a pivotal role in mediating the upregulation of ABC transporters in certain MDR cancer cells. This review will provide updated information about the induction of ABC transporters due to the aberrant regulation of ncRNAs in cancer cells. We will also discuss the measurement and biological profile of circulating ncRNAs in various body fluids as potential biomarkers for predicting the response of cancer patients to chemotherapy. Sequence variations, such as alternative polyadenylation of mRNA and single nucleotide polymorphism (SNPs) at miRNA target sites, which may indicate the interaction of miRNA-mediated gene regulation with genetic variations to modulate the MDR phenotype, will be reviewed. Finally, we will highlight novel strategies that could be used to modulate ncRNAs and circumvent ABC transporter-mediated MDR.
Collapse
Affiliation(s)
- Kenneth K W To
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region.
| | - Zoufang Huang
- Department of Hematology, The First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China
| | - Hang Zhang
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Charles R Ashby
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, United States
| | - Liwu Fu
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
| |
Collapse
|
|
13
|
Seyhan AA. Trials and Tribulations of MicroRNA Therapeutics. Int J Mol Sci 2024; 25:1469. [PMID: 38338746 PMCID: PMC10855871 DOI: 10.3390/ijms25031469] [Citation(s) in RCA: 85] [Impact Index Per Article: 85.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 01/15/2024] [Accepted: 01/17/2024] [Indexed: 02/12/2024] Open
Abstract
The discovery of the link between microRNAs (miRNAs) and a myriad of human diseases, particularly various cancer types, has generated significant interest in exploring their potential as a novel class of drugs. This has led to substantial investments in interdisciplinary research fields such as biology, chemistry, and medical science for the development of miRNA-based therapies. Furthermore, the recent global success of SARS-CoV-2 mRNA vaccines against the COVID-19 pandemic has further revitalized interest in RNA-based immunotherapies, including miRNA-based approaches to cancer treatment. Consequently, RNA therapeutics have emerged as highly adaptable and modular options for cancer therapy. Moreover, advancements in RNA chemistry and delivery methods have been pivotal in shaping the landscape of RNA-based immunotherapy, including miRNA-based approaches. Consequently, the biotechnology and pharmaceutical industry has witnessed a resurgence of interest in incorporating RNA-based immunotherapies and miRNA therapeutics into their development programs. Despite substantial progress in preclinical research, the field of miRNA-based therapeutics remains in its early stages, with only a few progressing to clinical development, none reaching phase III clinical trials or being approved by the US Food and Drug Administration (FDA), and several facing termination due to toxicity issues. These setbacks highlight existing challenges that must be addressed for the broad clinical application of miRNA-based therapeutics. Key challenges include establishing miRNA sensitivity, specificity, and selectivity towards their intended targets, mitigating immunogenic reactions and off-target effects, developing enhanced methods for targeted delivery, and determining optimal dosing for therapeutic efficacy while minimizing side effects. Additionally, the limited understanding of the precise functions of miRNAs limits their clinical utilization. Moreover, for miRNAs to be viable for cancer treatment, they must be technically and economically feasible for the widespread adoption of RNA therapies. As a result, a thorough risk evaluation of miRNA therapeutics is crucial to minimize off-target effects, prevent overdosing, and address various other issues. Nevertheless, the therapeutic potential of miRNAs for various diseases is evident, and future investigations are essential to determine their applicability in clinical settings.
Collapse
Affiliation(s)
- Attila A. Seyhan
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI 02912, USA;
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI 02912, USA
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, RI 02912, USA
- Legorreta Cancer Center, Brown University, Providence, RI 02912, USA
| |
Collapse
|
|
14
|
Paudel B, Jeong SY, Martinez CP, Rickman A, Haluck-Kangas A, Bartom ET, Fredriksen K, Affaneh A, Kessler JA, Mazzulli JR, Murmann AE, Rogalski E, Geula C, Ferreira A, Heckmann BL, Green DR, Sadleir KR, Vassar R, Peter ME. Death Induced by Survival gene Elimination (DISE) correlates with neurotoxicity in Alzheimer's disease and aging. Nat Commun 2024; 15:264. [PMID: 38238311 PMCID: PMC10796375 DOI: 10.1038/s41467-023-44465-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 12/13/2023] [Indexed: 01/22/2024] Open
Abstract
Alzheimer's disease (AD) is characterized by progressive neurodegeneration, but the specific events that cause cell death remain poorly understood. Death Induced by Survival gene Elimination (DISE) is a cell death mechanism mediated by short (s) RNAs acting through the RNA-induced silencing complex (RISC). DISE is thus a form of RNA interference, in which G-rich 6mer seed sequences in the sRNAs (position 2-7) target hundreds of C-rich 6mer seed matches in genes essential for cell survival, resulting in the activation of cell death pathways. Here, using Argonaute precipitation and RNAseq (Ago-RP-Seq), we analyze RISC-bound sRNAs to quantify 6mer seed toxicity in several model systems. In mouse AD models and aging brain, in induced pluripotent stem cell-derived neurons from AD patients, and in cells exposed to Aβ42 oligomers, RISC-bound sRNAs show a shift to more toxic 6mer seeds compared to controls. In contrast, in brains of "SuperAgers", humans over age 80 who have superior memory performance, RISC-bound sRNAs are shifted to more nontoxic 6mer seeds. Cells depleted of nontoxic sRNAs are sensitized to Aβ42-induced cell death, and reintroducing nontoxic RNAs is protective. Altogether, the correlation between DISE and Aβ42 toxicity suggests that increasing the levels of nontoxic miRNAs in the brain or blocking the activity of toxic RISC-bound sRNAs could ameliorate neurodegeneration.
Collapse
Affiliation(s)
- Bidur Paudel
- Department of Medicine/Division Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Si-Yeon Jeong
- Department of Medicine/Division Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
- Ministry of Food and Drug Safety, Pharmaceutical Safety Bureau, Pharmaceutical Policy Division 187, Osongsaengmyeong 2-ro, Osong-eup, Heungdeok-gu, Cheongju-si, Chungcheongbuk-do, Republic of Korea
| | - Carolina Pena Martinez
- USF Health Byrd Alzheimer's Center and Neuroscience Institute; Department of Molecular Medicine, Morsani College of Medicine, Tampa, FL, 33613, USA
| | - Alexis Rickman
- USF Health Byrd Alzheimer's Center and Neuroscience Institute; Department of Molecular Medicine, Morsani College of Medicine, Tampa, FL, 33613, USA
| | - Ashley Haluck-Kangas
- Department of Medicine/Division Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Elizabeth T Bartom
- Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
- Department of Preventive Medicine/Division of Biostatistics, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Kristina Fredriksen
- Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Amira Affaneh
- Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - John A Kessler
- Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Joseph R Mazzulli
- Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Andrea E Murmann
- Department of Medicine/Division Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Emily Rogalski
- Mesulam Center for Cognitive Neurology and Alzheimer's Disease, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
- Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
- Healthy Aging & Alzheimer's Research Care (HAARC) Center, Department of Neurology, The University of Chicago, Chicago, IL, 60637, USA
| | - Changiz Geula
- Mesulam Center for Cognitive Neurology and Alzheimer's Disease, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
- Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Adriana Ferreira
- Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Bradlee L Heckmann
- USF Health Byrd Alzheimer's Center and Neuroscience Institute; Department of Molecular Medicine, Morsani College of Medicine, Tampa, FL, 33613, USA
| | - Douglas R Green
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - Katherine R Sadleir
- Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Robert Vassar
- Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
- Mesulam Center for Cognitive Neurology and Alzheimer's Disease, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Marcus E Peter
- Department of Medicine/Division Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
- Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
| |
Collapse
|
|
15
|
Cui Y, Qi Y, Ding L, Ding S, Han Z, Wang Y, Du P. miRNA dosage control in development and human disease. Trends Cell Biol 2024; 34:31-47. [PMID: 37419737 DOI: 10.1016/j.tcb.2023.05.009] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 05/23/2023] [Accepted: 05/29/2023] [Indexed: 07/09/2023]
Abstract
In mammals, miRNAs recognize target mRNAs via base pairing, which leads to a complex 'multiple-to-multiple' regulatory network. Previous studies have focused on the regulatory mechanisms and functions of individual miRNAs, but alterations of many individual miRNAs do not strongly disturb the miRNA regulatory network. Recent studies revealed the important roles of global miRNA dosage control events in physiological processes and pathogenesis, suggesting that miRNAs can be considered as a 'cellular buffer' that controls cell fate. Here, we review the current state of research on how global miRNA dosage is tightly controlled to regulate development, tumorigenesis, neurophysiology, and immunity. We propose that methods of controlling global miRNA dosage may serve as effective therapeutic tools to cure human diseases.
Collapse
Affiliation(s)
- Yingzi Cui
- MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, 100871, China
| | - Ye Qi
- MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, 100871, China; Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China
| | - Li Ding
- MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, 100871, China
| | - Shuangjin Ding
- Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, 100871, China
| | - Zonglin Han
- Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, 100871, China
| | - Yangming Wang
- Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, 100871, China.
| | - Peng Du
- MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, 100871, China; Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China.
| |
Collapse
|
|
16
|
Kiyuna LA, Candido DS, Bechara LRG, Jesus ICG, Ramalho LS, Krum B, Albuquerque RP, Campos JC, Bozi LHM, Zambelli VO, Alves AN, Campolo N, Mastrogiovanni M, Bartesaghi S, Leyva A, Durán R, Radi R, Arantes GM, Cunha-Neto E, Mori MA, Chen CH, Yang W, Mochly-Rosen D, MacRae IJ, Ferreira LRP, Ferreira JCB. 4-Hydroxynonenal impairs miRNA maturation in heart failure via Dicer post-translational modification. Eur Heart J 2023; 44:4696-4712. [PMID: 37944136 DOI: 10.1093/eurheartj/ehad662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 09/08/2023] [Accepted: 09/25/2023] [Indexed: 11/12/2023] Open
Abstract
BACKGROUND AND AIMS Developing novel therapies to battle the global public health burden of heart failure remains challenging. This study investigates the underlying mechanisms and potential treatment for 4-hydroxynonenal (4-HNE) deleterious effects in heart failure. METHODS Biochemical, functional, and histochemical measurements were applied to identify 4-HNE adducts in rat and human failing hearts. In vitro studies were performed to validate 4-HNE targets. RESULTS 4-HNE, a reactive aldehyde by-product of mitochondrial dysfunction in heart failure, covalently inhibits Dicer, an RNase III endonuclease essential for microRNA (miRNA) biogenesis. 4-HNE inhibition of Dicer impairs miRNA processing. Mechanistically, 4-HNE binds to recombinant human Dicer through an intermolecular interaction that disrupts both activity and stability of Dicer in a concentration- and time-dependent manner. Dithiothreitol neutralization of 4-HNE or replacing 4-HNE-targeted residues in Dicer prevents 4-HNE inhibition of Dicer in vitro. Interestingly, end-stage human failing hearts from three different heart failure aetiologies display defective 4-HNE clearance, decreased Dicer activity, and miRNA biogenesis impairment. Notably, boosting 4-HNE clearance through pharmacological re-activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2) using Alda-1 or its improved orally bioavailable derivative AD-9308 restores Dicer activity. ALDH2 is a major enzyme responsible for 4-HNE removal. Importantly, this response is accompanied by improved miRNA maturation and cardiac function/remodelling in a pre-clinical model of heart failure. CONCLUSIONS 4-HNE inhibition of Dicer directly impairs miRNA biogenesis in heart failure. Strikingly, decreasing cardiac 4-HNE levels through pharmacological ALDH2 activation is sufficient to re-establish Dicer activity and miRNA biogenesis; thereby representing potential treatment for patients with heart failure.
Collapse
Affiliation(s)
- Ligia A Kiyuna
- Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 2415 - Butanta, 05508-000 São Paulo-SP, Brazil
| | - Darlan S Candido
- Laboratory of Immunology, Heart Institute, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Luiz R G Bechara
- Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 2415 - Butanta, 05508-000 São Paulo-SP, Brazil
| | - Itamar C G Jesus
- Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 2415 - Butanta, 05508-000 São Paulo-SP, Brazil
| | - Lisley S Ramalho
- Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 2415 - Butanta, 05508-000 São Paulo-SP, Brazil
| | - Barbara Krum
- Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 2415 - Butanta, 05508-000 São Paulo-SP, Brazil
| | - Ruda P Albuquerque
- Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 2415 - Butanta, 05508-000 São Paulo-SP, Brazil
| | - Juliane C Campos
- Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 2415 - Butanta, 05508-000 São Paulo-SP, Brazil
| | - Luiz H M Bozi
- Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 2415 - Butanta, 05508-000 São Paulo-SP, Brazil
| | | | - Ariane N Alves
- Department of Biochemistry, Institute of Chemistry, University of Sao Paulo, São Paulo, Brazil
| | - Nicolás Campolo
- Departamento de Bioquímica and Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina, Universidad de la República (UdelaR), Montevideo, Uruguay
| | - Mauricio Mastrogiovanni
- Departamento de Bioquímica and Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina, Universidad de la República (UdelaR), Montevideo, Uruguay
| | - Silvina Bartesaghi
- Departamento de Bioquímica and Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina, Universidad de la República (UdelaR), Montevideo, Uruguay
| | - Alejandro Leyva
- Unidad de Bioquímica y Proteómica Analítica (UByPA), Instituto de Investigaciones Biológicas Celemente Estable & Institut Pasteur de Montevideo, Montevideo, Uruguay
| | - Rosario Durán
- Unidad de Bioquímica y Proteómica Analítica (UByPA), Instituto de Investigaciones Biológicas Celemente Estable & Institut Pasteur de Montevideo, Montevideo, Uruguay
| | - Rafael Radi
- Departamento de Bioquímica and Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina, Universidad de la República (UdelaR), Montevideo, Uruguay
| | - Guilherme M Arantes
- Department of Biochemistry, Institute of Chemistry, University of Sao Paulo, São Paulo, Brazil
| | - Edécio Cunha-Neto
- Laboratory of Immunology, Heart Institute, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Marcelo A Mori
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (Unicamp), São Paulo, Brazil
| | - Che-Hong Chen
- Department of Chemical and Systems Biology, Stanford University School of Medicine, CCSR 3145A, 269 Campus Drive, Stanford, CA 94305, USA
| | - Wenjin Yang
- Foresee Pharmaceuticals, Co., Ltd, Taipei, Taiwan
| | - Daria Mochly-Rosen
- Department of Chemical and Systems Biology, Stanford University School of Medicine, CCSR 3145A, 269 Campus Drive, Stanford, CA 94305, USA
| | - Ian J MacRae
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA
| | - Ludmila R P Ferreira
- Laboratory of Immunology, Heart Institute, University of São Paulo School of Medicine, São Paulo, Brazil
- Department of Morphology, Institute of Biological Sciences, Federal University of Minas Gerais, Minas Gerais, Brazil
- Brazilian National Institute of Vaccine Science and Technology, Federal University of Minas Gerais, Minas Gerais, Brazil
| | - Julio C B Ferreira
- Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 2415 - Butanta, 05508-000 São Paulo-SP, Brazil
- Department of Chemical and Systems Biology, Stanford University School of Medicine, CCSR 3145A, 269 Campus Drive, Stanford, CA 94305, USA
| |
Collapse
|
|
17
|
Kim JA, Crawford KA, Spada PA, Martin LR, Zhang J, Wong R, Reid JM, Stewart CF, Frank TM, Liu Q, Michalek JE, Keller C. Non-chemotherapy adjuvant agents in TP53 mutant Ewing sarcoma. Sci Rep 2023; 13:14360. [PMID: 37658148 PMCID: PMC10474113 DOI: 10.1038/s41598-023-40751-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 08/16/2023] [Indexed: 09/03/2023] Open
Abstract
Ewing sarcoma (EWS) is a malignant tumor arising in bone or soft tissue that occurs in adolescent and young adult patients as well as adults later in life. Although non-metastatic EWS is typically responsive to treatment when newly diagnosed, relapsed cases have an unmet need for which no standard treatment approach exists. Recent phase III clinical trials for EWS comparing 7 vs 5 chemotherapy drugs have failed to improve survival. To extend the durability of remission for EWS, we investigated 3 non-chemotherapy adjuvant therapy drug candidates to be combined with chemotherapy. The efficacy of these adjuvant drugs was investigated via anchorage-dependent growth assays, anchorage-independent soft-agar colony formation assays and EWS xenograft mouse models. Enoxacin and entinostat were the most effective adjuvant drug in both long-term in vitro and in vivo adjuvant studies. In the context that enoxacin is an FDA-approved antibiotic, and that entinostat is an investigational agent not yet FDA-approved, we propose enoxacin as an adjuvant drug for further preclinical and clinical investigation in EWS patients.
Collapse
Affiliation(s)
- Jin-Ah Kim
- Children's Cancer Therapy Development Institute, 9025 NE Von Neumann Drive Ste 110, Hillsboro, OR, 97006, USA.
| | - Kenneth A Crawford
- Children's Cancer Therapy Development Institute, 9025 NE Von Neumann Drive Ste 110, Hillsboro, OR, 97006, USA
| | - Piero A Spada
- Children's Cancer Therapy Development Institute, 9025 NE Von Neumann Drive Ste 110, Hillsboro, OR, 97006, USA
| | - Leah R Martin
- Children's Cancer Therapy Development Institute, 9025 NE Von Neumann Drive Ste 110, Hillsboro, OR, 97006, USA
| | - Jiaqi Zhang
- Children's Cancer Therapy Development Institute, 9025 NE Von Neumann Drive Ste 110, Hillsboro, OR, 97006, USA
| | - Rain Wong
- Children's Cancer Therapy Development Institute, 9025 NE Von Neumann Drive Ste 110, Hillsboro, OR, 97006, USA
| | - Joel M Reid
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, 55905, USA
| | - Clinton F Stewart
- Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, 38105-2794, USA
| | - Timothy M Frank
- Children's Cancer Therapy Development Institute, 9025 NE Von Neumann Drive Ste 110, Hillsboro, OR, 97006, USA
| | - Qianqian Liu
- Department of Epidemiology and Biostatistics, University of Texas Health Science Center, San Antonio, TX, 78229, USA
| | - Joel E Michalek
- Department of Epidemiology and Biostatistics, University of Texas Health Science Center, San Antonio, TX, 78229, USA
| | - Charles Keller
- Children's Cancer Therapy Development Institute, 9025 NE Von Neumann Drive Ste 110, Hillsboro, OR, 97006, USA.
| |
Collapse
|
|
18
|
Yadav S, Shah D, Dalai P, Agrawal-Rajput R. The tale of antibiotics beyond antimicrobials: Expanding horizons. Cytokine 2023; 169:156285. [PMID: 37393846 DOI: 10.1016/j.cyto.2023.156285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 06/02/2023] [Accepted: 06/24/2023] [Indexed: 07/04/2023]
Abstract
Antibiotics had proved to be a godsend for mankind since their discovery. They were once the magical solution to the vexing problem of infection-related deaths. German scientist Paul Ehrlich had termed salvarsan as the silver bullet to treatsyphilis.As time passed, the magic of newly discovered silver bullets got tarnished with raging antibiotic resistance among bacteria and associated side-effects. Still, antibiotics remain the primary line of treatment for bacterial infections. Our understanding of their chemical and biological activities has increased immensely with advancement in the research field. Non-antibacterial effects of antibiotics are studied extensively to optimise their safer, broad-range use. These non-antibacterial effects could be both useful and harmful to us. Various researchers across the globe including our lab are studying the direct/indirect effects and molecular mechanisms behind these non-antibacterial effects of antibiotics. So, it is interesting for us to sum up the available literature. In this review, we have briefed the possible reason behind the non-antibacterial effects of antibiotics, owing to the endosymbiotic origin of host mitochondria. We further discuss the physiological and immunomodulatory effects of antibiotics. We then extend the review to discuss molecular mechanisms behind the plausible use of antibiotics as anticancer agents.
Collapse
Affiliation(s)
- Shivani Yadav
- Immunology Lab, Department of Biotechnology and Bioengineering, Indian Institute of Advanced Research, Gandhinagar, India
| | - Dhruvi Shah
- Immunology Lab, Department of Biotechnology and Bioengineering, Indian Institute of Advanced Research, Gandhinagar, India
| | - Parmeswar Dalai
- Immunology Lab, Department of Biotechnology and Bioengineering, Indian Institute of Advanced Research, Gandhinagar, India
| | - Reena Agrawal-Rajput
- Immunology Lab, Department of Biotechnology and Bioengineering, Indian Institute of Advanced Research, Gandhinagar, India.
| |
Collapse
|
|
19
|
Abdelaziz N, Therachiyil L, Sadida HQ, Ali AM, Khan OS, Singh M, Khan AQ, Akil ASAS, Bhat AA, Uddin S. Epigenetic inhibitors and their role in cancer therapy. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2023; 380:211-251. [PMID: 37657859 DOI: 10.1016/bs.ircmb.2023.04.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/03/2023]
Abstract
Epigenetic modifications to DNA are crucial for normal cellular and biological functioning. DNA methylation, histone modifications, and chromatin remodeling are the most common epigenetic mechanisms. These changes are heritable but still reversible. The aberrant epigenetic alterations, such as DNA methylation, histone modification, and non-coding RNA (ncRNA)-mediated gene regulation, play an essential role in developing various human diseases, including cancer. Recent studies show that synthetic and dietary epigenetic inhibitors attenuate the abnormal epigenetic modifications in cancer cells and therefore have strong potential for cancer treatment. In this chapter, we have highlighted various types of epigenetic modifications, their mechanism, and as drug targets for epigenetic therapy.
Collapse
Affiliation(s)
- Nouha Abdelaziz
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Lubna Therachiyil
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar
| | - Hana Q Sadida
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, Doha, Qatar
| | | | - Omar S Khan
- Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, IL, USA
| | - Mayank Singh
- Department of Medical Oncology (Lab), BRAIRCH All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Abdul Q Khan
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Ammira S Al-Shabeeb Akil
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, Doha, Qatar
| | - Ajaz A Bhat
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, Doha, Qatar.
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Department of Biosciences, Integral University, Lucknow, Uttar Pradesh, India.
| |
Collapse
|
|
20
|
Yehia AM, Elsakka EGE, Abulsoud AI, Abdelmaksoud NM, Elshafei A, Elkhawaga SY, Ismail A, Mokhtar MM, El-Mahdy HA, Hegazy M, Elballal MS, Mohammed OA, El-Husseiny HM, Midan HM, El-Dakroury WA, Zewail MB, Abdel Mageed SS, Moustafa YM, Mostafa RM, Elkady MA, Doghish AS. Decoding the role of miRNAs in multiple myeloma pathogenesis: A focus on signaling pathways. Pathol Res Pract 2023; 248:154715. [PMID: 37517169 DOI: 10.1016/j.prp.2023.154715] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 07/21/2023] [Accepted: 07/24/2023] [Indexed: 08/01/2023]
Abstract
Multiple myeloma (MM) is a cancer of plasma cells that has been extensively studied in recent years, with researchers increasingly focusing on the role of microRNAs (miRNAs) in regulating gene expression in MM. Several non-coding RNAs have been demonstrated to regulate MM pathogenesis signaling pathways. These pathways might regulate MM development, apoptosis, progression, and therapeutic outcomes. They are Wnt/β-catenin, PI3K/Akt/mTOR, P53 and KRAS. This review highlights the impending role of miRNAs in MM signaling and their relationship with MM therapeutic interventions.
Collapse
Affiliation(s)
- Amr Mohamed Yehia
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Elsayed G E Elsakka
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Ahmed I Abulsoud
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt; Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Nourhan M Abdelmaksoud
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Ahmed Elshafei
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Samy Y Elkhawaga
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Ahmed Ismail
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Mahmoud Mohamed Mokhtar
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Hesham A El-Mahdy
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt.
| | - Maghawry Hegazy
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Mohammed S Elballal
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Osama A Mohammed
- Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt; Department of Clinical Pharmacology, Faculty of Medicine, Bisha University, Bisha 61922, Saudi Arabia
| | - Hussein M El-Husseiny
- Department of Surgery, Anesthesiology, and Radiology, Faculty of Veterinary Medicine, Benha University, Moshtohor, Toukh, Elqaliobiya 13736, Egypt; Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai Cho, Fuchu-shi, Tokyo 183-8509, Japan
| | - Heba M Midan
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Walaa A El-Dakroury
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Moataz B Zewail
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Sherif S Abdel Mageed
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Yasser M Moustafa
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | | | - Mohamed A Elkady
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt; Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt.
| |
Collapse
|
|
21
|
Greco F, Lorefice E, Carissimi C, Laudadio I, Ciccosanti F, Di Rienzo M, Colavita F, Meschi S, Maggi F, Fimia GM, Fulci V. A microRNA Arising from the Negative Strand of SARS-CoV-2 Genome Targets FOS to Reduce AP-1 Activity. Noncoding RNA 2023; 9:33. [PMID: 37368333 DOI: 10.3390/ncrna9030033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 05/16/2023] [Accepted: 05/19/2023] [Indexed: 06/28/2023] Open
Abstract
Virus-encoded microRNAs were first reported in the Epstein-Barr virus in 2004. Subsequently, a few hundred viral miRNAs have been identified, mainly in DNA viruses belonging to the herpesviridae family. To date, only 30 viral miRNAs encoded by RNA viruses are reported by miRBase. Since the outbreak of the SARS-CoV-2 pandemic, several studies have predicted and, in some cases, experimentally validated miRNAs originating from the positive strand of the SARS-CoV-2 genome. By integrating NGS data analysis and qRT-PCR approaches, we found that SARS-CoV-2 also encodes for a viral miRNA arising from the minus (antisense) strand of the viral genome, in the region encoding for ORF1ab, herein referred to as SARS-CoV-2-miR-AS1. Our data show that the expression of this microRNA increases in a time course analysis of SARS-CoV-2 infected cells. Furthermore, enoxacin treatment enhances the accumulation of the mature SARS-CoV-2-miR-AS1 in SARS-CoV-2 infected cells, arguing for a Dicer-dependent processing of this small RNA. In silico analysis suggests that SARS-CoV-2-miR-AS1 targets a set of genes which are translationally repressed during SARS-CoV-2 infection. We experimentally validated that SARS-CoV-2-miR-AS1 targets FOS, thus repressing the AP-1 transcription factor activity in human cells.
Collapse
Affiliation(s)
- Francesco Greco
- Dipartimento di Medicina Molecolare, Università di Roma "La Sapienza", 00161 Rome, Italy
| | - Elisa Lorefice
- Dipartimento di Medicina Molecolare, Università di Roma "La Sapienza", 00161 Rome, Italy
| | - Claudia Carissimi
- Dipartimento di Medicina Molecolare, Università di Roma "La Sapienza", 00161 Rome, Italy
| | - Ilaria Laudadio
- Dipartimento di Medicina Molecolare, Università di Roma "La Sapienza", 00161 Rome, Italy
| | - Fabiola Ciccosanti
- Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases IRCCS 'L. Spallanzani', 00149 Rome, Italy
| | - Martina Di Rienzo
- Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases IRCCS 'L. Spallanzani', 00149 Rome, Italy
| | - Francesca Colavita
- Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases IRCCS 'L. Spallanzani', 00149 Rome, Italy
| | - Silvia Meschi
- Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases IRCCS 'L. Spallanzani', 00149 Rome, Italy
| | - Fabrizio Maggi
- Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases IRCCS 'L. Spallanzani', 00149 Rome, Italy
| | - Gian Maria Fimia
- Dipartimento di Medicina Molecolare, Università di Roma "La Sapienza", 00161 Rome, Italy
- Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases IRCCS 'L. Spallanzani', 00149 Rome, Italy
| | - Valerio Fulci
- Dipartimento di Medicina Molecolare, Università di Roma "La Sapienza", 00161 Rome, Italy
- Istituto Pasteur Italia-Fondazione Cenci Bolognetti, 00161 Rome, Italy
| |
Collapse
|
|
22
|
Safi A, Saberiyan M, Sanaei MJ, Adelian S, Davarani Asl F, Zeinaly M, Shamsi M, Ahmadi R. The role of noncoding RNAs in metabolic reprogramming of cancer cells. Cell Mol Biol Lett 2023; 28:37. [PMID: 37161350 PMCID: PMC10169341 DOI: 10.1186/s11658-023-00447-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 04/11/2023] [Indexed: 05/11/2023] Open
Abstract
Metabolic reprogramming is a well-known feature of cancer that allows malignant cells to alter metabolic reactions and nutrient uptake, thereby promoting tumor growth and spread. It has been discovered that noncoding RNAs (ncRNAs), including microRNA (miRNA), long noncoding RNA (lncRNA), and circular RNA (circRNA), have a role in a variety of biological functions, control physiologic and developmental processes, and even influence disease. They have been recognized in numerous cancer types as tumor suppressors and oncogenic agents. The role of ncRNAs in the metabolic reprogramming of cancer cells has recently been noticed. We examine this subject, with an emphasis on the metabolism of glucose, lipids, and amino acids, and highlight the therapeutic use of targeting ncRNAs in cancer treatment.
Collapse
Affiliation(s)
- Amir Safi
- Clinical Biochemistry Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Mohammadreza Saberiyan
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Mohammad-Javad Sanaei
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Samaneh Adelian
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Fateme Davarani Asl
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Mahsa Zeinaly
- Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran
| | - Mahdi Shamsi
- Department of Cell and Molecular Biology, Najafabad Branch, Islamic Azad University, Najafabad, Iran
| | - Reza Ahmadi
- Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Rahmatiyeh Region, Shahrekord, Iran.
| |
Collapse
|
|
23
|
Abstract
BACKGROUND Autoimmune hepatitis has an unknown cause and genetic associations that are not disease-specific or always present. Clarification of its missing causality and heritability could improve prevention and management strategies. AIMS Describe the key epigenetic and genetic mechanisms that could account for missing causality and heritability in autoimmune hepatitis; indicate the prospects of these mechanisms as pivotal factors; and encourage investigations of their pathogenic role and therapeutic potential. METHODS English abstracts were identified in PubMed using multiple key search phases. Several hundred abstracts and 210 full-length articles were reviewed. RESULTS Environmental induction of epigenetic changes is the prime candidate for explaining the missing causality of autoimmune hepatitis. Environmental factors (diet, toxic exposures) can alter chromatin structure and the production of micro-ribonucleic acids that affect gene expression. Epistatic interaction between unsuspected genes is the prime candidate for explaining the missing heritability. The non-additive, interactive effects of multiple genes could enhance their impact on the propensity and phenotype of autoimmune hepatitis. Transgenerational inheritance of acquired epigenetic marks constitutes another mechanism of transmitting parental adaptations that could affect susceptibility. Management strategies could range from lifestyle adjustments and nutritional supplements to precision editing of the epigenetic landscape. CONCLUSIONS Autoimmune hepatitis has a missing causality that might be explained by epigenetic changes induced by environmental factors and a missing heritability that might reflect epistatic gene interactions or transgenerational transmission of acquired epigenetic marks. These unassessed or under-evaluated areas warrant investigation.
Collapse
Affiliation(s)
- Albert J Czaja
- Mayo Clinic College of Medicine and Science, Rochester, MN, USA.
- Professor Emeritus of Medicine, Mayo Clinic College of Medicine and Science, 200 First Street SW, Rochester, MN, 55905, USA.
| |
Collapse
|
|
24
|
Luo Y, Peng L, Shan W, Sun M, Luo L, Liang W. Machine learning in the development of targeting microRNAs in human disease. Front Genet 2023; 13:1088189. [PMID: 36685965 PMCID: PMC9845262 DOI: 10.3389/fgene.2022.1088189] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 12/12/2022] [Indexed: 01/05/2023] Open
Abstract
A microRNA is a small, single-stranded, non-coding ribonucleic acid that plays a crucial role in RNA silencing and can regulate gene expression. With the in-depth study of miRNA in development and disease, miRNA has become an attractive target for novel therapeutic strategies. Exploring miRNA targeting therapy only through experiments is expensive and laborious, so it is essential to develop novel and efficient computational methods to narrow down the search. Recent advances in machine learning applied in biomedical informatics provide opportunities to explore miRNA-targeting drugs, thus promoting miRNA therapeutics. This review provides an overview of recent advancements in miRNA targeting therapeutic using machine learning. First, we mainly describe the basics of predicting miRNA targeting drugs, including pharmacogenomic data resources and data preprocessing. Then we present primary machine learning algorithms and elaborate their application in discovering relationships among miRNAs, drugs, and diseases. Along with the progress of miRNA targeting therapeutics, we finally analyze and discuss the current challenges and opportunities that machine learning confronts.
Collapse
Affiliation(s)
- Yuxun Luo
- School of Computer Science and Engineering, Hunan University of Science and Technology, Xiangtan, China,Hunan Key Laboratory for Service computing and Novel Software Technology, Xiangtan, China
| | - Li Peng
- School of Computer Science and Engineering, Hunan University of Science and Technology, Xiangtan, China,Hunan Key Laboratory for Service computing and Novel Software Technology, Xiangtan, China
| | - Wenyu Shan
- School of Computer Science, University of South China, Hengyang, China
| | - Mengyue Sun
- School of Polymer Science and Polymer Engineering, The University of Akron, Akron, OH, United States
| | - Lingyun Luo
- School of Computer Science, University of South China, Hengyang, China
| | - Wei Liang
- School of Computer Science and Engineering, Hunan University of Science and Technology, Xiangtan, China,Hunan Key Laboratory for Service computing and Novel Software Technology, Xiangtan, China,*Correspondence: Wei Liang,
| |
Collapse
|
|
25
|
Sekar D, Tusubira D, Ross K. TDP-43 and NEAT long non-coding RNA: Roles in neurodegenerative disease. Front Cell Neurosci 2022; 16:954912. [PMID: 36385948 PMCID: PMC9650703 DOI: 10.3389/fncel.2022.954912] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 10/11/2022] [Indexed: 01/03/2023] Open
Abstract
Understanding and ameliorating neurodegenerative diseases represents a key challenge for supporting the health span of the aging population. Diverse protein aggregates have been implicated in such neurodegenerative disorders, including amyloid-β, α-synuclein, tau, fused in sarcoma (FUS), and transactivation response element (TAR) DNA-binding protein 43 (TDP-43). Recent years have seen significant growth in our mechanistic knowledge of relationships between these proteins and some of the membrane-less nuclear structures that fulfill key roles in the cell function. These include the nucleolus, nuclear speckles, and paraspeckles. The ability of macromolecular protein:RNA complexes to partition these nuclear condensates through biophysical processes that involve liquid-liquid phase separation (LLPS) has also gained attention recently. The paraspeckle, which is scaffolded by the architectural long-non-coding RNA nuclear enriched abundant transcript 1 (NEAT1) plays central roles in RNA processing and metabolism and has been linked dynamically to TDP-43. In this mini-review, we outline essential early and recent insights in relation to TDP-43 proteinopathies. We then appraise the relationships between TDP-43 and NEAT1 in the context of neuronal paraspeckles and neuronal stress. We highlight key areas for investigation based on recent advances in our understanding of how TDP-43 affects neuronal function, especially in relation to messenger ribosomal nucleic acid (mRNA) splicing. Finally, we offer perspectives that should be considered for translational pipelines in order to improve health outcomes for the management of neurodegenerative diseases.
Collapse
Affiliation(s)
- Durairaj Sekar
- Centre for Cellular and Molecular Research, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai, India
| | - Deusdedit Tusubira
- Department of Biochemistry, Mbarara University of Science and Technology, Mbarara, Uganda
| | - Kehinde Ross
- School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, United Kingdom
- Institute for Health Research, Liverpool John Moores University, Liverpool, United Kingdom
| |
Collapse
|
|
26
|
Urzì O, Olofsson Bagge R, Crescitelli R. The dark side of foetal bovine serum in extracellular vesicle studies. J Extracell Vesicles 2022; 11:e12271. [PMID: 36214482 PMCID: PMC9549727 DOI: 10.1002/jev2.12271] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/1912] [Revised: 12/12/1912] [Accepted: 12/12/1912] [Indexed: 11/06/2022] Open
Abstract
Extracellular vesicles (EVs) have been shown to be involved in cell-cell communication and to take part in both physiological and pathological processes. Thanks to their exclusive cargo, which includes proteins, lipids, and nucleic acids from the originating cells, they are gaining interest as potential biomarkers of disease. In recent years, their appealing features have been fascinating researchers from all over the world, thus increasing the number of in vitro studies focused on EV release, content, and biological activities. Cultured cell lines are the most-used source of EVs; however, the EVs released in cell cultures are influenced by the cell culture conditions, such as the use of foetal bovine serum (FBS). FBS is the most common supplement for cell culture media, but it is also a source of contaminants, such as exogenous bovine EVs, RNA, and protein aggregates, that can contaminate the cell-derived EVs and influence their cargo composition. The presence of FBS contaminants in cell-derived EV samples is a well-known issue that limits the clinical applications of EVs, thus increasing the need for standardization. In this review, we will discuss the pros and cons of using FBS in cell cultures as a source of EVs, as well as the protocols used to remove contaminants from FBS.
Collapse
Affiliation(s)
- Ornella Urzì
- Sahlgrenska Center for Cancer Research and Wallenberg Centre for Molecular and Translational MedicineDepartment of SurgeryInstitute of Clinical SciencesSahlgrenska AcademyUniversity of GothenburgGothenburgSweden
- Department of BiomedicineNeurosciences and Advanced Diagnostics (Bi.N.D)University of PalermoPalermoItaly
| | - Roger Olofsson Bagge
- Sahlgrenska Center for Cancer Research and Wallenberg Centre for Molecular and Translational MedicineDepartment of SurgeryInstitute of Clinical SciencesSahlgrenska AcademyUniversity of GothenburgGothenburgSweden
- Department of SurgerySahlgrenska University HospitalRegion Västra GötalandGothenburgSweden
| | - Rossella Crescitelli
- Sahlgrenska Center for Cancer Research and Wallenberg Centre for Molecular and Translational MedicineDepartment of SurgeryInstitute of Clinical SciencesSahlgrenska AcademyUniversity of GothenburgGothenburgSweden
| |
Collapse
|
|
27
|
Zhu W, Fu L, Xu C, Peng K, Liu Y, Tang H, Huang Y, Yang X. Enoxacin ameliorates polycystic ovary syndrome by promoting the browning of white adipose tissue and restoring gut dysbiosis. Front Pharmacol 2022; 13:978019. [PMID: 36147348 PMCID: PMC9486322 DOI: 10.3389/fphar.2022.978019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Accepted: 08/15/2022] [Indexed: 12/02/2022] Open
Abstract
Polycystic ovary syndrome (PCOS) is a complex endocrine disorder syndrome characterized by polycystic ovary, ovulation disorder and hyperandrogenemia, and is often accompanied by metabolic disorders. Enoxacin has been reported to protect against diet-induced obesity and insulin resistance by promoting fat thermogenesis. However, the function of enoxacin in PCOS remains unknown. This study aimed to investigate the impact of the enoxacin on the regulation of PCOS mouse model induced by dehydroepiandrosterone (DHEA). Here, we found that reproductive endocrine disorder, glucose intolerance, and ovarian dysfunction in PCOS mice induced by DHEA were attenuated by enoxacin treatment. Mechanistically, we identified that enoxacin can promote white fat browning and improve metabolic disorders, thus ameliorating DHEA-induced reproductive dysfunction. Moreover, these beneficial effects might be associated with the restoration of gut dysbiosis. These findings provide a novel therapeutic target for enoxacin in the treatment of PCOS.
Collapse
Affiliation(s)
- Wanlong Zhu
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Liya Fu
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Changjing Xu
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Ke Peng
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Yuanzhi Liu
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Hui Tang
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yilan Huang
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- School of Pharmacy, Southwest Medical University, Luzhou, China
- *Correspondence: Yilan Huang, ; Xuping Yang,
| | - Xuping Yang
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- School of Pharmacy, Southwest Medical University, Luzhou, China
- *Correspondence: Yilan Huang, ; Xuping Yang,
| |
Collapse
|
|
28
|
Enoxacin-based derivatives: antimicrobial and antibiofilm agent: a biology-oriented drug synthesis (BIODS) approach. Future Med Chem 2022; 14:947-962. [PMID: 35695000 DOI: 10.4155/fmc-2022-0065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Background: To find alternative molecules against Klebsiella pneumonia, Proteus mirabilis and methicillin-resistant Staphylococcus aureus, new enoxacin derivatives were synthesized and screened. Methods: All derivatives exhibited promising antibacterial activities as compared to standard enoxacin (2 μg/ml) and standard cefixime (82 μg/ml). Compounds 2, 3 and 5 significantly downregulated the gene expression of biofilm-forming genes. Conclusion: Based on our results, these molecules may serve as potential drug candidates to cure several bacterial infections in the future.
Collapse
|
|
29
|
Jałbrzykowska K, Chrzanowska A, Roszkowski P, Struga M. The New Face of a Well-Known Antibiotic: A Review of the Anticancer Activity of Enoxacin and Its Derivatives. Cancers (Basel) 2022; 14:cancers14133056. [PMID: 35804828 PMCID: PMC9264829 DOI: 10.3390/cancers14133056] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 06/15/2022] [Accepted: 06/19/2022] [Indexed: 12/14/2022] Open
Abstract
Simple Summary Enoxacin is a second-generation quinolone with promising anticancer activity. In contrast to other members of the quinolone group, it exhibits an extraordinary cytotoxic mechanism of action. Enoxacin enhances RNA interference and promotes microRNA processing, as well as the production of free radicals. Interestingly, apart from its proapoptotic, cell cycle arresting and cytostatic effects, enoxacin manifests a limitation of cancer invasiveness. The underlying mechanisms are the competitive inhibition of vacuolar H+-ATPase subunits and c-Jun N-terminal kinase signaling pathway suppression. The newly synthesized enoxacin derivatives have shown a magnified cytotoxic effect with an emphasis on prooxidative, proapoptotic and microRNA interference actions. The mentioned mechanisms seem to contribute to a safer, more selective and more effective anticancer therapy. Abstract Enoxacin as a second-generation synthetic quinolone is known for its antibacterial action; however, in recent years there have been studies focusing on its anticancer potential. Interestingly, it turns out that compared to other fluoroquinolones, enoxacin exhibits uncommon cytotoxic properties. Besides its influence on apoptosis, the cell cycle and cell growth, it exhibits a regulatory action on microRNA biogenesis. It was revealed that the molecular targets of the enoxacin-mediated inhibition of osteoclastogenesis are vacuolar H+-ATPase subunits and the c-Jun N-terminal kinase signaling pathway, causing a decrease in cell invasiveness. Interestingly, the prooxidative nature of the subjected fluoroquinolone enhanced the cytotoxic effect. Crucial for the anticancer activity were the carboxyl group at the third carbon atom, fluorine at the seventh carbon atom and nitrogen at the eighth position of naphyridine. Modifications of the parent drug improved the induction of oxidative stress, cell cycle arrest and the dysregulation of microRNA. The inhibition of V-ATPase–microfilament binding was also observed. Enoxacin strongly affected various cancer but not normal cells, excluding keratinocytes, which suffered from phototoxicity. It seems to be an underestimated anticancer drug with pleiotropic action. Furthermore, its usage as a safe antibiotic with well-known pharmacokinetics and selectivity will enhance the development of anticancer treatment strategies. This review covers articles published within the years 2000–2021, with a strong focus on the recent years (2016–2021). However, some canonical papers published in twentieth century are also mentioned.
Collapse
Affiliation(s)
- Karolina Jałbrzykowska
- Chair and Department of Biochemistry, Medical University of Warsaw, Banacha 1, 02-097 Warszawa, Poland;
| | - Alicja Chrzanowska
- Chair and Department of Biochemistry, Medical University of Warsaw, Banacha 1, 02-097 Warszawa, Poland;
- Correspondence: (A.C.); (M.S.); Tel.: +48-22-5720693 (A.C. & M.S.)
| | - Piotr Roszkowski
- Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland;
| | - Marta Struga
- Chair and Department of Biochemistry, Medical University of Warsaw, Banacha 1, 02-097 Warszawa, Poland;
- Correspondence: (A.C.); (M.S.); Tel.: +48-22-5720693 (A.C. & M.S.)
| |
Collapse
|
|
30
|
Xu W, Jiang H, Liu J, Li H. Non-Coding RNAs: New Dawn for Diabetes Mellitus Induced Erectile Dysfunction. Front Mol Biosci 2022; 9:888624. [PMID: 35813828 PMCID: PMC9257010 DOI: 10.3389/fmolb.2022.888624] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 06/01/2022] [Indexed: 11/21/2022] Open
Abstract
Erectile dysfunction (ED) is a common sexual dysfunction in males, with multifactorial alterations which consist of psychological and organic. Diabetes mellitus (DM) induced erectile dysfunction (DMED) is a disconcerting and critical complication of DM, and remarkably different from non-diabetic ED. The response rate of phosphodiesterase type 5 inhibitor (PDE5i), a milestone for ED therapy, is far from satisfactory in DMED. Unfortunately, the contributing mechanisms of DMED remains vague. Hence, It is urgent to seek for novel prospective biomarkers or targets of DMED. Numerous studies have proved that non-coding RNAs (ncRNAs) play essential roles in the pathogenesis process of DM, which comprise of long non-coding RNAs (lncRNAs) and small non-coding RNAs (sncRNAs) like microRNAs (miRNAs), PIWI-interacting RNAs (piRNAs) and circular RNAs (circRNAs). However, the implications of ncRNAs in DMED are still understudied. This review highlights the pathophysiology of DMED, summarizes identified mechanisms of ncRNAs associated with DMED and covers the topic of perspectives for ncRNAs in DMED.
Collapse
Affiliation(s)
- Wenchao Xu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hongyang Jiang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jihong Liu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Jihong Liu, ; Hao Li,
| | - Hao Li
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Jihong Liu, ; Hao Li,
| |
Collapse
|
|
31
|
Peng T, He Y, Wang T, Yu J, Ma X, Zhou Z, Sheng Y, Li L, Peng H, Li S, Zou J, Yuan Y, Zhao Y, Shi H, Li F, Liu W, Hu K, Lu X, Zhang G, Wang F. Discovery of a Novel Small-Molecule Inhibitor Disrupting TRBP-Dicer Interaction against Hepatocellular Carcinoma via the Modulation of microRNA Biogenesis. J Med Chem 2022; 65:11010-11033. [PMID: 35695407 DOI: 10.1021/acs.jmedchem.2c00189] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
MicroRNAs (miRNAs) are key players in human hepatocellular carcinoma (HCC) tumorigenesis. Therefore, small molecules targeting components of miRNA biogenesis may provide new therapeutic means for HCC treatment. By a high-throughput screening and structural simplification, we identified a small molecule, CIB-3b, which suppresses the growth and metastasis of HCC in vitro and in vivo by modulating expression profiles of miRNAome and proteome in HCC cells. Mechanistically, CIB-3b physically binds to transactivation response (TAR) RNA-binding protein 2 (TRBP) and disrupts the TRBP-Dicer interaction, thereby altering the activity of Dicer and mature miRNA production. Structure-activity relationship study via the synthesis of 45 CIB-3b derivatives showed that some compounds exhibited a similar inhibitory effect on miRNA biogenesis to CIB-3b. These results support TRBP as a potential therapeutic target in HCC and warrant further development of CIB-3b along with its analogues as a novel therapeutic strategy for the treatment of HCC.
Collapse
Affiliation(s)
- Ting Peng
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.,Antibiotics Research and Re-Evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu 610052, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yujiao He
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.,Antibiotics Research and Re-Evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu 610052, China
| | - Tao Wang
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
| | - Jialing Yu
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xiaofang Ma
- Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Zongyuan Zhou
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yuwen Sheng
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Lingyu Li
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Huipan Peng
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
| | - Sheng Li
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
| | - Jiawei Zou
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
| | - Yi Yuan
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
| | - Yongyun Zhao
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
| | - Hailong Shi
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Fu Li
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
| | - Wanli Liu
- Ministry of Education Key Laboratory of Protein Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Life Sciences, Institute for Immunology, Tsinghua University, Beijing 100084, China
| | - Kaifeng Hu
- Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Xiaoxia Lu
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
| | - Guolin Zhang
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.,Xiongan Institute of Innovation, Chinese Academy of Sciences, Hebei 071700, China
| | - Fei Wang
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.,Xiongan Institute of Innovation, Chinese Academy of Sciences, Hebei 071700, China
| |
Collapse
|
|
32
|
Czaja AJ. Examining micro-ribonucleic acids as diagnostic and therapeutic prospects in autoimmune hepatitis. Expert Rev Clin Immunol 2022; 18:591-607. [PMID: 35510750 DOI: 10.1080/1744666x.2022.2074839] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Micro-ribonucleic acids modulate the immune response by affecting the post-transcriptional expression of genes that influence the proliferation and function of activated immune cells, including regulatory T cells. Individual expressions or patterns in peripheral blood and liver tissue may have diagnostic value, reflect treatment response, or become therapeutic targets. The goals of this review are to present the properties and actions of micro-ribonucleic acids, indicate the key individual expressions in autoimmune hepatitis, and describe prospective clinical applications in diagnosis and management. AREAS COVERED Abstracts were identified in PubMed using the search words "microRNAs", "microRNAs in liver disease", and "microRNAs in autoimmune hepatitis". The number of abstracts reviewed exceeded 2000, and the number of full-length articles reviewed was 108. EXPERT OPINION Individual micro-ribonucleic acids, miR-21, miR-122, and miR-155, have been associated with biochemical severity, histological grade of inflammation, and pivotal pathogenic mechanisms in autoimmune hepatitis. Antisense oligonucleotides that down-regulate deleterious individual gene expressions, engineered molecules that impair targeting of gene products, and drugs that non-selectively up-regulate the biogenesis of potentially deficient gene regulators are feasible treatment options. Micro-ribonucleic acids constitute an under-evaluated area in autoimmune hepatitis that promises to improve diagnosis, pathogenic concepts, and therapy.
Collapse
Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| |
Collapse
|
|
33
|
Aggarwal V, Tuli HS, Tania M, Srivastava S, Ritzer EE, Pandey A, Aggarwal D, Barwal TS, Jain A, Kaur G, Sak K, Varol M, Bishayee A. Molecular mechanisms of action of epigallocatechin gallate in cancer: Recent trends and advancement. Semin Cancer Biol 2022; 80:256-275. [PMID: 32461153 DOI: 10.1016/j.semcancer.2020.05.011] [Citation(s) in RCA: 118] [Impact Index Per Article: 39.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 05/08/2020] [Accepted: 05/17/2020] [Indexed: 12/22/2022]
Abstract
Epigallocatechin gallate (EGCG), also known as epigallocatechin-3-gallate, is an ester of epigallocatechin and gallic acid. EGCG, abundantly found in tea, is a polyphenolic flavonoid that has the potential to affect human health and disease. EGCG interacts with various recognized cellular targets and inhibits cancer cell proliferation by inducing apoptosis and cell cycle arrest. In addition, scientific evidence has illustrated the promising role of EGCG in inhibiting tumor cell metastasis and angiogenesis. It has also been found that EGCG may reverse drug resistance of cancer cells and could be a promising candidate for synergism studies. The prospective importance of EGCG in cancer treatment is owed to its natural origin, safety, and low cost which presents it as an attractive target for further development of novel cancer therapeutics. A major challenge with EGCG is its low bioavailability which is being targeted for improvement by encapsulating EGCG in nano-sized vehicles for further delivery. However, there are major limitations of the studies on EGCG, including study design, experimental bias, and inconsistent results and reproducibility among different study cohorts. Additionally, it is important to identify specific EGCG pharmacological targets in the tumor-specific signaling pathways for development of novel combined therapeutic treatments with EGCG. The present review highlights the ongoing development to identify cellular and molecular targets of EGCG in cancer. Furthermore, the role of nanotechnology-mediated EGCG combinations and delivery systems will also be discussed.
Collapse
Affiliation(s)
- Vaishali Aggarwal
- Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh 160 012, Punjab, India
| | - Hardeep Singh Tuli
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala 133 207, Haryana, India.
| | - Mousumi Tania
- Division of Molecular Cancer, Red Green Research Center, Dhaka 1205, Bangladesh
| | - Saumya Srivastava
- Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Prayagraj 211 004, Uttar Pradesh, India
| | - Erin E Ritzer
- Lake Erie College of Osteopathic Medicine, Bradenton 34211, FL, USA
| | - Anjana Pandey
- Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Prayagraj 211 004, Uttar Pradesh, India
| | - Diwakar Aggarwal
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala 133 207, Haryana, India
| | - Tushar Singh Barwal
- Department of Zoology, Central University of Punjab, Bathinda 151 001, Punjab, India
| | - Aklank Jain
- Department of Zoology, Central University of Punjab, Bathinda 151 001, Punjab, India
| | - Ginpreet Kaur
- Department of Pharmacology, Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, Mumbai 400 056, Maharastra, India
| | | | - Mehmet Varol
- Department of Molecular Biology and Genetics, Faculty of Science, Mugla Sitki Kocman University, Muğla TR48000, Turkey
| | - Anupam Bishayee
- Lake Erie College of Osteopathic Medicine, Bradenton 34211, FL, USA.
| |
Collapse
|
|
34
|
Zhang Z, Huang Q, Yu L, Zhu D, Li Y, Xue Z, Hua Z, Luo X, Song Z, Lu C, Zhao T, Liu Y. The Role of miRNA in Tumor Immune Escape and miRNA-Based Therapeutic Strategies. Front Immunol 2022; 12:807895. [PMID: 35116035 PMCID: PMC8803638 DOI: 10.3389/fimmu.2021.807895] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 12/22/2021] [Indexed: 12/19/2022] Open
Abstract
Tumor immune escape is a critical step in the malignant progression of tumors and one of the major barriers to immunotherapy, making immunotherapy the most promising therapeutic approach against tumors today. Tumor cells evade immune surveillance by altering the structure of their own, or by causing abnormal gene and protein expression, allowing for unrestricted development and invasion. These genetic or epigenetic changes have been linked to microRNAs (miRNAs), which are important determinants of post-transcriptional regulation. Tumor cells perform tumor immune escape by abnormally expressing related miRNAs, which reduce the killing effect of immune cells, disrupt the immune response, and disrupt apoptotic pathways. Consequently, there is a strong trend toward thoroughly investigating the role of miRNAs in tumor immune escape and utilizing them in tumor treatment. However, because of the properties of miRNAs, there is an urgent need for a safe, targeted and easily crossed biofilm vehicle to protect and deliver them in vivo, and exosomes, with their excellent biological properties, have successfully beaten traditional vehicles to provide strong support for miRNA therapy. This review summarizes the multiple roles of miRNAs in tumor immune escape and discusses their potential applications as an anti-tumor therapy. Also, this work proposes exosomes as a new opportunity for miRNA therapy, to provide novel ideas for the development of more effective tumor-fighting therapeutic approaches based on miRNAs.
Collapse
Affiliation(s)
- Zhengjia Zhang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Qingcai Huang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Liuchunyang Yu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Dongjie Zhu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Yang Li
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Zeyu Xue
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Zhenglai Hua
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Xinyi Luo
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Zhiqian Song
- Institute of Basic Theory, China Academy of Chinese Medical Sciences, Beijing, China
| | - Cheng Lu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
- *Correspondence: Yuanyan Liu, ; Cheng Lu, ; Ting Zhao,
| | - Ting Zhao
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
- *Correspondence: Yuanyan Liu, ; Cheng Lu, ; Ting Zhao,
| | - Yuanyan Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
- *Correspondence: Yuanyan Liu, ; Cheng Lu, ; Ting Zhao,
| |
Collapse
|
|
35
|
Hei YY, Wang S, Xi XX, Wang HP, Guo Y, Xin M, Jiang C, Lu S, Zhang SQ. Design, synthesis, and evaluation of fluoroquinolone derivatives as MicroRNA-21 small-molecule inhibitors. J Pharm Anal 2022; 12:653-663. [PMID: 36105166 PMCID: PMC9463491 DOI: 10.1016/j.jpha.2021.12.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 12/31/2021] [Accepted: 12/31/2021] [Indexed: 01/10/2023] Open
Abstract
MicroRNA-21 (miRNA-21) is highly expressed in various tumors. Small-molecule inhibition of miRNA-21 is considered to be an attractive novel cancer therapeutic strategy. In this study, fluoroquinolone derivatives A1–A43 were synthesized and used as miRNA-21 inhibitors. Compound A36 showed the most potent inhibitory activity and specificity for miRNA-21 in a dual-luciferase reporter assay in HeLa cells. Compound A36 significantly reduced the expression of mature miRNA-21 and increased the protein expression of miRNA-21 target genes, including programmed cell death protein 4 (PDCD4) and phosphatase and tensin homology deleted on chromosome ten (PTEN), at 10 μM in HeLa cells. The Cell Counting Kit-8 assay (CCK-8) was used to evaluate the antiproliferative activity of A36; the results showed that the IC50 value range of A36 against six tumor cell lines was between 1.76 and 13.0 μM. Meanwhile, A36 did not display cytotoxicity in BEAS-2B cells (lung epithelial cells from a healthy human donor). Furthermore, A36 significantly induced apoptosis, arrested cells at the G0/G1 phase, and inhibited cell-colony formation in HeLa cells. In addition, mRNA deep sequencing showed that treatment with A36 could generate 171 dysregulated mRNAs in HeLa cells, while the expression of miRNA-21 target gene dual-specificity phosphatase 5 (DUSP5) was significantly upregulated at both the mRNA and protein levels. Collectively, these findings demonstrated that A36 is a novel miRNA-21 inhibitor.
Fluoroquinolone derivatives A1–A43 were synthesized and evaluated as miRNA-21 small-compound inhibitors. The quinolone derivative A36 was validated as an active and specific miRNA-21 small-compound inhibitor. A36 displayed differential anti-cell proliferation activity between normal and miRNA-21-overexpressing cancer cells.
Collapse
Affiliation(s)
- Yuan-Yuan Hei
- Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
- Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, 710061, China
| | - Si Wang
- Institute of Molecular and Translational Medicine (IMTM), and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
- Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, 710061, China
| | - Xiao-Xiao Xi
- Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
| | - Hai-Peng Wang
- Department of Medical Oncology, Shaanxi Provincial People's Hospital, Xi'an, 710068, China
| | - Yuanxu Guo
- Institute of Molecular and Translational Medicine (IMTM), and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
- Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, 710061, China
| | - Minhang Xin
- Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
- Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, 710061, China
| | - Congshan Jiang
- Institute of Molecular and Translational Medicine (IMTM), and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
- Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, 710061, China
- Corresponding author. Institute of Molecular and Translational Medicine (IMTM), and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China.
| | - Shemin Lu
- Institute of Molecular and Translational Medicine (IMTM), and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
- Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, 710061, China
| | - San-Qi Zhang
- Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
- Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, 710061, China
- Corresponding author. Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China.
| |
Collapse
|
|
36
|
Haluck-Kangas A, Patel M, Paudel B, Vaidyanathan A, Murmann AE, Peter ME. DISE/6mer seed toxicity-a powerful anti-cancer mechanism with implications for other diseases. J Exp Clin Cancer Res 2021; 40:389. [PMID: 34893072 PMCID: PMC8662895 DOI: 10.1186/s13046-021-02177-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 11/05/2021] [Indexed: 01/03/2023] Open
Abstract
micro(mi)RNAs are short noncoding RNAs that through their seed sequence (pos. 2-7/8 of the guide strand) regulate cell function by targeting complementary sequences (seed matches) located mostly in the 3' untranslated region (3' UTR) of mRNAs. Any short RNA that enters the RNA induced silencing complex (RISC) can kill cells through miRNA-like RNA interference when its 6mer seed sequence (pos. 2-7 of the guide strand) has a G-rich nucleotide composition. G-rich seeds mediate 6mer Seed Toxicity by targeting C-rich seed matches in the 3' UTR of genes critical for cell survival. The resulting Death Induced by Survival gene Elimination (DISE) predominantly affects cancer cells but may contribute to cell death in other disease contexts. This review summarizes recent findings on the role of DISE/6mer Seed Tox in cancer; its therapeutic potential; its contribution to therapy resistance; its selectivity, and why normal cells are protected. In addition, we explore the connection between 6mer Seed Toxicity and aging in relation to cancer and certain neurodegenerative diseases.
Collapse
Affiliation(s)
- Ashley Haluck-Kangas
- Division Hematology/Oncology and Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, 303 East Superior Street, Lurie 6-123, Chicago, IL 60611 USA
| | - Monal Patel
- Division Hematology/Oncology and Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, 303 East Superior Street, Lurie 6-123, Chicago, IL 60611 USA
| | - Bidur Paudel
- Division Hematology/Oncology and Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, 303 East Superior Street, Lurie 6-123, Chicago, IL 60611 USA
| | - Aparajitha Vaidyanathan
- Division Hematology/Oncology and Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, 303 East Superior Street, Lurie 6-123, Chicago, IL 60611 USA
| | - Andrea E. Murmann
- Division Hematology/Oncology and Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, 303 East Superior Street, Lurie 6-123, Chicago, IL 60611 USA
| | - Marcus E. Peter
- Division Hematology/Oncology and Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, 303 East Superior Street, Lurie 6-123, Chicago, IL 60611 USA
| |
Collapse
|
|
37
|
Dougherty U, Mustafi R, Zhu H, Zhu X, Deb D, Meredith SC, Ayaloglu-Butun F, Fletcher M, Sanchez A, Pekow J, Deng Z, Amini N, Konda VJ, Rao VL, Sakuraba A, Kwesi A, Kupfer SS, Fichera A, Joseph L, Hart J, He F, He TC, West-Szymanski D, Li YC, Bissonnette M. Upregulation of polycistronic microRNA-143 and microRNA-145 in colonocytes suppresses colitis and inflammation-associated colon cancer. Epigenetics 2021; 16:1317-1334. [PMID: 33356812 PMCID: PMC8813074 DOI: 10.1080/15592294.2020.1863117] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 11/08/2020] [Accepted: 12/07/2020] [Indexed: 12/25/2022] Open
Abstract
Because ADAM17 promotes colonic tumorigenesis, we investigated potential miRNAs regulating ADAM17; and examined effects of diet and tumorigenesis on these miRNAs. We also examined pre-miRNA processing and tumour suppressor roles of several of these miRNAs in experimental colon cancer. Using TargetScan, miR-145, miR-148a, and miR-152 were predicted to regulate ADAM17. miR-143 was also investigated as miR-143 and miR-145 are co-transcribed and associated with decreased tumour growth. HCT116 colon cancer cells (CCC) were co-transfected with predicted ADAM17-regulating miRNAs and luciferase reporters controlled by ADAM17-3'UTR. Separately, pre-miR-143 processing by colonic cells was measured. miRNAs were quantified by RT-PCR. Tumours were induced with AOM/DSS in WT and transgenic mice (Tg) expressing pre-miR-143/miR-145 under villin promoter. HCT116 transfection with miR-145, -148a or -152, but not scrambled miRNA inhibited ADAM17 expression and luciferase activity. The latter was suppressed by mutations in ADAM17-3'UTR. Lysates from colonocytes, but not CCC, processed pre-miR-143 and mixing experiments suggested CCC lacked a competency factor. Colonic miR-143, miR-145, miR-148a, and miR-152 were downregulated in tumours and more moderately by feeding mice a Western diet. Tg mice were resistant to DSS colitis and had significantly lower cancer incidence and tumour multiplicity. Tg expression blocked up-regulation of putative targets of miR-143 and miR-145, including ADAM17, K-Ras, XPO5, and SET. miR-145, miR-148a, and miR-152 directly suppress colonocyte ADAM17 and are down-regulated in colon cancer. This is the first direct demonstration of tumour suppressor roles for miR-143 and miR-145 in an in vivo model of colonic tumorigenesis.
Collapse
Affiliation(s)
| | - Reba Mustafi
- Department of Medicine, University of Chicago, Chicago IL, USA
| | - Hongyan Zhu
- Department of Medicine, University of Chicago, Chicago IL, USA
| | - Xiaorong Zhu
- Department of Medicine, University of Chicago, Chicago IL, USA
| | - Dilip Deb
- Department of Medicine, University of Chicago, Chicago IL, USA
| | | | | | | | - Arantxa Sanchez
- Department of Medicine, University of Chicago, Chicago IL, USA
| | - Joel Pekow
- Department of Medicine, University of Chicago, Chicago IL, USA
| | - Zifeng Deng
- Department of Medicine, University of Chicago, Chicago IL, USA
| | - Nader Amini
- Department of Medicine, University of Chicago, Chicago IL, USA
| | - Vani J Konda
- Department of Medicine, Baylor University, Dallas, TX, USA
| | - Vijaya L. Rao
- Department of Medicine, University of Chicago, Chicago IL, USA
| | | | - Akushika Kwesi
- Department of Medicine, University of Chicago, Chicago IL, USA
| | - Sonia S Kupfer
- Department of Medicine, University of Chicago, Chicago IL, USA
| | | | - Loren Joseph
- Departments of Pathology, Beth Israel, Harvard Medical School, Boston, MA, USA
| | - John Hart
- Departments of Pathology, University of Chicago, Chicago IL, USA
| | - Fang He
- Departments of Orthopedics, The University of Chicago, Chicago, IL, USA
| | - Tong-Chuan He
- Departments of Orthopedics, The University of Chicago, Chicago, IL, USA
| | | | - Yan Chun Li
- Department of Medicine, University of Chicago, Chicago IL, USA
| | | |
Collapse
|
|
38
|
Shaw A, Gullerova M. Home and Away: The Role of Non-Coding RNA in Intracellular and Intercellular DNA Damage Response. Genes (Basel) 2021; 12:1475. [PMID: 34680868 PMCID: PMC8535248 DOI: 10.3390/genes12101475] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 09/20/2021] [Accepted: 09/21/2021] [Indexed: 12/14/2022] Open
Abstract
Non-coding RNA (ncRNA) has recently emerged as a vital component of the DNA damage response (DDR), which was previously believed to be solely regulated by proteins. Many species of ncRNA can directly or indirectly influence DDR and enhance DNA repair, particularly in response to double-strand DNA breaks, which may hold therapeutic potential in the context of cancer. These include long non-coding RNA (lncRNA), microRNA, damage-induced lncRNA, DNA damage response small RNA, and DNA:RNA hybrid structures, which can be categorised as cis or trans based on the location of their synthesis relative to DNA damage sites. Mechanisms of RNA-dependent DDR include the recruitment or scaffolding of repair factors at DNA break sites, the regulation of repair factor expression, and the stabilisation of repair intermediates. DDR can also be communicated intercellularly via exosomes, leading to bystander responses in healthy neighbour cells to generate a population-wide response to damage. Many microRNA species have been directly implicated in the propagation of bystander DNA damage, autophagy, and radioresistance, which may prove significant for enhancing cancer treatment via radiotherapy. Here, we review recent developments centred around ncRNA and their contributions to intracellular and intercellular DDR mechanisms.
Collapse
Affiliation(s)
| | - Monika Gullerova
- Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK;
| |
Collapse
|
|
39
|
Nishimoto Y, Nakagawa S, Okano H. NEAT1 lncRNA and amyotrophic lateral sclerosis. Neurochem Int 2021; 150:105175. [PMID: 34481908 DOI: 10.1016/j.neuint.2021.105175] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 08/14/2021] [Accepted: 08/30/2021] [Indexed: 12/15/2022]
Abstract
Amyotrophic lateral sclerosis (ALS) is a representative neurological disease that is known to devastate entire motor neurons within a period of just a few years. Discoveries of the specific pathologies of relevant RNA-binding proteins, including TAR DNA-binding protein-43 (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS/TLS), and the causative genes of both familial and sporadic ALS have provided crucial information that could lead to a cure. In recent ALS research the GGGGCC-repeat expansion in the C9orf72 gene was identified as one of the most important pathological findings, suggesting the significance of both nuclear dysfunction due to dipeptide repeat proteins (DPRs) and RNA toxicity (such as pathological alterations of non-coding RNAs). In research on model animals carrying ALS-related molecules, the determination of whether a factor is protective or toxic has been controversial. Herein, we review the findings regarding NEAT1 RNA and C9orf72 GGGGCC repeats associated with ALS, from the viewpoint of conversion from the protective stage in the nucleus in early-phase ALS to late-phase induction of cell death. This review will provide insights for the development of RNA effectors as novel ALS treatments.
Collapse
Affiliation(s)
- Yoshinori Nishimoto
- Department of Neurology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, Japan; Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, Japan.
| | - Shinichi Nakagawa
- RNA Biology Laboratory, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
| | - Hideyuki Okano
- Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, Japan.
| |
Collapse
|
|
40
|
Fu Z, Wang L, Li S, Chen F, Au-Yeung KKW, Shi C. MicroRNA as an Important Target for Anticancer Drug Development. Front Pharmacol 2021; 12:736323. [PMID: 34512363 PMCID: PMC8425594 DOI: 10.3389/fphar.2021.736323] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 08/10/2021] [Indexed: 12/15/2022] Open
Abstract
Cancer has become the second greatest cause of death worldwide. Although there are several different classes of anticancer drugs that are available in clinic, some tough issues like side-effects and low efficacy still need to dissolve. Therefore, there remains an urgent need to discover and develop more effective anticancer drugs. MicroRNAs (miRNAs) are a class of small endogenous non-coding RNAs that regulate gene expression by inhibiting mRNA translation or reducing the stability of mRNA. An abnormal miRNA expression profile was found to exist widely in cancer cell, which induces limitless replicative potential and evading apoptosis. MiRNAs function as oncogenes (oncomiRs) or tumor suppressors during tumor development and progression. It was shown that regulation of specific miRNA alterations using miRNA mimics or antagomirs can normalize the gene regulatory network and signaling pathways, and reverse the phenotypes in cancer cells. The miRNA hence provides an attractive target for anticancer drug development. In this review, we will summarize the latest publications on the role of miRNA in anticancer therapeutics and briefly describe the relationship between abnormal miRNAs and tumorigenesis. The potential of miRNA-based therapeutics for anticancer treatment has been critically discussed. And the current strategies in designing miRNA targeting therapeutics are described in detail. Finally, the current challenges and future perspectives of miRNA-based therapy are conferred.
Collapse
Affiliation(s)
- Zhiwen Fu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
| | - Liu Wang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
| | - Shijun Li
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
| | - Fen Chen
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
| | | | - Chen Shi
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
| |
Collapse
|
|
41
|
Itoh A, Adams D, Huang W, Wu Y, Kachapati K, Bednar KJ, Leung PSC, Zhang W, Flavell RA, Gershwin ME, Ridgway WM. Enoxacin Up-Regulates MicroRNA Biogenesis and Down-Regulates Cytotoxic CD8 T-Cell Function in Autoimmune Cholangitis. Hepatology 2021; 74:835-846. [PMID: 33462854 DOI: 10.1002/hep.31724] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 12/01/2020] [Accepted: 12/23/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS Primary biliary cholangitis (PBC) is a prototypical organ-specific autoimmune disease that is mediated by autoreactive T-cell attack and destruction of cholangiocytes. Despite the clear role of autoimmunity in PBC, immune-directed therapies have failed to halt PBC, including biologic therapies effective in other autoimmune diseases. MicroRNA (miRNA) dysregulation is implicated in the pathogenesis (PBC). In the dominant-negative TGF-β receptor type II (dnTGFβRII) mouse model of PBC, autoreactive CD8 T cells play a major pathogenic role and demonstrate a striking pattern of miRNA down-regulation. Enoxacin is a small molecule fluoroquinolone that enhances miRNA biogenesis, partly by stabilizing the interaction of transactivation response RNA-binding protein with Argonaute (Ago) 2. APPROACH AND RESULTS We hypothesized that correcting aberrant T-cell miRNA expression with enoxacin in dnTGFβRII mice could modulate autoreactive T-cell function and prevent PBC. Here, we show that liver-infiltrating dnTGFβRII CD8 T cells have significantly decreased levels of the miRNA biogenesis molecules prolyl 4-hydroxylase subunit alpha 1 (P4HA1) and Ago2 along with significantly increased levels of granzyme B and perforin. Enoxacin treatment significantly up-regulated miRNAs in dnTGFβRII CD8 T cells and effectively treated autoimmune cholangitis in dnTGFβRII mice. Enoxacin treatment directly altered T cells both ex vivo and in vitro, resulting in altered memory subset numbers, decreased proliferation, and decreased interferon-γ production. Enoxacin significantly decreased CD8 T-cell expression of the transcription factor, Runx3, and significantly decreased perforin expression at both the mRNA and protein levels. CONCLUSIONS Enoxacin increases miRNA expression in dnTGFβRII CD8 T cells, reduces CD8 T-cell pathogenicity, and effectively halted progression of autoimmune biliary disease. Targeting the miRNA pathway is a therapeutic approach to autoimmunity that corrects pathological miRNA abnormalities in autoreactive T cells.
Collapse
Affiliation(s)
- Arata Itoh
- Division of Immunology, Allergy and RheumatologyUniversity of Cincinnati College of MedicineCincinnatiOH
| | - David Adams
- Division of Immunology, Allergy and RheumatologyUniversity of Cincinnati College of MedicineCincinnatiOH
| | - Wenting Huang
- Division of Immunology, Allergy and RheumatologyUniversity of Cincinnati College of MedicineCincinnatiOH
| | - Yuehong Wu
- Division of Immunology, Allergy and RheumatologyUniversity of Cincinnati College of MedicineCincinnatiOH
| | - Kritika Kachapati
- Division of Immunology, Allergy and RheumatologyUniversity of Cincinnati College of MedicineCincinnatiOH
| | - Kyle J Bednar
- Division of Immunology, Allergy and RheumatologyUniversity of Cincinnati College of MedicineCincinnatiOH
| | - Patrick S C Leung
- Division of Rheumatology, Allergy and Clinical ImmunologyUniversity of California, DavisDavisCA
| | - Weici Zhang
- Division of Rheumatology, Allergy and Clinical ImmunologyUniversity of California, DavisDavisCA
| | - Richard A Flavell
- Department of Internal MedicineYale University School of MedicineNew HavenCT
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical ImmunologyUniversity of California, DavisDavisCA
| | - William M Ridgway
- Division of Immunology, Allergy and RheumatologyUniversity of Cincinnati College of MedicineCincinnatiOH.,Division of Rheumatology, Allergy and Clinical ImmunologyUniversity of California, DavisDavisCA
| |
Collapse
|
|
42
|
Li LM, Chen C, Ran RX, Huang JT, Sun HL, Zeng C, Zhang Z, Zhang W, Liu SM. Loss of TARBP2 Drives the Progression of Hepatocellular Carcinoma via miR-145-SERPINE1 Axis. Front Oncol 2021; 11:620912. [PMID: 34249676 PMCID: PMC8265608 DOI: 10.3389/fonc.2021.620912] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Accepted: 03/09/2021] [Indexed: 12/13/2022] Open
Abstract
The clinical outcomes of hepatocellular carcinoma (HCC) remain dismal. Elucidating the molecular mechanisms for the progression of aggressive HCC holds the promise for developing novel intervention strategies. The transactivation response element RNA-binding protein (TRBP/TARBP2), a key component of microRNA (miRNA) processing and maturation machinery has been shown to play conflicting roles in tumor development and progression. We sought to investigate the expression of TARBP2 in HCC using well-characterized HCC cell lines, patient-derived tissues and blood samples. Additionally, the potential prognostic and diagnostic value of TARBP2 in HCC were analyzed using Kaplan-Meier plots and ROC curve. Cell counting kit-8 (CCK-8), wound healing and transwell assays examined the ability of TARBP2 to induce cell proliferation, migration, and invasion in HCC cell lines. RNA sequencing was applied to identify the downstream elements of TARBP2. The interaction of potential targets of TARBP2, miR-145 and serpin family E member 1 (SERPINE1), was assessed using luciferase reporter assay. TARBP2 expression was down-regulated in HCC cell lines relative to normal hepatocyte cells, with a similar pattern further confirmed in tissue and blood samples. Notably, the loss of TARBP2 was demonstrated to promote proliferation, migration, and invasion in HCC cell lines. Interestingly, the reduction of TARBP2 was shown to result in the upregulation of SERPINE1, also known as plasminogen activator inhibitor (PAI-1), which is a vital gene of the HIF-1 signaling pathway. Knockdown of SERPINE1 rescued the TARBP2-lost phenotype. Moreover, TARBP2 depletion induced the upregulation of SERPINE1 through reducing the processing of miR-145, which directly targets SERPINE1. Finally, overexpression of miR-145 repressed SERPINE1 and rescued the functions in sh-TARBP2 HCC cells. Our findings underscore a linear TARBP2-miR-145-SERPINE1 pathway that drives HCC progression, with the potential as a novel intervention target for aggressive HCC.
Collapse
Affiliation(s)
- Li-Man Li
- Department of Clinical Laboratory, Center for Gene Diagnosis, and Program of Clinical Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Chang Chen
- Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Ruo-Xi Ran
- Department of Clinical Laboratory, Center for Gene Diagnosis, and Program of Clinical Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Jing-Tao Huang
- Department of Clinical Laboratory, Center for Gene Diagnosis, and Program of Clinical Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China.,Department of Clinical Laboratory, Renmin Hospital, Wuhan University, Wuhan, China
| | - Hui-Lung Sun
- Department of Chemistry and Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, Chicago, IL, United States
| | - Chang Zeng
- Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Zhou Zhang
- Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Wei Zhang
- Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States.,Institute of Precision Medicine, Jining Medical University, Jining, China
| | - Song-Mei Liu
- Department of Clinical Laboratory, Center for Gene Diagnosis, and Program of Clinical Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Province Key Laboratory of Allergy and Immunology, Wuhan, China
| |
Collapse
|
|
43
|
Tyagi G, Kapoor N, Chandra G, Gambhir L. Cure lies in nature: medicinal plants and endophytic fungi in curbing cancer. 3 Biotech 2021; 11:263. [PMID: 33996375 DOI: 10.1007/s13205-021-02803-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 04/21/2021] [Indexed: 12/15/2022] Open
Abstract
Success of targeted cancer treatment modalities has generated an ambience of plausible cure for cancer. However, cancer remains to be the major cause of mortality across the globe. The emergence of chemoresistance, relapse after treatment and associated adverse effects has posed challenges to the present therapeutic regimes. Thus, investigating new therapeutic agents of natural origin and delineating the underlying mechanism of action is necessary. Since ages and still in continuum, the phytochemicals have been the prime source of identifying bioactive agents against cancer. They have been exploited for isolating targeted specific compounds to modulate the key regulating signaling pathways of cancer pathogenesis and progression. Capsaicin (alkaloid compound in chilli), catechin, epicatechin, epigallocatechin and epigallocatechin-3-gallate (phytochemicals in green tea), lutein (carotenoid found in yellow fruits), Garcinol (phenolic compound present in kokum tree) and many other naturally available compounds are also very valuable to develop the drugs to treat the cancer. An alternate repository of similar chemical diversity exists in the form of endophytic fungi inhabiting the medicinal plants. There is a high diversity of plant associated endophytic fungi in nature which are potent producers of anti-cancer compounds and offers even stronger hope for the discovery of an efficient anti-cancer drug. These fungi provide various bioactive molecules, such as terpenoids, flavonoids, alkaloids, phenolic compounds, quinines, steroids etc. exhibiting anti-cancerous property. The review discusses the relevance of phytochemicals in chemoprevention and as modulators of miRNA. The perspective advocates the imperative role of anti-cancerous secondary metabolites containing repository of endophytic fungi, as an alternative route of drug discovery.
Collapse
Affiliation(s)
- Garima Tyagi
- Department of Biotechnology, School of Basic & Applied Sciences, Shri Guru Ram Rai University, Dehradun, Uttrakhand 248001 India
| | - Neha Kapoor
- School of Applied Sciences, Suresh Gyan Vihar University, Jaipur, Rajasthan 302017 India
| | - Girish Chandra
- Department of Seed Science and Technology, School of Agricultural Sciences, Shri Guru Ram Rai University, Dehradun, Uttrakhand 248001 India
| | - Lokesh Gambhir
- School of Applied Sciences, Suresh Gyan Vihar University, Jaipur, Rajasthan 302017 India
| |
Collapse
|
|
44
|
Targeting miRNA dysregulation with small molecules: the case of enoxacin. Future Med Chem 2021; 13:1245-1248. [PMID: 34060341 DOI: 10.4155/fmc-2021-0061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
|
|
45
|
Zhou Z, Li Y, Ma X, Cao B, Peng T, Sheng Y, Peng H, Li R, Cao Y, Xi R, Li F, Wang M, Sun H, Zhang G, Zhang H, Hu K, Xiao W, Wang F. Identification of a Novel TAR RNA-Binding Protein 2 Modulator with Potential Therapeutic Activity against Hepatocellular Carcinoma. J Med Chem 2021; 64:7404-7421. [PMID: 34038111 DOI: 10.1021/acs.jmedchem.1c00018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Imbalance miRNAs contribute to tumor formation; therefore, the development of small-molecule compounds that regulate miRNA biogenesis is an important strategy in oncotherapy. Here, (-)-Gomisin M1 (GM) was found to modulate miRNA biogenesis to inhibit the proliferation, migration, and invasion of hepatocellular carcinoma (HCC) cells. GM modulated expression profiles of miRNA and protein in HCC cells and suppressed tumor growth in a mouse model. Mechanistically, GM affected miRNA maturation by targeting TAR RNA-binding protein 2 (TRBP), with an efficacy higher than that of enoxacin, and promoted the binding of TRBP with Dicer. Structural simplification and a preliminary structure-activity relationship study via the synthesis of 20 GM derivatives showed that compound 9 exhibited more potent inhibitory activity in HCC cell proliferation and affinity for TRBP than did GM. These results suggest that TRBP may be a novel potential therapeutic target in HCC and compound 9 may be a potential drug candidate for the treatment of HCC.
Collapse
Affiliation(s)
- Zongyuan Zhou
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yiming Li
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Research & Development Center for Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming 650091, China
| | - Xiaofang Ma
- Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Biyun Cao
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Research & Development Center for Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming 650091, China
| | - Ting Peng
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yuwen Sheng
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Huipan Peng
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Runze Li
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yu Cao
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Ruiying Xi
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Fu Li
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
| | - Mengru Wang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Research & Development Center for Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming 650091, China
| | - Handong Sun
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China
| | - Guolin Zhang
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
| | - Hongbin Zhang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Research & Development Center for Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming 650091, China
| | - Kaifeng Hu
- Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Weilie Xiao
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Research & Development Center for Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming 650091, China
| | - Fei Wang
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.,Xiongan Institute of Innovation, Chinese Academy of Sciences, Hebei 071700, China
| |
Collapse
|
|
46
|
Ahmadi A, Moradi S. In silico analysis suggests the RNAi-enhancing antibiotic enoxacin as a potential inhibitor of SARS-CoV-2 infection. Sci Rep 2021; 11:10271. [PMID: 33986351 PMCID: PMC8119475 DOI: 10.1038/s41598-021-89605-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 04/29/2021] [Indexed: 02/06/2023] Open
Abstract
COVID-19 has currently become the biggest challenge in the world. There is still no specific medicine for COVID-19, which leaves a critical gap for the identification of new drug candidates for the disease. Recent studies have reported that the small-molecule enoxacin exerts an antiviral activity by enhancing the RNAi pathway. The aim of this study is to analyze if enoxacin can exert anti-SARS-CoV-2 effects. We exploit multiple computational tools and databases to examine (i) whether the RNAi mechanism, as the target pathway of enoxacin, could act on the SARS-CoV-2 genome, and (ii) microRNAs induced by enoxacin might directly silence viral components as well as the host cell proteins mediating the viral entry and replication. We find that the RNA genome of SARS-CoV-2 might be a suitable substrate for DICER activity. We also highlight several enoxacin-enhanced microRNAs which could target SARS-CoV-2 components, pro-inflammatory cytokines, host cell components facilitating viral replication, and transcription factors enriched in lung stem cells, thereby promoting their differentiation and lung regeneration. Finally, our analyses identify several enoxacin-targeted regulatory modules that were critically associated with exacerbation of the SARS-CoV-2 infection. Overall, our analysis suggests that enoxacin could be a promising candidate for COVID-19 treatment through enhancing the RNAi pathway.
Collapse
Affiliation(s)
- Amirhossein Ahmadi
- Department of Biological Science and Technology, Faculty of Nano and Bio Science and Technology, Persian Gulf University, Bushehr, 75169,, Iran
| | - Sharif Moradi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
| |
Collapse
|
|
47
|
Chattopadhyay P, Srinivasa Vasudevan J, Pandey R. Noncoding RNAs: modulators and modulatable players during infection-induced stress response. Brief Funct Genomics 2021; 20:28-41. [PMID: 33491070 PMCID: PMC7929421 DOI: 10.1093/bfgp/elaa026] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 12/09/2020] [Accepted: 12/11/2020] [Indexed: 12/16/2022] Open
Abstract
The human genome has an almost equal distribution of unique and transposable genetic elements. Although at the transcriptome level, a relatively higher contribution from transposable elements derived RNA has been reported. This is further highlighted with evidence from pervasive transcription. Of the total RNA, noncoding RNAs (ncRNAs) are significant contributors to the transcriptome pool with sizeable fraction from repetitive elements of the human genome, inclusive of Long Interspersed Nuclear Elements (LINEs) and Short Interspersed Nuclear Elements (SINEs). ncRNAs are increasingly being implicated in diverse functional roles especially during conditions of stress. These stress responses are driven through diverse mediators, inclusive of long and short ncRNAs. ncRNAs such as MALAT1, GAS5, miR-204 and miR-199a-5p have been functionally involved during oxidative stress, endoplasmic reticulum (ER) stress and unfolded protein response (UPR). Also, within SINEs, Alu RNAs derived from primate-specific Alu repeats with ~11% human genome contribution, playing a significant role. Pathogenic diseases, including the recent COVID-19, leads to differential regulation of ncRNAs. Although, limited evidence suggests the need for an inquest into the role of ncRNAs in determining the host response towards pathogen challenge.
Collapse
Affiliation(s)
| | | | - Rajesh Pandey
- Corresponding author: Rajesh Pandey, INtegrative GENomics of HOst-PathogEn (INGEN-HOPE) laboratory. CSIR-Institute of Genomics and Integrative Biology (CSIR-IGIB), North Campus, Near Jubilee Hall, Mall Road, Delhi-110007, India. Tel.: +91 9811029551; E-mail:
| |
Collapse
|
|
48
|
Dalhoff A. Selective toxicity of antibacterial agents-still a valid concept or do we miss chances and ignore risks? Infection 2021; 49:29-56. [PMID: 33367978 PMCID: PMC7851017 DOI: 10.1007/s15010-020-01536-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 10/04/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Selective toxicity antibacteribiotics is considered to be due to interactions with targets either being unique to bacteria or being characterized by a dichotomy between pro- and eukaryotic pathways with high affinities of agents to bacterial- rather than eukaryotic targets. However, the theory of selective toxicity oversimplifies the complex modes of action of antibiotics in pro- and eukaryotes. METHODS AND OBJECTIVE This review summarizes data describing multiple modes of action of antibiotics in eukaryotes. RESULTS Aminoglycosides, macrolides, oxazolidinones, chloramphenicol, clindamycin, tetracyclines, glycylcyclines, fluoroquinolones, rifampicin, bedaquillin, ß-lactams inhibited mitochondrial translation either due to binding to mitosomes, inhibition of mitochondrial RNA-polymerase-, topoisomerase 2ß-, ATP-synthesis, transporter activities. Oxazolidinones, tetracyclines, vancomycin, ß-lactams, bacitracin, isoniazid, nitroxoline inhibited matrix-metalloproteinases (MMP) due to chelation with zinc and calcium, whereas fluoroquinols fluoroquinolones and chloramphenicol chelated with these cations, too, but increased MMP activities. MMP-inhibition supported clinical efficacies of ß-lactams and daptomycin in skin-infections, and of macrolides, tetracyclines in respiratory-diseases. Chelation may have contributed to neuroprotection by ß-lactams and fluoroquinolones. Aminoglycosides, macrolides, chloramphenicol, oxazolidins oxazolidinones, tetracyclines caused read-through of premature stop codons. Several additional targets for antibiotics in human cells have been identified like interaction of fluoroquinolones with DNA damage repair in eukaryotes, or inhibition of mucin overproduction by oxazolidinones. CONCLUSION The effects of antibiotics on eukaryotes are due to identical mechanisms as their antibacterial activities because of structural and functional homologies of pro- and eukaryotic targets, so that the effects of antibiotics on mammals are integral parts of their overall mechanisms of action.
Collapse
Affiliation(s)
- Axel Dalhoff
- Christian-Albrechts-University of Kiel, Institue for Infection Medicine, Brunswiker Str. 4, D-24105, Kiel, Germany.
| |
Collapse
|
|
49
|
Scroggs SLP, Gass JT, Chinnasamy R, Widen SG, Azar SR, Rossi SL, Arterburn JB, Vasilakis N, Hanley KA. Evolution of resistance to fluoroquinolones by dengue virus serotype 4 provides insight into mechanism of action and consequences for viral fitness. Virology 2021; 552:94-106. [PMID: 33120225 PMCID: PMC7528753 DOI: 10.1016/j.virol.2020.09.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 08/30/2020] [Accepted: 09/08/2020] [Indexed: 02/07/2023]
Abstract
Drugs against flaviviruses such as dengue (DENV) and Zika (ZIKV) virus are urgently needed. We previously demonstrated that three fluoroquinolones, ciprofloxacin, enoxacin, and difloxacin, suppress replication of six flaviviruses. To investigate the barrier to resistance and mechanism(s) of action of these drugs, DENV-4 was passaged in triplicate in HEK-293 cells in the presence or absence of each drug. Resistance to ciprofloxacin was detected by the seventh passage and to difloxacin by the tenth, whereas resistance to enoxacin did not occur within ten passages. Two putative resistance-conferring mutations were detected in the envelope gene of ciprofloxacin and difloxacin-resistant DENV-4. In the absence of ciprofloxacin, ciprofloxacin-resistant viruses sustained a significantly higher viral titer than control viruses in HEK-293 and HuH-7 cells and resistant viruses were more stable than control viruses at 37 °C. These results suggest that the mechanism of action of ciprofloxacin and difloxacin involves interference with virus binding or entry.
Collapse
Affiliation(s)
- Stacey L P Scroggs
- Department of Biology, New Mexico State University, Las Cruces, NM, USA.
| | - Jordan T Gass
- Department of Biology, New Mexico State University, Las Cruces, NM, USA
| | - Ramesh Chinnasamy
- Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, NM, USA
| | - Steven G Widen
- Department of Biochemistry & Molecular Biology, The University of Texas Medical Branch, Galveston, TX, USA
| | - Sasha R Azar
- Department of Pathology, The University of University of Texas Medical Branch, Galveston, TX, USA
| | - Shannan L Rossi
- Department of Pathology, The University of University of Texas Medical Branch, Galveston, TX, USA; Institute for Human Infection and Immunity, The University of University of Texas Medical Branch, Galveston, TX, USA
| | - Jeffrey B Arterburn
- Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, NM, USA
| | - Nikos Vasilakis
- Department of Pathology, The University of University of Texas Medical Branch, Galveston, TX, USA; Center for Biodefense and Emerging Infectious Diseases, The University of University of Texas Medical Branch, Galveston, TX, USA; Center for Tropical Diseases, The University of University of Texas Medical Branch, Galveston, TX, USA; Institute for Human Infection and Immunity, The University of University of Texas Medical Branch, Galveston, TX, USA
| | - Kathryn A Hanley
- Department of Biology, New Mexico State University, Las Cruces, NM, USA
| |
Collapse
|
|
50
|
Ofoeyeno N, Ekpenyong E, Braconi C. Pathogenetic Role and Clinical Implications of Regulatory RNAs in Biliary Tract Cancer. Cancers (Basel) 2020; 13:E12. [PMID: 33375055 PMCID: PMC7792779 DOI: 10.3390/cancers13010012] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 12/18/2020] [Accepted: 12/19/2020] [Indexed: 02/07/2023] Open
Abstract
Biliary tract cancer (BTC) is characterised by poor prognosis and low overall survival in patients. This is generally due to minimal understanding of its pathogenesis, late diagnosis and limited therapeutics in preventing or treating BTC patients. Non-coding RNA (ncRNA) are small RNAs (mRNA) that are not translated to proteins. ncRNAs were considered to be of no importance in the genome, but recent studies have shown they play essential roles in biology and oncology such as transcriptional repression and degradation, thus regulating mRNA transcriptomes. This has led to investigations into the role of ncRNAs in the pathogenesis of BTC, and their clinical implications. In this review, the mechanisms of action of ncRNA are discussed and the role of microRNAs in BTC is summarised. The scope of this review will be limited to miRNA as they have been shown to play the most significant roles in BTC progression. There is huge potential in miRNA-based biomarkers and therapeutics in BTC, but more studies, research and technological advancements are required before it can be translated into clinical practice for patients.
Collapse
Affiliation(s)
- Nduka Ofoeyeno
- The Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK;
| | | | - Chiara Braconi
- The Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK;
- Beatson West of Scotland Cancer Centre, Glasgow G12 Y0N, UK
| |
Collapse
|