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Avitabile C, Cerasa MT, D'Aniello A, Saviano M, Moccia M. Recent Cutting-Edge Technologies for the Delivery of Peptide Nucleic Acid. Chemistry 2025:e202500469. [PMID: 40351137 DOI: 10.1002/chem.202500469] [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: 02/06/2025] [Revised: 04/30/2025] [Accepted: 05/05/2025] [Indexed: 05/14/2025]
Abstract
Peptide nucleic acids (PNAs) have garnered significant attention due to their enhanced chemical, physical, and binding properties in comparison to natural nucleic acids. This prompted their application in antigene/antisense approach, assigning them a pivotal role in gene editing and, more recently, showing their potential as "bilingual" molecules being able "to speak" both nucleic acid and protein language. However, to expand the applications of PNAs in therapy, the challenge of effectively delivering PNAs to cells needs to be addressed. Among several delivery approaches employed so far, the nanotechnology-based ones showed great potential. In this review, we provide an overview of the latest in the field (2019 to present), beginning from peptide-based delivery systems, as well as cutting-edge approaches involving nanoparticles, liposomes, and calixarene, showing how they have inspired the development of smarter delivery approaches to boost PNAs applications.
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Affiliation(s)
- Concetta Avitabile
- Consiglio Nazionale delle Ricerche, Istituto di Cristallografia URT-Caserta, via Vivaldi 43, Caserta, 81100, Italy
| | - Maria Teresa Cerasa
- Dipartimento di Scienze e Tecnologie Chimiche, Università di Roma Tor Vergata, via della Ricerca scientifica 1, Roma, 00133, Italy
- Consiglio Nazionale delle Ricerche, Istituto di Cristallografia, Strada Provinciale 35d, n. 9, Montelibretti (RM), Caserta, 00010, Italy
| | - Antonia D'Aniello
- Consiglio Nazionale delle Ricerche, Istituto di Cristallografia URT-Caserta, via Vivaldi 43, Caserta, 81100, Italy
| | - Michele Saviano
- Consiglio Nazionale delle Ricerche, Istituto di Cristallografia URT-Caserta, via Vivaldi 43, Caserta, 81100, Italy
| | - Maria Moccia
- Consiglio Nazionale delle Ricerche, Istituto di Cristallografia, Strada Provinciale 35d, n. 9, Montelibretti (RM), Caserta, 00010, Italy
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Alibrahim MN, Gloghini A, Carbone A. Classic Hodgkin lymphoma: Pathobiological features that impact emerging therapies. Blood Rev 2025; 71:101271. [PMID: 39904647 DOI: 10.1016/j.blre.2025.101271] [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: 11/28/2024] [Revised: 01/28/2025] [Accepted: 01/29/2025] [Indexed: 02/06/2025]
Abstract
Classic Hodgkin lymphoma (cHL) is defined by distinctive Hodgkin Reed-Sternberg (HRS) cells, which are CD30+/CD15+ multinucleated tumor cells lacking typical B-cell markers. These cells comprise <5 % of tumor mass but orchestrate an extensive immunosuppressive tumor microenvironment (TME). Classic HL was curable with radiation therapy and multi-agent chemotherapy. Despite high cure rates, treatment-related toxicities remain significant. The goals of multimodality therapy are to achieve a cure while minimizing treatment-associated toxicity. Advances in molecular insights into HRS cells have led to transformative therapies, including checkpoint inhibitors, antibody-drug conjugates like brentuximab vedotin, which have shown remarkable efficacy, especially in relapsed or refractory disease. However, challenges persist due to the heterogeneity of cHL, driven by the complex biology of HRS cells and their surrounding tumor microenvironment. Novel approaches such as single-cell RNA sequencing and circulating tumor DNA profiling provide promising strategies to address these challenges. This review examines the origin, morphology, phenotype, and genetic profiles of HRS cells, highlighting key pathobiological features, including biomarkers and Epstein-Barr Virus involvement. It also explores the biological mechanisms underlying HRS cell survival and evaluates standard and emerging therapies, offering insights into the rationale for novel treatment strategies.
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Affiliation(s)
| | - Annunziata Gloghini
- Department of Avanced Pathology, Fondazione IRCCS, Istituto Nazionale dei Tumori Milano, Italy.
| | - Antonino Carbone
- Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico, National Cancer Institute, Aviano, Italy.
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3
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Golovina E, Kokavec J, Kazantsev D, Yurikova O, Bajecny M, Savvulidi FG, Simersky R, Lenobel R, Tost J, Herynek V, Sefc L, Sebela M, Klener P, Zemanova Z, Stopka T, Vargova KS. Deficiency of miR-155 in Leukemic B-Cells Results in Cell Cycle Arrest and Deregulation of MIR155HG/TP53INP1/CDKN1A/CCND1 network. Arch Med Res 2025; 56:103124. [PMID: 39591901 DOI: 10.1016/j.arcmed.2024.103124] [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: 01/04/2024] [Revised: 07/15/2024] [Accepted: 10/30/2024] [Indexed: 11/28/2024]
Abstract
BACKGROUND Cell cycle progression and leukemia development are tightly regulated processes in which even a small imbalance in the expression of cell cycle regulatory molecules and microRNAs (miRNAs) can lead to an increased risk of cancer/leukemia development. Here, we focus on the study of a ubiquitous, multifunctional, and oncogenic miRNA-hsa-miR-155-5p (miR-155, MIR155HG), which is overexpressed in malignancies including chronic lymphocytic leukemia (CLL). Nonetheless, the precise mechanism of how miR-155 regulates the cell cycle in leukemic cells remains the subject of extensive research. METHODS We edited the CLL cell line MEC-1 by CRISPR/Cas9 to introduce a short deletion within the MIR155HG gene. To describe changes at the transcriptome and miRNome level in miR-155-deficient cells, we performed mRNA-seq/miRNA-seq and validated changes by qRT-PCR. Flow cytometry was used to measure cell cycle kinetics. A WST-1 assay, hemocytometer, and Annexin V/PI staining assessed cell viability and proliferation. RESULTS The limited but phenotypically robust miR-155 modification impaired cell proliferation, cell cycle, and cell ploidy. This was accompanied by overexpression of the negative cell cycle regulator p21/CDKN1A and Cyclin D1 (CCND1). We confirmed the overexpression of canonical miR-155 targets such as PU.1, FOS, SHIP-1, TP53INP1 and revealed new potential targets (FCRL5, ISG15, and MX1). CONCLUSIONS We demonstrate that miR-155 deficiency impairs cell proliferation, cell cycle, transcriptome, and miRNome via deregulation of the MIR155HG/TP53INP1/CDKN1A/CCND1 axis. Our CLL model is valuable for further studies to manipulate miRNA levels to revert highly aggressive leukemic cells to nearly benign or non-leukemic types.
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Affiliation(s)
- Elena Golovina
- Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Juraj Kokavec
- Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University, First Faculty of Medicine, Charles University, Vestec, Czech Republic
| | - Dmitry Kazantsev
- Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Oxana Yurikova
- Al-Farabi Kazakh National University, Faculty of Biology and Biotechnology, Almaty, Kazakhstan
| | - Martin Bajecny
- Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic; The Center for Advanced Preclinical Imaging, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Filipp Georgijevic Savvulidi
- Department of Animal Science, Faculty of Agrobiology, Food and Natural Resources, Czech University, Prague, Kamýcká, Czech Republic
| | - Radim Simersky
- Department of Chemical Biology, Faculty of Science, Palacký University, Olomouc, Czech Republic
| | - Rene Lenobel
- Laboratory of Growth Regulators, Institute of Experimental Botany of the Czech Academy of Sciences and Palacký University, Olomouc, Czech Republic
| | - Jorg Tost
- Centre National de Recherche en Génomique Humaine, CEA-Institut de Biologie Francois Jacob, Universite Paris-Saclay, Évry, France
| | - Vit Herynek
- The Center for Advanced Preclinical Imaging, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Ludek Sefc
- The Center for Advanced Preclinical Imaging, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Marek Sebela
- Department of Biochemistry, Faculty of Science, Palacký University, Olomouc, Czech Republic
| | - Pavel Klener
- Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Zuzana Zemanova
- Institute of Medical Biochemistry and Laboratory Diagnostics, General University Hospital, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Tomas Stopka
- Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University, First Faculty of Medicine, Charles University, Vestec, Czech Republic
| | - Karina Savvulidi Vargova
- Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic.
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4
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Wei X, Xiong X, Chen Z, Chen B, Zhang C, Zhang W. MicroRNA155 in non-small cell lung cancer: a potential therapeutic target. Front Oncol 2025; 15:1517995. [PMID: 39963112 PMCID: PMC11830606 DOI: 10.3389/fonc.2025.1517995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Accepted: 01/09/2025] [Indexed: 02/20/2025] Open
Abstract
Lung cancer (LC) is the second most commonly diagnosed cancer among both men and women, and it stands as the leading cause of cancer-related mortality, characterized by high rates of morbidity and mortality. Among its subtypes, non-small cell lung cancer (NSCLC) is the most prevalent and one of the most challenging malignant tumors to treat. To date, various therapeutic approaches, including surgery, radiotherapy, and chemotherapy, have been employed in the management of lung cancer; however, due to its aggressive nature, the survival rates remain low. Consequently, exploring novel treatment strategies is of paramount importance. MicroRNAs (miRNAs), a large family of non-coding RNAs, play crucial roles in regulating several key biological processes, including cell proliferation, differentiation, inflammation, and apoptosis. Among these, microRNA155(miR-155) is one of the most conserved and versatile miRNAs, predominantly overexpressed in various diseases, including malignant tumors. This review elucidates the biological functions and roles of miR-155 in NSCLC and discusses its potential significance as a therapeutic target for future research directions and clinical applications.
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Affiliation(s)
- Xiangju Wei
- The First Clinical College, Xuzhou Medical University, Xuzhou, China
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Xianmin Xiong
- The First Clinical College, Xuzhou Medical University, Xuzhou, China
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Ze Chen
- The First Clinical College, Xuzhou Medical University, Xuzhou, China
| | - Bi Chen
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Cantang Zhang
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Wenhui Zhang
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
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Han B, Kroeze A, van den Berg H, Roessink I, van den Brink NW. Modulatory effects of inorganic mercury (Hg (II)) and lead (Pb (II)) on immune responses of Pekin ducklings (Anas platyrhynchos domesticus) upon a viral-like immune challenge. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2024; 287:117267. [PMID: 39500255 DOI: 10.1016/j.ecoenv.2024.117267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Revised: 10/11/2024] [Accepted: 10/28/2024] [Indexed: 11/24/2024]
Abstract
Trace metal contamination is ubiquitous around the world and may affect the health of wildlife. Divalent trace metals, including ions of mercury (Hg) and lead (Pb), have been shown to be immunotoxic to avian species. However, little is known about the immunomodulatory effects of trace metal exposure on viral infections, especially in young birds, who may be more sensitive. Therefore, the objective of the current study is to provide more insights in the causality between trace metal exposure and the effects of exposure on the immune responses in young waterfowls. Pekin duckling was used as an animal model to investigate the effects of inorganic divalent Hg (II) and Pb (II) on avian immune responses upon a viral-like challenge with double-stranded RNA. Our results indicate that Hg (II) altered the immune gene expression 24 h post-challenge, as reflected by induction of pro-inflammatory genes IL-8, iNOS, TLR3 and TLR7, and a significant decrease of microRNA-155. Ducklings exposed to Pb (II) showed lower levels of natural antibodies, reduced white blood cell counts and lower heterophil proportions 24 h post-challenge. Although inorganic divalent Hg (II) and Pb (II) showed specific differential effects on the immune response of Pekin ducklings, the overall adverse immunomodulatory outcomes in both cases point to inflammation, impaired B-cell function, and weaker immunocompetence.
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Affiliation(s)
- Biyao Han
- Sub-department of Toxicology, Wageningen University, Wageningen, the Netherlands
| | - Alan Kroeze
- Sub-department of Toxicology, Wageningen University, Wageningen, the Netherlands
| | - Hans van den Berg
- Sub-department of Toxicology, Wageningen University, Wageningen, the Netherlands
| | - Ivo Roessink
- Wageningen Environmental Research, Wageningen, the Netherlands
| | - Nico W van den Brink
- Sub-department of Toxicology, Wageningen University, Wageningen, the Netherlands.
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Jasim SA, Ahmed AT, Kubaev A, Kyada A, Alshahrani MY, Sharma S, Al-Hetty HRAK, Vashishth R, Chauhan AS, Abosaoda MK. Exosomal microRNA as a key regulator of PI3K/AKT pathways in human tumors. Med Oncol 2024; 41:265. [PMID: 39400677 DOI: 10.1007/s12032-024-02529-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 09/27/2024] [Indexed: 10/15/2024]
Abstract
MicroRNAs (miRNAs) are conserved non-protein-coding RNAs that are naturally present in organisms and can control gene expression by suppressing the translation of mRNA or causing the degradation of mRNA. MicroRNAs are highly concentrated in the PI3K/AKT pathway, and abnormal activation of the PI3K/AKT pathway plays a role in cancer progression. The AKT/PI3K pathway is critical for cellular functions and can be stimulated by cytokines and in normal situations. It is involved in regulating various intracellular signal transduction, including development, differentiation, transcriptional regulation, protein, and synthesis. There is a growing body of evidence indicating that miRNAs, which are abundant in exosomes released by different cells, can control cellular biological activities via modulating the PI3K/AKT pathway, hence influencing cancer progression and drug resistance. This article provides an overview of the latest research progress regarding the function and medical use of the PI3K/AKT pathway and exosomal miRNA/AKT/PI3K axis in the behaviors of cancer cells.
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Affiliation(s)
- Saade Abdalkareem Jasim
- Medical Laboratory Techniques Department, Al-Maarif University College, Ramadi, Anbar, Iraq
- Biotechnology Department, College of Applied Science, Fallujah University, Anbar, Iraq
| | - Abdulrahman T Ahmed
- Department of Nursing, Al-Maarif University College, AL-Anbar Governorate, Ramadi, Iraq.
| | - Aziz Kubaev
- Department of Maxillofacial Surgery, Samarkand State Medical University, 18 Amir Temur Street, 140100, Samarkand, Uzbekistan
| | - Ashishkumar Kyada
- Department of Pharmacy, Faculty of Health Sciences, Marwadi University, Rajkot, Gujarat, 360003, India
| | - Mohammad Y Alshahrani
- King Khalid University, AlQura'a, P.O. Box 960, Abha, Saudi Arabia
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Shilpa Sharma
- Chandigarh Pharmacy College, Chandigarh Group of Colleges-Jhanjeri, Mohali, Punjab, 140307, India
| | | | - Raghav Vashishth
- Department of Surgery, National Institute of Medical Sciences, NIMS University Rajasthan, Jaipur, India
| | - Ashish Singh Chauhan
- Division of Research and Innovation, Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Munther Kadhim Abosaoda
- College of Pharmacy, the Islamic University, Najaf, Iraq
- College of Pharmacy, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- College of Pharmacy, the Islamic University of Babylon, Babylon, Iraq
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7
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Lu YY, Li Y, Chen ZL, Xiong XH, Wang QY, Dong HL, Zhu C, Cui JZ, Hu A, Wang L, Song N, Liu G, Chen HP. Genetic switch selectively kills hepatocellular carcinoma cell based on microRNA and tissue-specific promoter. Mol Cell Probes 2024; 77:101981. [PMID: 39197503 DOI: 10.1016/j.mcp.2024.101981] [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: 05/28/2024] [Revised: 08/26/2024] [Accepted: 08/26/2024] [Indexed: 09/01/2024]
Abstract
The clinical treatment of hepatocellular carcinoma (HCC) is still a heavy burden worldwide. Intracellular microRNAs (miRNAs) commonly express abnormally in cancers, thus they are potential therapeutic targets for cancer treatment. miR-21 is upregulated in HCC whereas miR-122 is enriched in normal hepatocyte but downregulated in HCC. In our study, we first generated a reporter genetic switch compromising of miR-21 and miR-122 sponges as sensor, green fluorescent protein (GFP) as reporter gene and L7Ae:K-turn as regulatory element. The reporter expression was turned up in miR-21 enriched environment while turned down in miR-122 enriched environment, indicating that the reporter switch is able to respond distinctly to different miRNA environment. Furthermore, an AAT promoter, which is hepatocyte-specific, is applied to increase the specificity to hepatocyte. A killing switch with AAT promoter and an apoptosis-inducing element, Bax, in addition to miR-21 and miR-122 significantly inhibited cell viability in Huh-7 by 70 % and in HepG2 by 60 %. By contrast, cell viability was not affected in five non-HCC cells. Thus, we provide a novel feasible strategy to improve the safety of miRNA-based therapeutic agent to cancer.
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Affiliation(s)
- Yuan-Yuan Lu
- Institutes of Physical Science and Information Technology, Anhui University, Hefei, 230000, China; Academy of Military Medical Sciences, Beijing, 100850, China
| | - Yi Li
- Academy of Military Medical Sciences, Beijing, 100850, China; Center for Disease Control and Prevention in Northern Theater Command of the People's Liberation Army, Shenyang, 110031, China
| | - Zhi-Li Chen
- Academy of Military Medical Sciences, Beijing, 100850, China
| | - Xiang-Hua Xiong
- Academy of Military Medical Sciences, Beijing, 100850, China
| | - Qing-Yang Wang
- Academy of Military Medical Sciences, Beijing, 100850, China
| | - Hao-Long Dong
- Academy of Military Medical Sciences, Beijing, 100850, China
| | - Chen Zhu
- Academy of Military Medical Sciences, Beijing, 100850, China
| | - Jia-Zhen Cui
- Academy of Military Medical Sciences, Beijing, 100850, China
| | - Ao Hu
- Institutes of Physical Science and Information Technology, Anhui University, Hefei, 230000, China; Academy of Military Medical Sciences, Beijing, 100850, China
| | - Lei Wang
- Department of Orthopedic Surgery, Senior Department of Orthopedics, The Fourth Medical Center of PLA General Hospital, Beijing, 100048, China.
| | - Na Song
- Department of Critical Care Medicine, People's Hospital of Laoling, Laoling, 253600, China
| | - Gang Liu
- Academy of Military Medical Sciences, Beijing, 100850, China.
| | - Hui-Peng Chen
- Academy of Military Medical Sciences, Beijing, 100850, China
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8
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Abedi Kichi Z, Dini N, Rojhannezhad M, Shirvani Farsani Z. Noncoding RNAs in B cell non-Hodgkins lymphoma. Gene 2024; 917:148480. [PMID: 38636814 DOI: 10.1016/j.gene.2024.148480] [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: 01/05/2024] [Revised: 04/07/2024] [Accepted: 04/15/2024] [Indexed: 04/20/2024]
Abstract
B-cell non-Hodgkins lymphomas (BCNHLs) are a category of B-cell cancers that show heterogeneity. These blood disorders are derived from different levels of B-cell maturity. Among NHL cases, ∼80-90 % are derived from B-cells. Recent studies have demonstrated that noncoding RNAs (ncRNAs) contribute to almost all parts of mechanisms and are essential in tumorigenesis, including B-cell non-Hodgkins lymphomas. The study of ncRNA dysregulations in B-cell lymphoma unravels important mysteries in lymphoma's molecular etiology. It seems also necessary for discovering novel trials as well as investigating the potential of ncRNAs as markers for their diagnosis and prognosis. In the current study, we summarize the role of ncRNAs involving miRNAs, long noncoding RNAs, as well as circular RNAs in the development or progression of BCNHLs.
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Affiliation(s)
- Zahra Abedi Kichi
- Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, IR Iran; Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians University Munich, Germany
| | - Niloofar Dini
- Department of Cell and Molecular Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Mahbubeh Rojhannezhad
- Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, IR Iran
| | - Zeinab Shirvani Farsani
- Department of Cell and Molecular Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran.
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9
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Tili E, Otsu H, Commisso TL, Palamarchuk A, Balatti V, Michaille JJ, Nuovo GJ, Croce CM. MiR-155-targeted IcosL controls tumor rejection. Proc Natl Acad Sci U S A 2024; 121:e2408649121. [PMID: 38980909 PMCID: PMC11260163 DOI: 10.1073/pnas.2408649121] [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: 05/03/2024] [Accepted: 06/08/2024] [Indexed: 07/11/2024] Open
Abstract
Elevated levels of miR-155 in solid and liquid malignancies correlate with aggressiveness of the disease. In this manuscript, we show that miR-155 targets transcripts encoding IcosL, the ligand for Inducible T-cell costimulator (Icos), thus impairing the ability of T cells to recognize and eliminate malignant cells. We specifically found that overexpression of miR-155 in B cells of Eµ-miR-155 mice causes loss of IcosL expression as they progress toward malignancy. Similarly, in mice where miR-155 expression is controlled by a Cre-Tet-OFF system, miR-155 induction led to malignant infiltrates lacking IcosL expression. Conversely, turning miR-155 OFF led to tumor regression and emergence of infiltrates composed of IcosL-positive B cells and Icos-positive T cells forming immunological synapses. Therefore, we next engineered malignant cells to express IcosL, in order to determine whether IcosL expression would increase tumor infiltration by cytotoxic T cells and reduce tumor progression. Indeed, overexpressing an IcosL-encoding cDNA in MC38 murine colon cancer cells before injection into syngeneic C57BL6 mice reduced tumor size and increased intratumor CD8+ T cell infiltration, that formed synapses with IcosL-expressing MC38 cells. Our results underscore the fact that by targeting IcosL transcripts, miR-155 impairs the infiltration of tumors by cytotoxic T cells, as well as the importance of IcosL on enhancing the immune response against malignant cells. These findings should lead to the development of more effective anticancer treatments based on maintaining, increasing, or restoring IcosL expression by malignant cells, along with impairing miR-155 activity.
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Affiliation(s)
- Esmerina Tili
- Department of Anesthesiology, Wexner Medical Center, College of Medicine, The Ohio State University, Columbus, OH43210
- The Ohio State University, Comprehensive Cancer Center, Department of Cancer Biology and Genetics, Wexner Medical Center, Columbus, OH43210
| | - Hajime Otsu
- The Ohio State University, Comprehensive Cancer Center, Department of Cancer Biology and Genetics, Wexner Medical Center, Columbus, OH43210
| | - Teresa L. Commisso
- The Ohio State University, Comprehensive Cancer Center, Department of Cancer Biology and Genetics, Wexner Medical Center, Columbus, OH43210
| | - Alexey Palamarchuk
- The Ohio State University, Comprehensive Cancer Center, Department of Cancer Biology and Genetics, Wexner Medical Center, Columbus, OH43210
| | - Veronica Balatti
- The Ohio State University, Comprehensive Cancer Center, Department of Cancer Biology and Genetics, Wexner Medical Center, Columbus, OH43210
| | - Jean-Jacques Michaille
- The Ohio State University, Comprehensive Cancer Center, Department of Cancer Biology and Genetics, Wexner Medical Center, Columbus, OH43210
| | | | - Carlo M. Croce
- The Ohio State University, Comprehensive Cancer Center, Department of Cancer Biology and Genetics, Wexner Medical Center, Columbus, OH43210
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10
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Rahmati A, Mafi A, Vakili O, Soleymani F, Alishahi Z, Yahyazadeh S, Gholinezhad Y, Rezaee M, Johnston TP, Sahebkar A. Non-coding RNAs in leukemia drug resistance: new perspectives on molecular mechanisms and signaling pathways. Ann Hematol 2024; 103:1455-1482. [PMID: 37526673 DOI: 10.1007/s00277-023-05383-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 07/22/2023] [Indexed: 08/02/2023]
Abstract
Like almost all cancer types, timely diagnosis is needed for leukemias to be effectively cured. Drug efflux, attenuated drug uptake, altered drug metabolism, and epigenetic alterations are just several of the key mechanisms by which drug resistance develops. All of these mechanisms are orchestrated by up- and downregulators, in which non-coding RNAs (ncRNAs) do not encode specific proteins in most cases; albeit, some of them have been found to exhibit the potential for protein-coding. Notwithstanding, ncRNAs are chiefly known for their contribution to the regulation of physiological processes, as well as the pathological ones, such as cell proliferation, apoptosis, and immune responses. Specifically, in the case of leukemia chemo-resistance, ncRNAs have been recognized to be responsible for modulating the initiation and progression of drug resistance. Herein, we comprehensively reviewed the role of ncRNAs, specifically its effect on molecular mechanisms and signaling pathways, in the development of leukemia drug resistance.
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Affiliation(s)
- Atefe Rahmati
- Department of Hematology and Blood Banking, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Basic Sciences, Faculty of Medicine, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - Alireza Mafi
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Omid Vakili
- Department of Clinical Biochemistry, Autophagy Research Center, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Firooze Soleymani
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Zahra Alishahi
- Department of Basic Sciences, Faculty of Medicine, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - Sheida Yahyazadeh
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Yasaman Gholinezhad
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Malihe Rezaee
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Thomas P Johnston
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, the, Islamic Republic of Iran.
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, the, Islamic Republic of Iran.
- Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, the, Islamic Republic of Iran.
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Dowaidar M. Uptake pathways of cell-penetrating peptides in the context of drug delivery, gene therapy, and vaccine development. Cell Signal 2024; 117:111116. [PMID: 38408550 DOI: 10.1016/j.cellsig.2024.111116] [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: 01/03/2024] [Revised: 02/19/2024] [Accepted: 02/21/2024] [Indexed: 02/28/2024]
Abstract
Cell-penetrating peptides have been extensively utilized for the purpose of facilitating the intracellular delivery of cargo that is impermeable to the cell membrane. The researchers have exhibited proficient delivery capabilities for oligonucleotides, thereby establishing cell-penetrating peptides as a potent instrument in the field of gene therapy. Furthermore, they have demonstrated a high level of efficiency in delivering several additional payloads. Cell penetrating peptides (CPPs) possess the capability to efficiently transport therapeutic molecules to specific cells, hence offering potential remedies for many illnesses. Hence, their utilization is imperative for the improvement of therapeutic vaccines. In contemporary studies, a plethora of cell-penetrating peptides have been unveiled, each characterized by its own distinct structural attributes and associated mechanisms. Although it is widely acknowledged that there are multiple pathways through which particles might be internalized, a comprehensive understanding of the specific mechanisms by which these particles enter cells has to be fully elucidated. The absorption of cell-penetrating peptides can occur through either direct translocation or endocytosis. However, it is worth noting that categories of cell-penetrating peptides are not commonly linked to specific entrance mechanisms. Furthermore, research has demonstrated that cell-penetrating peptides (CPPs) possess the capacity to enhance antigen uptake by cells and facilitate the traversal of various biological barriers. The primary objective of this work is to examine the mechanisms by which cell-penetrating peptides are internalized by cells and their significance in facilitating the administration of drugs, particularly in the context of gene therapy and vaccine development. The current study investigates the immunostimulatory properties of numerous vaccine components administered using different cell-penetrating peptides (CPPs). This study encompassed a comprehensive discussion on various topics, including the uptake pathways and mechanisms of cell-penetrating peptides (CPPs), the utilization of CPPs as innovative vectors for gene therapy, the role of CPPs in vaccine development, and the potential of CPPs for antigen delivery in the context of vaccine development.
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Affiliation(s)
- Moataz Dowaidar
- Bioengineering Department, King Fahd University of Petroleum and Minerals (KFUPM), Dhahran 31261, Saudi Arabia; Interdisciplinary Research Center for Hydrogen Technologies and Carbon Management, King Fahd University of Petroleum and Minerals (KFUPM), Dhahran 31261, Saudi Arabia; Biosystems and Machines Research Center, King Fahd University of Petroleum and Minerals (KFUPM), Dhahran 31261, Saudi Arabia.
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12
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Eshraghi R, Rafiei M, Hadian Jazi Z, Shafie D, Raisi A, Mirzaei H. MicroRNA-155 and exosomal microRNA-155: Small pieces in the cardiovascular diseases puzzle. Pathol Res Pract 2024; 257:155274. [PMID: 38626659 DOI: 10.1016/j.prp.2024.155274] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 03/23/2024] [Accepted: 03/26/2024] [Indexed: 04/18/2024]
Abstract
MicroRNAs (miRs, miRNAs) are known to have a part in various human illnesses, such as those related to the heart. One particular miRNA, miR-155, has been extensively studied and has been found to be involved in hematopoietic lineage differentiation, immunity, viral infections, inflammation, as well as vascular remodeling. These processes have all been connected to cardiovascular diseases, including heart failure, diabetic heart disease, coronary artery disease, and abdominal aortic aneurysm. The impacts of miR-155 depend on the type of cell it is acting on and the specific target genes involved, resulting in different mechanisms of disease. Although, the exact part of miR-155 in cardiovascular illnesses is yet not fully comprehended, as some studies have shown it to promote the development of atherosclerosis while others have shown it to prevent it. As a result, to comprehend the underlying processes of miR-155 in cardiovascular disorders, further thorough study is required. It has been discovered that exosomes that could be absorbed by adjacent or distant cells, control post-transcriptional regulation of gene expression by focusing on mRNA. Exosomal miRNAs have been found to have a range of functions, including participating in inflammatory reactions, cell movement, growth, death, autophagy, as well as epithelial-mesenchymal transition. An increasing amount of research indicates that exosomal miRNAs are important for cardiovascular health and have a major role in the development of a number of cardiovascular disorders, including pulmonary hypertension, atherosclerosis, acute coronary syndrome, heart failure, and myocardial ischemia-reperfusion injury. Herein the role of miR-155 and its exosomal form in heart diseases are summarized.
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Affiliation(s)
- Reza Eshraghi
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran.
| | - Moein Rafiei
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Zahra Hadian Jazi
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Davood Shafie
- Cardiology/Heart Failure and Transplantation, Heart Failure Research Center, Isfahan Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Arash Raisi
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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13
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Abdul Manap AS, Wisham AA, Wong FW, Ahmad Najmi HR, Ng ZF, Diba RS. Mapping the function of MicroRNAs as a critical regulator of tumor-immune cell communication in breast cancer and potential treatment strategies. Front Cell Dev Biol 2024; 12:1390704. [PMID: 38726321 PMCID: PMC11079208 DOI: 10.3389/fcell.2024.1390704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Accepted: 04/09/2024] [Indexed: 05/12/2024] Open
Abstract
Among women, breast cancer ranks as the most prevalent form of cancer, and the presence of metastases significantly reduces prognosis and diminishes overall survival rates. Gaining insights into the biological mechanisms governing the conversion of cancer cells, their subsequent spread to other areas of the body, and the immune system's monitoring of tumor growth will contribute to the advancement of more efficient and targeted therapies. MicroRNAs (miRNAs) play a critical role in the interaction between tumor cells and immune cells, facilitating tumor cells' evasion of the immune system and promoting cancer progression. Additionally, miRNAs also influence metastasis formation, including the establishment of metastatic sites and the transformation of tumor cells into migratory phenotypes. Specifically, dysregulated expression of these genes has been associated with abnormal expression of oncogenes and tumor suppressor genes, thereby facilitating tumor development. This study aims to provide a concise overview of the significance and function of miRNAs in breast cancer, focusing on their involvement as tumor suppressors in the antitumor immune response and as oncogenes in metastasis formation. Furthermore, miRNAs hold tremendous potential as targets for gene therapy due to their ability to modulate specific pathways that can either promote or suppress carcinogenesis. This perspective highlights the latest strategies developed for miRNA-based therapies.
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Affiliation(s)
- Aimi Syamima Abdul Manap
- Department of Biomedical Science, College of Veterinary Medicine, King Faisal University, Al-Ahsa, Saudi Arabia
| | | | - Fei Wen Wong
- Faculty of Biosciences, MAHSA University, Kuala Langat, Selangor, Malaysia
| | | | - Zhi Fei Ng
- Faculty of Biosciences, MAHSA University, Kuala Langat, Selangor, Malaysia
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14
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Baydemir I, Dulfer EA, Netea MG, Domínguez-Andrés J. Trained immunity-inducing vaccines: Harnessing innate memory for vaccine design and delivery. Clin Immunol 2024; 261:109930. [PMID: 38342415 DOI: 10.1016/j.clim.2024.109930] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 02/05/2024] [Accepted: 02/06/2024] [Indexed: 02/13/2024]
Abstract
While the efficacy of many current vaccines is well-established, various factors can diminish their effectiveness, particularly in vulnerable groups. Amidst emerging pandemic threats, enhancing vaccine responses is critical. Our review synthesizes insights from immunology and epidemiology, focusing on the concept of trained immunity (TRIM) and the non-specific effects (NSEs) of vaccines that confer heterologous protection. We elucidate the mechanisms driving TRIM, emphasizing its regulation through metabolic and epigenetic reprogramming in innate immune cells. Notably, we explore the extended protective scope of vaccines like BCG and COVID-19 vaccines against unrelated infections, underscoring their role in reducing neonatal mortality and combating diseases like malaria and yellow fever. We also highlight novel strategies to boost vaccine efficacy, incorporating TRIM inducers into vaccine formulations to enhance both specific and non-specific immune responses. This approach promises significant advancements in vaccine development, aiming to improve global public health outcomes, especially for the elderly and immunocompromised populations.
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Affiliation(s)
- Ilayda Baydemir
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Nijmegen Medical Centre, 6500HB Nijmegen, the Netherlands
| | - Elisabeth A Dulfer
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Nijmegen Medical Centre, 6500HB Nijmegen, the Netherlands.
| | - Mihai G Netea
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Nijmegen Medical Centre, 6500HB Nijmegen, the Netherlands; Department of Immunology and Metabolism, Life & Medical Sciences Institute, University of Bonn, Bonn, Germany
| | - Jorge Domínguez-Andrés
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Nijmegen Medical Centre, 6500HB Nijmegen, the Netherlands
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15
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MacLelland V, Kravitz M, Gupta A. Therapeutic and diagnostic applications of antisense peptide nucleic acids. MOLECULAR THERAPY. NUCLEIC ACIDS 2024; 35:102086. [PMID: 38204913 PMCID: PMC10777018 DOI: 10.1016/j.omtn.2023.102086] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/12/2024]
Abstract
Peptide nucleic acids (PNAs) are synthetic nucleic acid analogs with a neutral N-(2-aminoethyl) glycine backbone. PNAs possess unique physicochemical characteristics such as increased resistance to enzymatic degradation, ionic strength and stability over a wide range of temperatures and pH, and low intrinsic electrostatic repulsion against complementary target oligonucleotides. PNA has been widely used as an antisense oligonucleotide (ASO). Despite the favorable characteristics of PNA, in comparison with other ASO technologies, the use of antisense PNA for novel therapeutics has lagged. This review provides a brief overview of PNA, its antisense mechanisms of action, delivery strategies, and highlights successful applications of PNA, focusing on anti-pathogenic, anti-neurodegenerative disease, anti-cancer, and diagnostic agents. For each application, several studies are discussed focusing on the different target sites of the PNA, design of different PNAs and the therapeutic outcome in different cell lines and animal models. Thereafter, persisting limitations slowing the successful integration of antisense PNA therapeutics are discussed in order to highlight actionable next steps in the development and optimization of PNA as an ASO.
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Affiliation(s)
- Victoria MacLelland
- Department of Pharmaceutical Sciences, University of Saint Joseph, West Hartford, CT 06117, USA
| | - Madeline Kravitz
- Department of Pharmaceutical Sciences, University of Saint Joseph, West Hartford, CT 06117, USA
| | - Anisha Gupta
- Department of Pharmaceutical Sciences, University of Saint Joseph, West Hartford, CT 06117, USA
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16
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Darbandi M, Bado IL. Tumor Microenvironment and Epigenetic Implications in Breast Cancer Progression. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1465:15-36. [PMID: 39586991 DOI: 10.1007/978-3-031-66686-5_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/27/2024]
Abstract
Breast cancer (BC) poses significant challenges, driven by its diverse nature and intricate dynamics. Epigenetic modifications, such as DNA methylation, histone modifications, and noncoding RNAs, have emerged as key regulators of gene expression and BC metastasis plasticity or therapeutic resistance. Targeting epigenetic regulators and pathways associated with therapeutic resistance holds promise for overcoming treatment obstacles and enhancing treatment efficacy.
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Affiliation(s)
- Mahsa Darbandi
- Department of Oncological Sciences, Tish Cancer Institute, Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - Igor L Bado
- Department of Oncological Sciences, Tish Cancer Institute, Icahn School of Medicine at Mount Sinai, New York City, NY, USA.
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17
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Gupta P, Sharma A, Mittal V. Polymeric Vehicles for Nucleic Acid Delivery: Enhancing the Therapeutic Efficacy and Cellular Uptake. RECENT ADVANCES IN DRUG DELIVERY AND FORMULATION 2024; 18:276-293. [PMID: 39356099 DOI: 10.2174/0126673878324536240805060143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 06/19/2024] [Accepted: 07/02/2024] [Indexed: 10/03/2024]
Abstract
BACKGROUND Therapeutic gene delivery may be facilitated by the use of polymeric carriers. When combined with nucleic acids to form nanoparticles or polyplexes, a variety of polymers may shield the cargo from in vivo breakdown and clearance while also making it easier for it to enter intracellular compartments. AIM AND OBJECTIVES Polymer synthesis design choices result in a wide variety of compounds and vehicle compositions. Depending on the application, these characteristics may be changed to provide enhanced endosomal escape, longer-lasting distribution, or stronger connection with nucleic acid cargo and cells. Here, we outline current methods for delivering genes in preclinical and clinical settings using polymers. METHODOLOGY Significant therapeutic outcomes have previously been attained using genetic material- delivering polymer vehicles in both in-vitro and animal models. When combined with nucleic acids to form nanoparticles or polyplexes, a variety of polymers may shield the cargo from in vivo breakdown and clearance while also making it easier for it to enter intracellular compartments. Many innovative diagnoses for nucleic acids have been investigated and put through clinical assessment in the past 20 years. RESULTS Polymer-based carriers have additional delivery issues due to their changes in method and place of biological action, as well as variances in biophysical characteristics. We cover recent custom polymeric carrier architectures that were tuned for nucleic acid payloads such genomemodifying nucleic acids, siRNA, microRNA, and plasmid DNA. CONCLUSION In conclusion, the development of polymeric carriers for gene delivery holds promise for therapeutic applications. Through careful design and optimization, these carriers can overcome various challenges associated with nucleic acid delivery, offering new avenues for treating a wide range of diseases.
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Affiliation(s)
- Parul Gupta
- Department of Pharmaceutics, Guru Gobind Singh College of Pharmacy, Yamunanagar, Haryana, 135001, India
| | - Anjali Sharma
- Department of Pharmaceutics, Guru Gobind Singh College of Pharmacy, Yamunanagar, Haryana, 135001, India
| | - Vishnu Mittal
- Department of Pharmaceutics, Guru Gobind Singh College of Pharmacy, Yamunanagar, Haryana, 135001, India
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18
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Hudson K, Mondia MW, Zhang Y, Saha S, Gibert MK, Dube C, Sun Y, Marcinkiewicz P, Fadul C, Abounader R. The role of microRNAs in brain metastasis. J Neurooncol 2024; 166:231-241. [PMID: 38194195 PMCID: PMC10834572 DOI: 10.1007/s11060-023-04541-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 12/12/2023] [Indexed: 01/10/2024]
Abstract
Brain metastasis (BM) is the most common type of brain tumor and frequently foreshadows disease progression and poor overall survival with patients having a median survival of 6 months. 70,000 new cases of BM are diagnosed each year in the United States (US) and the incidence rate for BM is increasing with improved detection. MicroRNAs (miRNAs) are small non-coding RNAs that serve as critical regulators of gene expression and can act as powerful oncogenes and tumor suppressors. MiRNAs have been heavily implicated in cancer and proposed as biomarkers or therapeutic targets or agents. In this review, we summarize an extensive body of scientific work investigating the role of microRNAs in BM. We discuss miRNA dysregulation, functions, targets, and mechanisms of action in BM and present the current standing of miRNAs as biomarkers and potential therapeutics for BM. We conclude with future directions of miRNA basic and clinical research in BM.
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Affiliation(s)
- Kadie Hudson
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, USA
| | - Mark Willy Mondia
- Department of Neurology, University of Virginia, Charlottesville, VA, USA
| | - Ying Zhang
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, USA
| | - Shekhar Saha
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, USA
| | - Myron K Gibert
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, USA
| | - Collin Dube
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, USA
| | - Yunan Sun
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, USA
| | - Pawel Marcinkiewicz
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, USA
| | - Camilo Fadul
- Department of Neurology, University of Virginia, Charlottesville, VA, USA
| | - Roger Abounader
- Department of Microbiology, Immunology, and Cancer Biology, Department of Neurology, University of Virginia, University of Virginia Cancer Center, Charlottesville, VA, USA.
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19
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Watanabe T. Gene targeted and immune therapies for nodal and gastrointestinal follicular lymphomas. World J Gastroenterol 2023; 29:6179-6197. [PMID: 38186866 PMCID: PMC10768399 DOI: 10.3748/wjg.v29.i48.6179] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Revised: 11/02/2023] [Accepted: 12/18/2023] [Indexed: 12/27/2023] Open
Abstract
Follicular lymphoma (FL) is the most common indolent B-cell lymphoma (BCL) globally. Recently, its incidence has increased in Europe, the United States, and Asia, with the number of gastrointestinal FL cases expected to increase. Genetic abnormalities related to t(14;18) translocation, BCL2 overexpression, NF-κB pathway-related factors, histone acetylases, and histone methyltransferases cause FL and enhance its proliferation. Meanwhile, microRNAs are commonly used in diagnosing FL and predicting patient prognosis. Many clinical trials on novel therapeutics targeting these genetic abnormalities and immunomodulatory mechanisms have been conducted, resulting in a marked improvement in therapeutic outcomes for FL. Although developing these innovative therapeutic agents targeting specific genetic mutations and immune pathways has provided hope for curative options, FL treatment has become more complex, requiring combinatorial therapeutic regimens. However, optimal treatment combinations have not yet been achieved, highlighting the importance of a complete under-standing regarding the pathogenesis of gastrointestinal FL. Accordingly, this article reviews key research on the molecular pathogenesis of nodal FL and novel therapies targeting the causative genetic mutations. Moreover, the results of clinical trials are summarized, with a particular focus on treating nodal and gastrointestinal FLs.
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Affiliation(s)
- Takuya Watanabe
- Department of Internal Medicine and Gastroenterology, Watanabe Internal Medicine Aoyama Clinic, Niigata 9502002, Japan
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20
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Singh G, Monga V. Peptide Nucleic Acids: Recent Developments in the Synthesis and Backbone Modifications. Bioorg Chem 2023; 141:106860. [PMID: 37748328 DOI: 10.1016/j.bioorg.2023.106860] [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: 04/12/2023] [Revised: 09/07/2023] [Accepted: 09/09/2023] [Indexed: 09/27/2023]
Abstract
Nucleic acid represents the ideal drug candidate for protein targets that are hard to target or against which drug development is not easy. Peptide nucleic acids (PNAs) are synthesized by attaching modified peptide backbones generally derived from repetitive N-2-aminoethyl glycine units in place of the regular phosphodiester backbone and represent synthetic impersonator of nucleic acids that offers an exciting research field due to their fascinating spectrum of biotechnological, diagnostic and potential therapeutic applications. The semi-rigid peptide nucleic acid backbone serves as a nearly-perfect template for attaching complimentary base pairs on DNA or RNA in a sequence-dependent manner as described by Watson-Crick models. PNAs and their analogues are endowed with exceptionally high affinity and specificity for receptor sites, essentially due to their polyamide backbone's uncharged and flexible nature. The present review compiled various strategies to modify the polypeptide backbone for improving the target selectivity and stability of the PNAs in the body. The investigated biological activities carried out on PNAs have also been summarized in the present review.
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Affiliation(s)
- Gurpreet Singh
- Department of Pharmaceutical Chemistry, ISF College of Pharmacy, GT Road, Ghal Kalan, Moga 142001, Punjab, India
| | - Vikramdeep Monga
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, VPO-Ghudda, Bathinda 151401, Punjab, India.
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21
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Shao J, Zhang Y, Chang Z, Du S, Li W, Bai Y, Lu C, Xu T. A novel ferroptosis-related microRNA signature with prognostic value in osteosarcoma. Acta Biochim Biophys Sin (Shanghai) 2023; 55:1758-1769. [PMID: 37814812 PMCID: PMC11000229 DOI: 10.3724/abbs.2023236] [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: 02/20/2023] [Accepted: 05/06/2023] [Indexed: 10/11/2023] Open
Abstract
The induction of ferroptosis is suggested to be a potential therapeutic strategy for cancers. MicroRNAs (miRNAs) are reported to play an important role in cell death processes. This study aims to construct and validate a risk model based on ferroptosis-related miRNAs (FR_miRNAs) to predict prognosis and identify novel therapeutic targets for osteosarcoma. Data from the Therapeutically Applicable Research to Generate Effective Treatments database are used as the training cohort. A prognostic signature based on two FR_miRNAs (miR-635 and miR-593) is developed using univariate Cox regression, least absolute shrinkage and selection operator regression, and multivariate Cox regression analyses. The area under the curve values of the prognostic signature to predict the 1-year, 2-year, 3-year, and 5-year overall survival rates in patients with osteosarcoma are 0.782, 0.781, 0.722, and 0.777, respectively, indicating a good predictive ability. Based on the risk score, patients are divided into low-risk and high-risk groups. Patients with high-risk scores are associated with poor survival. The risk level is determined to be an independent prognostic factor. A nomogram is established for predicting prognosis. The expression levels of PRNP (miR-635-related ferroptosis-related gene (FRG); P=0.024) and HILPDA (miR-593-related FRG; P=0.025) are significantly different between the low-risk and high-risk groups. All results are validated in an external cohort (GSE39040). The results of the functional assay reveal that miR-635 mimics inhibit osteosarcoma (OS) cell proliferation and migration, whereas miR-593 overexpression exerts the opposite effect. In conclusion, miR-635 and miR-593 exert contrasting regulatory effects on OS cell proliferation and migration.
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Affiliation(s)
- Jie Shao
- Department of Spine SurgeryChanghai HospitalNaval Medical University (Second Military Medical
University)Shanghai200043China
| | - Yi Zhang
- Department of Spine SurgeryChanghai HospitalNaval Medical University (Second Military Medical
University)Shanghai200043China
| | - Zhu Chang
- Department of Orthopaedic SurgeryNaval Medical University (Second Military Medical
University)Shanghai200052China
| | - Shiyao Du
- Department of Orthopaedic SurgeryNaval Medical University (Second Military Medical
University)Shanghai200052China
| | - Wei Li
- Department of Spine SurgeryChanghai HospitalNaval Medical University (Second Military Medical
University)Shanghai200043China
| | - Yushu Bai
- Department of Spine SurgeryChanghai HospitalNaval Medical University (Second Military Medical
University)Shanghai200043China
| | - Chunwen Lu
- Department of Orthopaedic SurgeryNaval Medical University (Second Military Medical
University)Shanghai200052China
| | - Tianming Xu
- Department of Orthopaedic SurgeryNaval Medical University (Second Military Medical
University)Shanghai200052China
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22
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Li H, Liu J, Qin X, Sun J, Liu Y, Jin F. Function of Long Noncoding RNAs in Glioma Progression and Treatment Based on the Wnt/β-Catenin and PI3K/AKT Signaling Pathways. Cell Mol Neurobiol 2023; 43:3929-3942. [PMID: 37747595 PMCID: PMC11407728 DOI: 10.1007/s10571-023-01414-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 09/09/2023] [Indexed: 09/26/2023]
Abstract
Gliomas are a deadly primary malignant tumor of the central nervous system, with glioblastoma (GBM) representing the most aggressive type. The clinical prognosis of GBM patients remains bleak despite the availability of multiple options for therapy, which has needed us to explore new therapeutic methods to face the rapid progression, short survival, and therapy resistance of glioblastomas. As the Human Genome Project advances, long noncoding RNAs (lncRNAs) have attracted the attention of researchers and clinicians in cancer research. Numerous studies have found aberrant expression of signaling pathways in glioma cells. For example, lncRNAs not only play an integral role in the drug resistance process by regulating the Wnt/β-catenin or PI3K/Akt signaling but are also involved in a variety of malignant biological behaviors such as glioma proliferation, migration, invasion, and tumor apoptosis. Therefore, the present review systematically assesses the existing research evidence on the malignant progression and drug resistance of glioma, focusing on the critical role and potential function of lncRNAs in the Wnt/β-catenin and PI3K/Akt classical pathways to promote and encourage further research in this field.
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Affiliation(s)
- Hanyun Li
- Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Jilan Liu
- Department of Medical Research Center, Affiliated Hospital of Jining Medical University, Jining, 272029, Shandong, China
| | - Xianyun Qin
- Department of Medical Research Center, Affiliated Hospital of Jining Medical University, Jining, 272029, Shandong, China
| | - Jikui Sun
- Department of Neurosurgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Medicine and Health Key Laboratory of Neurosurgery, Jinan, 250014, China.
| | - Yan Liu
- Cheeloo College of Medicine, Shandong University, Jinan, 250012, China.
- School of Mental Health, Jining Medical University, Jining, 272013, China.
| | - Feng Jin
- The Affiliated Qingdao Central Hospital of Qingdao University, The Second Affiliated Hospital of Medical College of Qingdao University, Qingdao, 266042, China.
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23
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Zhang P, Guo R, Zhang H, Yang W, Tian Y. Fluoropolymer Coated DNA Nanoclews for Volumetric Visualization of Oligonucleotides Delivery and Near Infrared Light Activated Anti-Angiogenic Oncotherapy. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2304633. [PMID: 37768835 PMCID: PMC10646232 DOI: 10.1002/advs.202304633] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Indexed: 09/30/2023]
Abstract
The potential of microRNA regulation in oncotherapy is limited by the lack of delivery vehicles. Herein, it is shown that fluoropolymer coated DNA nanoclews (FNCs) provide outstanding ability to deliver oligonucleotide through circulation and realize near infrared (NIR) light activated angiogenesis suppression to abrogate tumors. Oligonucleotides are loaded in DNA nanoclews through sequence specific bindings and then a fluorinated zwitterionic polymer is coated onto the surface of nanoclews. Further incorporating quantum dots in the polymer coating endows the vectors with NIR-IIb (1500-1700 nm) fluorescence and NIR light triggered release ability. The FNC vector can deliver oligonucleotides to cancer cells systemically and realize on-demand cytosolic release of the cargo with high transfection efficiency. Taking advantage of the NIR-IIb emission, the whole delivery process of FNCs is visualized volumetrically in vivo with a NIR light sheet microscope. Loaded by FNCs, an oligonucleotide can effectively silence the target miRNA when activated with NIR light, and inhibit angiogenesis inside tumor, leading to complete ablation of cancer. These findings suggest FNCs can be used as an efficient oligonucleotide delivery platform to modulate the expression of endogenous microRNA in gene therapy of cancer.
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Affiliation(s)
- Peng Zhang
- Biomaterials Research CenterSchool of Biomedical EngineeringGuangdong Provincial Key Laboratory of Construction and Detection in Tissue EngineeringSouthern Medical UniversityGuangzhou510515China
| | - Ranran Guo
- School of Biomedical EngineeringGuangzhou Medical UniversityGuangzhou510182China
| | - Haiting Zhang
- Biomaterials Research CenterSchool of Biomedical EngineeringGuangdong Provincial Key Laboratory of Construction and Detection in Tissue EngineeringSouthern Medical UniversityGuangzhou510515China
| | - Wuli Yang
- State Key Laboratory of Molecular Engineering of Polymers & Department of Macromolecular ScienceFudan UniversityShanghai200438China
| | - Ye Tian
- Biomaterials Research CenterSchool of Biomedical EngineeringGuangdong Provincial Key Laboratory of Construction and Detection in Tissue EngineeringSouthern Medical UniversityGuangzhou510515China
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24
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Moutabian H, Radi UK, Saleman AY, Adil M, Zabibah RS, Chaitanya MNL, Saadh MJ, Jawad MJ, Hazrati E, Bagheri H, Pal RS, Akhavan-Sigari R. MicroRNA-155 and cancer metastasis: Regulation of invasion, migration, and epithelial-to-mesenchymal transition. Pathol Res Pract 2023; 250:154789. [PMID: 37741138 DOI: 10.1016/j.prp.2023.154789] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Revised: 08/24/2023] [Accepted: 09/01/2023] [Indexed: 09/25/2023]
Abstract
Among the leading causes of death globally has been cancer. Nearly 90% of all cancer-related fatalities are attributed to metastasis, which is the growing of additional malignant growths out of the original cancer origin. Therefore, a significant clinical need for a deeper comprehension of metastasis exists. Beginning investigations are being made on the function of microRNAs (miRNAs) in the metastatic process. Tiny non-coding RNAs called miRNAs have a crucial part in controlling the spread of cancer. Some miRNAs regulate migration, invasion, colonization, cancer stem cells' properties, the epithelial-mesenchymal transition (EMT), and the microenvironment, among other processes, to either promote or prevent metastasis. One of the most well-conserved and versatile miRNAs, miR-155 is primarily distinguished by overexpression in a variety of illnesses, including malignant tumors. It has been discovered that altered miR-155 expression is connected to a number of physiological and pathological processes, including metastasis. As a result, miR-155-mediated signaling pathways were identified as possible cancer molecular therapy targets. The current research on miR-155, which is important in controlling cancer cells' invasion, and metastasis as well as migration, will be summarized in the current work. The crucial significance of the lncRNA/circRNA-miR-155-mRNA network as a crucial regulator of carcinogenesis and a player in the regulation of signaling pathways or related genes implicated in cancer metastasis will be covered in the final section. These might provide light on the creation of fresh treatment plans for controlling cancer metastasis.
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Affiliation(s)
- Hossein Moutabian
- Radiation Sciences Research Center (RSRC), AJA University of Medical Sciences, Tehran, Iran
| | - Usama Kadem Radi
- College of Pharmacy, National University of Science and Technology, Dhi Qar, Iraq
| | | | | | - Rahman S Zabibah
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | - Mv N L Chaitanya
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144402, India
| | - Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman 11831, Jordan; Applied Science Research Center. Applied Science Private University, Amman, Jordan
| | | | - Ebrahi Hazrati
- Trauma Research Center, AJA University of Medical Sciences, Tehran, Iran
| | - Hamed Bagheri
- Radiation Sciences Research Center (RSRC), AJA University of Medical Sciences, Tehran, Iran; Radiation Biology Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Rashmi Saxena Pal
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144402, India
| | - Reza Akhavan-Sigari
- Department of Neurosurgery, University Medical Center, Tuebingen, Germany; Department of Health Care Management and Clinical Research, Collegium Humanum Warsaw Management University, Warsaw, Poland
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25
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Gasparello J, Papi C, Zurlo M, Volpi S, Gambari R, Corradini R, Casnati A, Sansone F, Finotti A. Cationic Calix[4]arene Vectors to Efficiently Deliver AntimiRNA Peptide Nucleic Acids (PNAs) and miRNA Mimics. Pharmaceutics 2023; 15:2121. [PMID: 37631335 PMCID: PMC10460053 DOI: 10.3390/pharmaceutics15082121] [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: 06/04/2023] [Revised: 08/03/2023] [Accepted: 08/04/2023] [Indexed: 08/27/2023] Open
Abstract
One of the most appealing approaches for regulating gene expression, named the "microRNA therapeutic" method, is based on the regulation of the activity of microRNAs (miRNAs), the intracellular levels of which are dysregulated in many diseases, including cancer. This can be achieved by miRNA inhibition with antimiRNA molecules in the case of overexpressed microRNAs, or by using miRNA-mimics to restore downregulated microRNAs that are associated with the target disease. The development of new efficient, low-toxic, and targeted vectors of such molecules represents a key topic in the field of the pharmacological modulation of microRNAs. We compared the delivery efficiency of a small library of cationic calix[4]arene vectors complexed with fluorescent antimiRNA molecules (Peptide Nucleic Acids, PNAs), pre-miRNA (microRNA precursors), and mature microRNAs, in glioma- and colon-cancer cellular models. The transfection was assayed by cytofluorimetry, cell imaging assays, and RT-qPCR. The calix[4]arene-based vectors were shown to be powerful tools to facilitate the uptake of both neutral (PNAs) and negatively charged (pre-miRNAs and mature microRNAs) molecules showing low toxicity in transfected cells and ability to compete with commercially available vectors in terms of delivery efficiency. These results could be of great interest to validate microRNA therapeutics approaches for future application in personalized treatment and precision medicine.
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Affiliation(s)
- Jessica Gasparello
- Section of Biochemistry and Molecular Biology, Department of Life Sciences and Biotechnology, University of Ferrara, 44121 Ferrara, Italy; (J.G.); (C.P.); (M.Z.); (R.G.)
| | - Chiara Papi
- Section of Biochemistry and Molecular Biology, Department of Life Sciences and Biotechnology, University of Ferrara, 44121 Ferrara, Italy; (J.G.); (C.P.); (M.Z.); (R.G.)
| | - Matteo Zurlo
- Section of Biochemistry and Molecular Biology, Department of Life Sciences and Biotechnology, University of Ferrara, 44121 Ferrara, Italy; (J.G.); (C.P.); (M.Z.); (R.G.)
| | - Stefano Volpi
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, 43124 Parma, Italy; (S.V.); (R.C.); (A.C.)
| | - Roberto Gambari
- Section of Biochemistry and Molecular Biology, Department of Life Sciences and Biotechnology, University of Ferrara, 44121 Ferrara, Italy; (J.G.); (C.P.); (M.Z.); (R.G.)
| | - Roberto Corradini
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, 43124 Parma, Italy; (S.V.); (R.C.); (A.C.)
| | - Alessandro Casnati
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, 43124 Parma, Italy; (S.V.); (R.C.); (A.C.)
| | - Francesco Sansone
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, 43124 Parma, Italy; (S.V.); (R.C.); (A.C.)
| | - Alessia Finotti
- Section of Biochemistry and Molecular Biology, Department of Life Sciences and Biotechnology, University of Ferrara, 44121 Ferrara, Italy; (J.G.); (C.P.); (M.Z.); (R.G.)
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26
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Datta N, Johnson C, Kao D, Gurnani P, Alexander C, Polytarchou C, Monaghan TM. MicroRNA-based therapeutics for inflammatory disorders of the microbiota-gut-brain axis. Pharmacol Res 2023; 194:106870. [PMID: 37499702 DOI: 10.1016/j.phrs.2023.106870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Revised: 07/22/2023] [Accepted: 07/24/2023] [Indexed: 07/29/2023]
Abstract
An emerging but less explored shared pathophysiology across microbiota-gut-brain axis disorders is aberrant miRNA expression, which may represent novel therapeutic targets. miRNAs are small, endogenous non-coding RNAs that are important transcriptional repressors of gene expression. Most importantly, they regulate the integrity of the intestinal epithelial and blood-brain barriers and serve as an important communication channel between the gut microbiome and the host. A well-defined understanding of the mode of action, therapeutic strategies and delivery mechanisms of miRNAs is pivotal in translating the clinical applications of miRNA-based therapeutics. Accumulating evidence links disorders of the microbiota-gut-brain axis with a compromised gut-blood-brain-barrier, causing gut contents such as immune cells and microbiota to enter the bloodstream leading to low-grade systemic inflammation. This has the potential to affect all organs, including the brain, causing central inflammation and the development of neurodegenerative and neuropsychiatric diseases. In this review, we have examined in detail miRNA biogenesis, strategies for therapeutic application, delivery mechanisms, as well as their pathophysiology and clinical applications in inflammatory gut-brain disorders. The research data in this review was drawn from the following databases: PubMed, Google Scholar, and Clinicaltrials.gov. With increasing evidence of the pathophysiological importance for miRNAs in microbiota-gut-brain axis disorders, therapeutic targeting of cross-regulated miRNAs in these disorders displays potentially transformative and translational potential. Further preclinical research and human clinical trials are required to further advance this area of research.
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Affiliation(s)
- Neha Datta
- School of Medicine, University of Nottingham, Nottingham, UK
| | - Charlotte Johnson
- NIHR Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK; Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK
| | - Dina Kao
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Pratik Gurnani
- Division of Molecular Therapeutics & Formulation, School of Pharmacy, University of Nottingham, Nottingham, UK
| | - Cameron Alexander
- Division of Molecular Therapeutics & Formulation, School of Pharmacy, University of Nottingham, Nottingham, UK
| | - Christos Polytarchou
- Department of Biosciences, John van Geest Cancer Research Centre, School of Science & Technology, Nottingham Trent University, Nottingham, UK.
| | - Tanya M Monaghan
- NIHR Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK; Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK.
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27
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Kasina V, Wahane A, Liu CH, Yang L, Nieh MP, Slack FJ, Bahal R. Next-generation poly-L-histidine formulations for miRNA mimic delivery. Mol Ther Methods Clin Dev 2023; 29:271-283. [PMID: 37123088 PMCID: PMC10133875 DOI: 10.1016/j.omtm.2023.03.015] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 03/29/2023] [Indexed: 04/03/2023]
Abstract
Many diseases, especially cancer, are caused by the abnormal expression of non-coding microRNAs (miRNAs), which regulate gene expression, leading to the development of miRNA-based therapeutics. Synthetic miRNA inhibitors have shown promising efficacy in blocking the activity of aberrant miRNAs that are upregulated in disease-specific pathologies. On the other hand, miRNAs that aid in preventing certain diseases and are reduced in expression in the disease state need different strategies. To tackle this, miRNA mimics, which mimic the activity of endogenous miRNAs, can be delivered for those miRNAs downregulated in different disease states. However, the delivery of miRNA mimics remains a challenge. Here, we report a cationic polylactic-co-glycolic acid (PLGA)-poly-L-histidine delivery system to deliver miRNA mimics. We chose miR-34a mimics as a proof of concept for miRNA delivery. miR-34a-loaded PLGA-poly-L-histidine nanoparticles (NPs) were formulated and biophysically characterized to analyze the structural properties of miRNA mimic-loaded NPs. In vitro efficacy was determined by investigating miR-34a and downstream target levels and performing cell viability and apoptosis assays. We confirmed in vivo efficacy through prolonged survival of miR-34a NP-treated A549-derived xenograft mice treated intratumorally. The results of these studies establish PLGA-poly-L-histidine NPs as an effective delivery system for miRNA mimics for treating diseases characterized by downregulated miRNAs.
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Affiliation(s)
- Vishal Kasina
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA
| | - Aniket Wahane
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA
| | - Chung-Hao Liu
- Polymer Program, Institute of Materials Science, University of Connecticut, Storrs, CT 06269, USA
| | - Lin Yang
- National Synchrotron Light Source II, Brookhaven National Laboratory, Upton, NY 11973, USA
| | - Mu-Ping Nieh
- Polymer Program, Institute of Materials Science, University of Connecticut, Storrs, CT 06269, USA
- Department of Chemical and Biomolecular Engineering, University of Connecticut, Storrs, CT 06269, USA
| | - Frank J. Slack
- Department of Pathology, HMS Initiative for RNA Medicine, BIDMC Cancer Center, Harvard Medical School, Boston, MA 02215, USA
| | - Raman Bahal
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA
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28
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Wang N, Ma T, Yu B. Targeting epigenetic regulators to overcome drug resistance in cancers. Signal Transduct Target Ther 2023; 8:69. [PMID: 36797239 PMCID: PMC9935618 DOI: 10.1038/s41392-023-01341-7] [Citation(s) in RCA: 136] [Impact Index Per Article: 68.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Revised: 01/15/2023] [Accepted: 01/28/2023] [Indexed: 02/18/2023] Open
Abstract
Drug resistance is mainly responsible for cancer recurrence and poor prognosis. Epigenetic regulation is a heritable change in gene expressions independent of nucleotide sequence changes. As the common epigenetic regulation mechanisms, DNA methylation, histone modification, and non-coding RNA regulation have been well studied. Increasing evidence has shown that aberrant epigenetic regulations contribute to tumor resistance. Therefore, targeting epigenetic regulators represents an effective strategy to reverse drug resistance. In this review, we mainly summarize the roles of epigenetic regulation in tumor resistance. In addition, as the essential factors for epigenetic modifications, histone demethylases mediate the histone or genomic DNA modifications. Herein, we comprehensively describe the functions of the histone demethylase family including the lysine-specific demethylase family, the Jumonji C-domain-containing demethylase family, and the histone arginine demethylase family, and fully discuss their regulatory mechanisms related to cancer drug resistance. In addition, therapeutic strategies, including small-molecule inhibitors and small interfering RNA targeting histone demethylases to overcome drug resistance, are also described.
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Affiliation(s)
- Nan Wang
- Institute of Drug Discovery & Development, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Ting Ma
- Institute of Drug Discovery & Development, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
| | - Bin Yu
- Institute of Drug Discovery & Development, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
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29
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Wang Y, Malik S, Suh HW, Xiao Y, Deng Y, Fan R, Huttner A, Bindra RS, Singh V, Saltzman WM, Bahal R. Anti-seed PNAs targeting multiple oncomiRs for brain tumor therapy. SCIENCE ADVANCES 2023; 9:eabq7459. [PMID: 36753549 PMCID: PMC9908025 DOI: 10.1126/sciadv.abq7459] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 01/06/2023] [Indexed: 06/18/2023]
Abstract
Glioblastoma (GBM) is one of the most lethal malignancies with poor survival and high recurrence rates. Here, we aimed to simultaneously target oncomiRs 10b and 21, reported to drive GBM progression and invasiveness. We designed short (8-mer) γ-modified peptide nucleic acids (sγPNAs), targeting the seed region of oncomiRs 10b and 21. We entrapped these anti-miR sγPNAs in nanoparticles (NPs) formed from a block copolymer of poly(lactic acid) and hyperbranched polyglycerol (PLA-HPG). The surface of the NPs was functionalized with aldehydes to produce bioadhesive NPs (BNPs) with superior transfection efficiency and tropism for tumor cells. When combined with temozolomide, sγPNA BNPs administered via convection-enhanced delivery (CED) markedly increased the survival (>120 days) of two orthotopic (intracranial) mouse models of GBM. Hence, we established that BNPs loaded with anti-seed sγPNAs targeting multiple oncomiRs are a promising approach to improve the treatment of GBM, with a potential to personalize treatment based on tumor-specific oncomiRs.
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Affiliation(s)
- Yazhe Wang
- Department of Biomedical Engineering, Yale University, New Haven, CT 06511, USA
| | - Shipra Malik
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA
| | - Hee-Won Suh
- Department of Biomedical Engineering, Yale University, New Haven, CT 06511, USA
| | - Yong Xiao
- Department of Biomedical Engineering, Yale University, New Haven, CT 06511, USA
| | - Yanxiang Deng
- Department of Biomedical Engineering, Yale University, New Haven, CT 06511, USA
| | - Rong Fan
- Department of Biomedical Engineering, Yale University, New Haven, CT 06511, USA
| | - Anita Huttner
- Department of Pathology, Yale University, New Haven, CT 06510, USA
| | - Ranjit S. Bindra
- Department of Therapeutic Radiology, Yale University, New Haven, CT 06510, USA
| | - Vijender Singh
- Computational Biology Core, Institute for Systems Genomics, University of Connecticut, Storrs, CT 06269, USA
| | - W. Mark Saltzman
- Department of Biomedical Engineering, Yale University, New Haven, CT 06511, USA
| | - Raman Bahal
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA
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30
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Laura Francés J, Musolino E, Papait R, Pagiatakis C. Non-Coding RNAs in Cell-to-Cell Communication: Exploiting Physiological Mechanisms as Therapeutic Targets in Cardiovascular Pathologies. Int J Mol Sci 2023; 24:ijms24032205. [PMID: 36768528 PMCID: PMC9916956 DOI: 10.3390/ijms24032205] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/10/2023] [Accepted: 01/14/2023] [Indexed: 01/24/2023] Open
Abstract
Cardiovascular disease, the leading cause of death worldwide, has been characterized at the molecular level by alterations in gene expression that contribute to the etiology of the disease. Such alterations have been shown to play a critical role in the development of atherosclerosis, cardiac remodeling, and age-related heart failure. Although much is now known about the cellular and molecular mechanisms in this context, the role of epigenetics in the onset of cardiovascular disease remains unclear. Epigenetics, a complex network of mechanisms that regulate gene expression independently of changes to the DNA sequence, has been highly implicated in the loss of homeostasis and the aberrant activation of a myriad of cellular pathways. More specifically, non-coding RNAs have been gaining much attention as epigenetic regulators of various pathologies. In this review, we will provide an overview of the ncRNAs involved in cell-to-cell communication in cardiovascular disease, namely atherosclerosis, cardiac remodeling, and cardiac ageing, and the potential use of epigenetic drugs as novel therapeutic targets.
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Affiliation(s)
| | - Elettra Musolino
- Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy
| | - Roberto Papait
- IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy
- Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy
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31
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Deka Dey A, Yousefiasl S, Kumar A, Dabbagh Moghaddam F, Rahimmanesh I, Samandari M, Jamwal S, Maleki A, Mohammadi A, Rabiee N, Cláudia Paiva‐Santos A, Tamayol A, Sharifi E, Makvandi P. miRNA-encapsulated abiotic materials and biovectors for cutaneous and oral wound healing: Biogenesis, mechanisms, and delivery nanocarriers. Bioeng Transl Med 2023; 8:e10343. [PMID: 36684081 PMCID: PMC9842058 DOI: 10.1002/btm2.10343] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 04/21/2022] [Accepted: 04/23/2022] [Indexed: 01/25/2023] Open
Abstract
MicroRNAs (miRNAs) as therapeutic agents have attracted increasing interest in the past decade owing to their significant effectiveness in treating a wide array of ailments. These polymerases II-derived noncoding RNAs act through post-transcriptional controlling of different proteins and their allied pathways. Like other areas of medicine, researchers have utilized miRNAs for managing acute and chronic wounds. The increase in the number of patients suffering from either under-healing or over-healing wound demonstrates the limited efficacy of the current wound healing strategies and dictates the demands for simpler approaches with greater efficacy. Various miRNA can be designed to induce pathway beneficial for wound healing. However, the proper design of miRNA and its delivery system for wound healing applications are still challenging due to their limited stability and intracellular delivery. Therefore, new miRNAs are required to be identified and their delivery strategy needs to be optimized. In this review, we discuss the diverse roles of miRNAs in various stages of wound healing and provide an insight on the most recent findings in the nanotechnology and biomaterials field, which might offer opportunities for the development of new strategies for this chronic condition. We also highlight the advances in biomaterials and delivery systems, emphasizing their challenges and resolutions for miRNA-based wound healing. We further review various biovectors (e.g., adenovirus and lentivirus) and abiotic materials such as organic and inorganic nanomaterials, along with dendrimers and scaffolds, as the delivery systems for miRNA-based wound healing. Finally, challenges and opportunities for translation of miRNA-based strategies into clinical applications are discussed.
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Affiliation(s)
| | - Satar Yousefiasl
- School of DentistryHamadan University of Medical SciencesHamadanIran
| | - Arun Kumar
- Chitkara College of PharmacyChitkara UniversityPunjabIndia
| | - Farnaz Dabbagh Moghaddam
- Department of Biology, Science and Research BranchIslamic Azad UniversityTehranIran
- Institute for Photonics and Nanotechnologies, National Research Council, Via Fosso del Cavaliere, 100RomeItaly
| | - Ilnaz Rahimmanesh
- Applied Physiology Research CenterCardiovascular Research Institute, Isfahan University of Medical SciencesIsfahanIran
| | | | - Sumit Jamwal
- Department of Psychiatry, Yale School of MedicineYale UniversityNew HavenConnecticutUSA
| | - Aziz Maleki
- Department of Pharmaceutical Nanotechnology, School of PharmacyZanjan University of Medical SciencesZanjanIran
- Zanjan Pharmaceutical Nanotechnology Research Center (ZPNRC)Zanjan University of Medical SciencesZanjanIran
- Cancer Research CentreShahid Beheshti University of Medical SciencesTehranIran
| | | | - Navid Rabiee
- Department of PhysicsSharif University of TechnologyTehranIran
- School of EngineeringMacquarie UniversitySydneyNew South WalesAustralia
| | - Ana Cláudia Paiva‐Santos
- Department of Pharmaceutical TechnologyFaculty of Pharmacy of the University of Coimbra, University of CoimbraCoimbraPortugal
- LAQV, REQUIMTE, Department of Pharmaceutical TechnologyFaculty of Pharmacy of the University of Coimbra, University of CoimbraCoimbraPortugal
| | - Ali Tamayol
- Department of Biomedical EngineeringUniversity of ConnecticutFarmingtonConnecticutUSA
| | - Esmaeel Sharifi
- Department of Tissue Engineering and Biomaterials, School of Advanced Medical Sciences and TechnologiesHamadan University of Medical SciencesHamadanIran
| | - Pooyan Makvandi
- Istituto Italiano di Tecnologia, Centre for Materials InterfacesPontederaItaly
- School of Chemistry, Damghan UniversityDamghanIran
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32
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Effects of Cationic Dendrimers and Their Complexes with microRNAs on Immunocompetent Cells. Pharmaceutics 2022; 15:pharmaceutics15010148. [PMID: 36678776 PMCID: PMC9862986 DOI: 10.3390/pharmaceutics15010148] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/19/2022] [Accepted: 12/28/2022] [Indexed: 01/03/2023] Open
Abstract
Short regulatory oligonucleotides are considered prospective tools for immunotherapy. However, they require an adequate carrier to deliver potential therapeutics into immune cells. Herein, we explore the potential of polycationic dendrimers as carriers for microRNAs in peripheral blood mononuclear cells of healthy donors. As an oligonucleotide cargo, we use a synthetic mimic and an inhibitor of miR-155, an important factor in the development and functioning of immunocompetent cells. Dendrimers bind microRNAs into low-cytotoxic polyelectrolyte complexes that are efficiently uptaken by immunocompetent cells. We have shown these complexes to affect the number of T-regulatory cells, CD14+ and CD19+ cell subpopulations in non-activated mononuclear cells. The treatment affected the expression of HLA-DR on T-cells and PD-1 expression on T- and B-lymphocytes. It also affected the production of IL-4 and IL-10, but not the perforin and granzyme B production. Our findings suggest the potential of dendrimer-mediated microRNA-155 treatment for immunotherapy, though the activity of microRNA-dendrimer constructions on distinct immune cell subsets can be further improved.
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33
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Sharan M, Jha M, Chandel R, Syeda S, Mathur R, Jha NK, Jha SK, Goel H, Shrivastava A, Chauhan S, Pamidimarri S, Jha AK. Demethylation of CADM1 and SOCS1 using capsaicin in cervical cancer cell line. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2022; 396:649-657. [PMID: 36441265 DOI: 10.1007/s00210-022-02340-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 11/12/2022] [Indexed: 11/29/2022]
Abstract
Cervical cancer is one of the leading causes of women's mortality in developing countries. The prevalence of cervical cancer is higher in developing countries like India and continents like Africa. Hyper-methylation of tumor suppressor genes through human papillomavirus (HPV) infection is known to be one of the major causes of cervical cancer. The promoter hypermethylation of the cell adhesion molecule 1 (CADM1) and suppressor of cytokine signalling (SOCS1) genes due to DNMT1 overexpression leads to their epigenetic silencing followed by gene repression causing cervical cancer. In silico study on the inhibition effect of capsaicin on DNMT1 was simulated by different servers. The binding energy was observed to be -7.8 kcal/mol. In vitro studies on the effect of capsaicin on aberrant methylation of CADM1 and SOCS1 were performed on the adenocarcinoma cervical cancer cell line, HeLa. The IC50 of capsaicin was observed to be 160 μM through crystal violet assay. DNA methylation of the CADM1 and SOCS1 was analyzed by methylation-specific PCR along with their reversal using capsaicin (20 μM) by treating the cells for 72 h and 6 days. In silico results suggested that capsaicin has an inhibitory effect on DNMT1, which regulates DNA methylation leading to the hypermethylation of CADM1 and SOCS1 genes. The in vitro studies suggested that hypermethylation leads to the inhibition of CADM1 and SOCS1 expression, which could be reversed using capsaicin with visible changes in methylation-specific and unmethylation-specific bands in MS-PCR, respectively. The present study shows the reversal of methylation of CADM1 and SOCS1 after 72 h which showed a further increase in case of 6 days of treatment using 20 μM capsaicin, which makes capsaicin a potent candidate for causing demethylation of CADM1 and SOCS1 genes that may lead to the reactivation of the downregulated gene.
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Affiliation(s)
- Mahek Sharan
- Department of Zoology, Banaras Hindu University, Varanasi, Uttar Pradesh, India
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh, 201310, India
| | - Meenakshi Jha
- Department of Biotechnology, Amity University, Raipur, Chhattisgarh, India
| | | | - Saima Syeda
- Department of Zoology, Delhi University, Delhi, India
| | - Runjhun Mathur
- A.P.J Abdul Kalam University, Lucknow, Uttar Pradesh, India
| | - Niraj Kumar Jha
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh, 201310, India
- Department of Biotechnology, School of Applied & Life Sciences (SALS), Uttaranchal University, Dehradun, 248007, India
- Department of Biotechnology Engineering and Food Technology, Chandigarh University, Mohali, 140413, India
| | - Saurabh Kumar Jha
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh, 201310, India
- Department of Biotechnology, School of Applied & Life Sciences (SALS), Uttaranchal University, Dehradun, 248007, India
- Department of Biotechnology Engineering and Food Technology, Chandigarh University, Mohali, 140413, India
| | - Harsh Goel
- Laboratory of the Oncology Unit, Dr. B.R.A, Institute Rotary Cancer Hospital, AIIMS, Delhi, India
| | | | - Sushma Chauhan
- Department of Biotechnology, Amity University, Raipur, Chhattisgarh, India
| | - Sudheer Pamidimarri
- Department of Molecular Biology and Genetics, Gujarat Biotechnology University, Gandhinagar, Gujarat, India
| | - Abhimanyu Kumar Jha
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh, 201310, India.
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Hu Q, Zhang N, Sui T, Li G, Wang Z, Liu M, Zhu X, Huang B, Lu J, Li Z, Zhang Y. Anti-hsa-miR-59 alleviates premature senescence associated with Hutchinson-Gilford progeria syndrome in mice. EMBO J 2022; 42:e110937. [PMID: 36382717 PMCID: PMC9811625 DOI: 10.15252/embj.2022110937] [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: 02/15/2022] [Revised: 09/27/2022] [Accepted: 09/29/2022] [Indexed: 11/17/2022] Open
Abstract
Hutchinson-Gilford progeria syndrome (HGPS) is a lethal premature aging disorder without an effective therapeutic regimen. Because of their targetability and influence on gene expression, microRNAs (miRNAs) are attractive therapeutic tools to treat diseases. Here we identified that hsa-miR-59 (miR-59) was markedly upregulated in HGPS patient cells and in multiple tissues of an HGPS mouse model (LmnaG609G/G609G ), which disturbed the interaction between RNAPII and TFIIH, resulting in abnormal expression of cell cycle genes by targeting high-mobility group A family HMGA1 and HMGA2. Functional inhibition of miR-59 alleviated the cellular senescence phenotype of HGPS cells. Treatment with AAV9-mediated anti-miR-59 reduced fibrosis in the quadriceps muscle, heart, and aorta, suppressed epidermal thinning and dermal fat loss, and yielded a 25.5% increase in longevity of LmnaG609G/G609G mice. These results identify a new strategy for the treatment of HGPS and provide insight into the etiology of HGPS disease.
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Affiliation(s)
- Qianying Hu
- The Key Laboratory of Molecular Epigenetics of the Ministry of Education (MOE)Northeast Normal UniversityChangchunChina
| | - Na Zhang
- The Key Laboratory of Molecular Epigenetics of the Ministry of Education (MOE)Northeast Normal UniversityChangchunChina
| | - Tingting Sui
- The Key Laboratory of Zoonosis Research, Ministry of Education, College of Animal ScienceJilin UniversityChangchunChina
| | - Guanlin Li
- The Institute of Genetics and CytologyNortheast Normal UniversityChangchunChina
| | - Zhiyao Wang
- The Key Laboratory of Molecular Epigenetics of the Ministry of Education (MOE)Northeast Normal UniversityChangchunChina
| | - Mingyue Liu
- The Institute of Genetics and CytologyNortheast Normal UniversityChangchunChina
| | - Xiaojuan Zhu
- The Key Laboratory of Molecular Epigenetics of the Ministry of Education (MOE)Northeast Normal UniversityChangchunChina
| | - Baiqu Huang
- The Key Laboratory of Molecular Epigenetics of the Ministry of Education (MOE)Northeast Normal UniversityChangchunChina
| | - Jun Lu
- The Institute of Genetics and CytologyNortheast Normal UniversityChangchunChina
| | - Zhanjun Li
- The Key Laboratory of Zoonosis Research, Ministry of Education, College of Animal ScienceJilin UniversityChangchunChina
| | - Yu Zhang
- The Key Laboratory of Molecular Epigenetics of the Ministry of Education (MOE)Northeast Normal UniversityChangchunChina
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Shah AM, Giacca M. Small non-coding RNA therapeutics for cardiovascular disease. Eur Heart J 2022; 43:4548-4561. [PMID: 36106499 PMCID: PMC9659475 DOI: 10.1093/eurheartj/ehac463] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 07/29/2022] [Accepted: 08/11/2022] [Indexed: 01/07/2023] Open
Abstract
Novel bio-therapeutic agents that harness the properties of small, non-coding nucleic acids hold great promise for clinical applications. These include antisense oligonucleotides that inhibit messenger RNAs, microRNAs (miRNAs), or long non-coding RNAs; positive effectors of the miRNA pathway (short interfering RNAs and miRNA mimics); or small RNAs that target proteins (i.e. aptamers). These new therapies also offer exciting opportunities for cardiovascular diseases and promise to move the field towards more precise approaches based on disease mechanisms. There have been substantial advances in developing chemical modifications to improve the in vivo pharmacological properties of antisense oligonucleotides and reduce their immunogenicity. Carrier methods (e.g. RNA conjugates, polymers, and lipoplexes) that enhance cellular uptake of RNA therapeutics and stability against degradation by intracellular nucleases are also transforming the field. A number of small non-coding RNA therapies for cardiovascular indications are now approved. Moreover, there is a large pipeline of therapies in clinical development and an even larger list of putative therapies emerging from pre-clinical studies. Progress in this area is reviewed herein along with the hurdles that need to be overcome to allow a broader clinical translation.
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Affiliation(s)
- Ajay M Shah
- King’s College London, British Heart Foundation Centre of Research Excellence, School of Cardiovascular and Metabolic Medicine and Sciences, The James Black Centre, 125 Coldharbour Lane, London SE5 9NU, UK
| | - Mauro Giacca
- King’s College London, British Heart Foundation Centre of Research Excellence, School of Cardiovascular and Metabolic Medicine and Sciences, The James Black Centre, 125 Coldharbour Lane, London SE5 9NU, UK
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Dhuri K, Pradeep SP, Shi J, Anastasiadou E, Slack FJ, Gupta A, Zhong XB, Bahal R. Simultaneous Targeting of Multiple oncomiRs with Phosphorothioate or PNA-Based Anti-miRs in Lymphoma Cell Lines. Pharm Res 2022; 39:2709-2720. [PMID: 36071352 PMCID: PMC9879158 DOI: 10.1007/s11095-022-03383-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 08/27/2022] [Indexed: 01/29/2023]
Abstract
PURPOSE MicroRNAs (miRNAs) are short (~ 22 nts) RNAs that regulate gene expression via binding to mRNA. MiRNAs promoting cancer are known as oncomiRs. Targeting oncomiRs is an emerging area of cancer therapy. OncomiR-21 and oncomiR-155 are highly upregulated in lymphoma cells, which are dependent on these oncomiRs for survival. Targeting specific miRNAs and determining their effect on cancer cell progression and metastasis have been the focus of various studies. Inhibiting a single miRNA can have a limited effect, as there may be other overexpressed miRNAs present that may promote tumor proliferation. Herein, we target miR-21 and miR-155 simultaneously using nanoparticles delivered two different classes of antimiRs: phosphorothioates (PS) and peptide nucleic acids (PNAs) and compared their efficacy in lymphoma cell lines. METHODS Poly-Lactic-co-Glycolic acid (PLGA) nanoparticles (NPs) containing PS and PNA-based antimiR-21 and -155 were formulated, and comprehensive NP characterizations: morphology (scanning electron microscopy), size (differential light scattering), and surface charge (zeta potential) were performed. Cellular uptake analysis was performed using a confocal microscope and flow cytometry analysis. The oncomiR knockdown and the effect on downstream targets were confirmed by gene expression (real time-polymerase chain reaction) assay. RESULTS We demonstrated that simultaneous targeting with NP delivered PS and PNA-based antimiRs resulted in significant knockdown of miR-21 and miR-155, as well as their downstream target genes followed by reduced cell viability ex vivo. CONCLUSIONS This project demonstrated that targeting miRNA-155 and miR-21 simultaneously using nanotechnology and a diverse class of antisense oligomers can be used as an effective approach for lymphoma therapy.
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Affiliation(s)
- Karishma Dhuri
- Department of Pharmaceutical Science, University of Connecticut, Storrs, CT, 06269, USA
| | - Sai Pallavi Pradeep
- Department of Pharmaceutical Science, University of Connecticut, Storrs, CT, 06269, USA
| | - Jason Shi
- Department of Pharmaceutical Science, University of Connecticut, Storrs, CT, 06269, USA
| | - Eleni Anastasiadou
- HMS Initiative for RNA Medicine, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02115, USA
| | - Frank J Slack
- HMS Initiative for RNA Medicine, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02115, USA
| | - Anisha Gupta
- School of Pharmacy, University of Saint Joseph, West Hartford, CT, 06117, USA
| | - Xiao-Bo Zhong
- Department of Pharmaceutical Science, University of Connecticut, Storrs, CT, 06269, USA
| | - Raman Bahal
- Department of Pharmaceutical Science, University of Connecticut, Storrs, CT, 06269, USA.
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Clausse V, Zheng H, Amarasekara H, Kruhlak M, Appella DH. Thyclotides, tetrahydrofuran-modified peptide nucleic acids that efficiently penetrate cells and inhibit microRNA-21. Nucleic Acids Res 2022; 50:10839-10856. [PMID: 36215040 DOI: 10.1093/nar/gkac864] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 09/14/2022] [Accepted: 09/26/2022] [Indexed: 11/12/2022] Open
Abstract
Peptide nucleic acids (PNAs) are promising therapeutic molecules for gene modulation; however, they suffer from poor cell uptake. Delivery of PNAs into cells requires conjugation of the PNA to another large molecule, typically a cell-penetrating peptide or nanoparticle. In this study, we describe a new PNA-based molecule with cyclic tetrahydrofuran (THF) backbone modifications that in some cases considerably improve cell uptake. We refer to these THF-PNA oligomers as thyclotides. With THF groups at every position of the oligomer, the cell uptake of thyclotides targeted to miR-21 is enhanced compared with the corresponding unmodified PNA based on an aminoethylglycine backbone. An optimized thyclotide can efficiently enter cells without the use of cell-penetrating peptides, bind miR-21, its designated microRNA target, decrease expression of miR-21 and increase expression of three downstream targets (PTEN, Cdc25a and KRIT1). Using a plasmid with the PTEN-3'UTR coupled with luciferase, we further confirmed that a miR-21-targeted thyclotide prevents miR-21 from binding to its target RNA. Additionally, the thyclotide shows no cytotoxicity when administered at 200 times its active concentration. We propose that thyclotides be further explored as therapeutic candidates to modulate miRNA levels.
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Affiliation(s)
- Victor Clausse
- Synthetic Bioactive Molecules Section, Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA
| | - Hongchao Zheng
- Synthetic Bioactive Molecules Section, Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA
| | - Harsha Amarasekara
- Synthetic Bioactive Molecules Section, Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA
| | - Michael Kruhlak
- Microscopy Core Facility, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, MD 20892, USA
| | - Daniel H Appella
- Synthetic Bioactive Molecules Section, Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA
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Jain CK, Srivastava P, Pandey AK, Singh N, Kumar RS. miRNA therapeutics in precision oncology: a natural premium to nurture. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2022; 3:511-532. [PMID: 36071981 PMCID: PMC9446160 DOI: 10.37349/etat.2022.00098] [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: 04/06/2022] [Accepted: 06/02/2022] [Indexed: 11/22/2022] Open
Abstract
The dynamic spectrum of microRNA (miRNA) has grown significantly over the years with its identification and exploration in cancer therapeutics and is currently identified as an important resource for innovative strategies due to its functional behavior for gene regulation and modulation of complex biological networks. The progression of cancer is the consequence of uncontrolled, nonsynchronous procedural faults in the biological system. Diversified and variable cellular response of cancerous cells has always raised challenges in effective cancer therapy. miRNAs, a class of non-coding RNAs (ncRNAs), are the natural genetic gift, responsible to preserve the homeostasis of cell to nurture. The unprecedented significance of endogenous miRNAs has exhibited promising therapeutic potential in cancer therapeutics. Currently, miRNA mimic miR-34, and an antimiR aimed against miR-122 has entered the clinical trials for cancer treatments. This review, highlights the recent breakthroughs, challenges, clinical trials, and advanced delivery vehicles in the administration of miRNA therapies for precision oncology.
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Affiliation(s)
- Chakresh Kumar Jain
- Department of Biotechnology, Jaypee Institute of Information Technology, Noida 201307, India
| | - Poornima Srivastava
- Department of Biotechnology, Jaypee Institute of Information Technology, Noida 201307, India
| | - Amit Kumar Pandey
- Amity Institute of Biotechnology, Amity University Haryana, Panchgaon, Manesar, Haryana 122413, India
| | - Nisha Singh
- Department of Bioinformatics, Gujarat Biotechnology University, Gandhinagar, GIFT city 382355, India
| | - R Suresh Kumar
- Molecular Genetics Lab, Molecular Biology Group, National Institute of Cancer Prevention and Research (ICMR), Noida 201307, India
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Potential therapeutic applications of microRNAs in cancer diagnosis and treatment: Sharpening a double-edged sword? Eur J Pharmacol 2022; 932:175210. [PMID: 35981607 DOI: 10.1016/j.ejphar.2022.175210] [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: 06/21/2022] [Revised: 08/10/2022] [Accepted: 08/11/2022] [Indexed: 11/21/2022]
Abstract
Cancer is a leading cause of increased morbidity and mortality worldwide despite advancements in diagnosis and treatment. Lack of early detection and diagnosis of different cancers and adverse effects and toxicity associated with conventional cancer treatments, such as chemotherapy and radiation, remains a problem. MicroRNAs can act as oncogenes or tumour suppressors in different types of cancers. Their distinct gene expression in various stages and types of cancerous cells make them attractive targets for cancer diagnosis and therapy. The growing research and clinical interests in gene therapy and nano-drug delivery systems have led to the development of potential miRNA-targeted treatments encompassing miRNA mimics, antagonists, and their use in cancer chemotherapy sensitization. In this review, we discuss the recent advancements in understanding the role of miRNAs in cancer development and their potential use as biomarkers in clinical diagnostics and as targets in chemotherapy of cancer.
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40
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Zare M, Pemmada R, Madhavan M, Shailaja A, Ramakrishna S, Kandiyil SP, Donahue JM, Thomas V. Encapsulation of miRNA and siRNA into Nanomaterials for Cancer Therapeutics. Pharmaceutics 2022; 14:pharmaceutics14081620. [PMID: 36015246 PMCID: PMC9416290 DOI: 10.3390/pharmaceutics14081620] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 07/21/2022] [Accepted: 07/28/2022] [Indexed: 01/22/2023] Open
Abstract
Globally, cancer is amongst the most deadly diseases due to the low efficiency of the conventional and obsolete chemotherapeutic methodologies and their many downsides. The poor aqueous solubility of most anticancer medications and their low biocompatibility make them ineligible candidates for the design of delivery systems. A significant drawback associated with chemotherapy is that there are no advanced solutions to multidrug resistance, which poses a major obstacle in cancer management. Since RNA interference (RNAi) can repress the expression of genes, it is viewed as a novel tool for advanced drug delivery. this is being explored as a promising drug targeting strategy for the treatment of multiple diseases, including cancer. However, there are many obstructions that hinder the clinical uses of siRNA drugs due to their low permeation into cells, off-target impacts, and possible unwanted immune responses under physiological circumstances. Thus, in this article, we review the design measures for siRNA conveyance frameworks and potential siRNA and miRNA drug delivery systems for malignant growth treatment, including the use of liposomes, dendrimers, and micelle-based nanovectors and functional polymer-drug delivery systems. This article sums up the advancements and challenges in the use of nanocarriers for siRNA delivery and remarkably centers around the most critical modification strategies for nanocarriers to build multifunctional siRNA and miRNA delivery vectors. In short, we hope this review will throw light on the dark areas of RNA interference, which will further open novel research arenas in the development of RNAi drugs for cancer.
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Affiliation(s)
- Mina Zare
- Center for Nanotechnology and Sustainability, Department of Mechanical Engineering, National University of Singapore, Singapore 117581, Singapore; (M.Z.); (S.R.)
- Department of Food and Nutrition, University of Helsinki, 00014 Helsinki, Finland
| | - Rakesh Pemmada
- Departments of Materials Science and Engineering, Biomedical Engineering, University of Alabama at Birmingham (UAB), Birmingham, AL 35294, USA;
| | - Maya Madhavan
- Department of Biochemistry, Government College for Women, Thiruvananthapuram 695014, India
- Correspondence: (M.M.); (V.T.)
| | - Aswathy Shailaja
- Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA;
| | - Seeram Ramakrishna
- Center for Nanotechnology and Sustainability, Department of Mechanical Engineering, National University of Singapore, Singapore 117581, Singapore; (M.Z.); (S.R.)
| | | | - James M. Donahue
- School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
| | - Vinoy Thomas
- Departments of Materials Science and Engineering, Biomedical Engineering, University of Alabama at Birmingham (UAB), Birmingham, AL 35294, USA;
- Center for Nanoscale Materials and Biointegration (CNMB), Center for Clinical and Translational Science (CCTS), University of Alabama at Birmingham (UAB), Birmingham, AL 35294, USA
- Correspondence: (M.M.); (V.T.)
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Wagner A, Kosnacova H, Chovanec M, Jurkovicova D. Mitochondrial Genetic and Epigenetic Regulations in Cancer: Therapeutic Potential. Int J Mol Sci 2022; 23:ijms23147897. [PMID: 35887244 PMCID: PMC9321253 DOI: 10.3390/ijms23147897] [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: 06/20/2022] [Revised: 07/12/2022] [Accepted: 07/14/2022] [Indexed: 02/01/2023] Open
Abstract
Mitochondria are dynamic organelles managing crucial processes of cellular metabolism and bioenergetics. Enabling rapid cellular adaptation to altered endogenous and exogenous environments, mitochondria play an important role in many pathophysiological states, including cancer. Being under the control of mitochondrial and nuclear DNA (mtDNA and nDNA), mitochondria adjust their activity and biogenesis to cell demands. In cancer, numerous mutations in mtDNA have been detected, which do not inactivate mitochondrial functions but rather alter energy metabolism to support cancer cell growth. Increasing evidence suggests that mtDNA mutations, mtDNA epigenetics and miRNA regulations dynamically modify signalling pathways in an altered microenvironment, resulting in cancer initiation and progression and aberrant therapy response. In this review, we discuss mitochondria as organelles importantly involved in tumorigenesis and anti-cancer therapy response. Tumour treatment unresponsiveness still represents a serious drawback in current drug therapies. Therefore, studying aspects related to genetic and epigenetic control of mitochondria can open a new field for understanding cancer therapy response. The urgency of finding new therapeutic regimens with better treatment outcomes underlines the targeting of mitochondria as a suitable candidate with new therapeutic potential. Understanding the role of mitochondria and their regulation in cancer development, progression and treatment is essential for the development of new safe and effective mitochondria-based therapeutic regimens.
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Affiliation(s)
- Alexandra Wagner
- Department of Genetics, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, 845 05 Bratislava, Slovakia; (A.W.); (H.K.); (M.C.)
- Department of Simulation and Virtual Medical Education, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia
| | - Helena Kosnacova
- Department of Genetics, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, 845 05 Bratislava, Slovakia; (A.W.); (H.K.); (M.C.)
- Department of Simulation and Virtual Medical Education, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia
| | - Miroslav Chovanec
- Department of Genetics, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, 845 05 Bratislava, Slovakia; (A.W.); (H.K.); (M.C.)
| | - Dana Jurkovicova
- Department of Genetics, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, 845 05 Bratislava, Slovakia; (A.W.); (H.K.); (M.C.)
- Correspondence:
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Liu F, Chen J, Luo C, Meng X. Pathogenic Role of MicroRNA Dysregulation in Podocytopathies. Front Physiol 2022; 13:948094. [PMID: 35845986 PMCID: PMC9277480 DOI: 10.3389/fphys.2022.948094] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 06/10/2022] [Indexed: 11/13/2022] Open
Abstract
MicroRNAs (miRNAs) participate in the regulation of various important biological processes by regulating the expression of various genes at the post-transcriptional level. Podocytopathies are a series of renal diseases in which direct or indirect damage of podocytes results in proteinuria or nephrotic syndrome. Despite decades of research, the exact pathogenesis of podocytopathies remains incompletely understood and effective therapies are still lacking. An increasing body of evidence has revealed a critical role of miRNAs dysregulation in the onset and progression of podocytopathies. Moreover, several lines of research aimed at improving common podocytopathies diagnostic tools and avoiding invasive kidney biopsies have also identified circulating and urine miRNAs as possible diagnostic and prognostic biomarkers for podocytopathies. The present review mainly aims to provide an updated overview of the recent achievements in research on the potential applicability of miRNAs involved in renal disorders related to podocyte dysfunction by laying particular emphasis on focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), membranous nephropathy (MN), diabetic kidney disease (DKD) and IgA nephropathy (IgAN). Further investigation into these dysregulated miRNAs will not only generate novel insights into the mechanisms of podocytopathies, but also might yield novel strategies for the diagnosis and therapy of this disease.
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Affiliation(s)
- Feng Liu
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiefang Chen
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Changqing Luo
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Changqing Luo, ; Xianfang Meng,
| | - Xianfang Meng
- Department of Neurobiology, Institute of Brain Research, School of Basic Medical Sciences, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Changqing Luo, ; Xianfang Meng,
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Nanomaterial-Based Drug Delivery System Targeting Lymph Nodes. Pharmaceutics 2022; 14:pharmaceutics14071372. [PMID: 35890268 PMCID: PMC9325242 DOI: 10.3390/pharmaceutics14071372] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 05/28/2022] [Accepted: 06/22/2022] [Indexed: 02/06/2023] Open
Abstract
The lymphatic system plays an indispensable role in humoral balance, lipid metabolism, and immune regulation. The lymph nodes (LNs) are known as the primary sites of tumor metastasis and the metastatic LNs largely affected the prognosis of the patiens. A well-designed lymphatic-targeted system favors disease treatment as well as vaccination efficacy. In recent years, development of nanotechnologies and emerging biomaterials have gained increasing attention in developing lymph-node-targeted drug-delivery systems. By mimicking the endogenous macromolecules or lipid conjugates, lymph-node-targeted nanocarries hold potential for disease diagnosis and tumor therapy. This review gives an introduction to the physiological functions of LNs and the roles of LNs in diseases, followed by a review of typical lymph-node-targeted nanomaterial-based drug-delivery systems (e.g., liposomes, micelles, inorganic nanomaterials, hydrogel, and nanocapsules). Future perspectives and conclusions concerned with lymph-node-targeted drug-delivery systems are also provided.
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Stieg DC, Wang Y, Liu LZ, Jiang BH. ROS and miRNA Dysregulation in Ovarian Cancer Development, Angiogenesis and Therapeutic Resistance. Int J Mol Sci 2022; 23:ijms23126702. [PMID: 35743145 PMCID: PMC9223852 DOI: 10.3390/ijms23126702] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 06/05/2022] [Accepted: 06/14/2022] [Indexed: 12/11/2022] Open
Abstract
The diverse repertoires of cellular mechanisms that progress certain cancer types are being uncovered by recent research and leading to more effective treatment options. Ovarian cancer (OC) is among the most difficult cancers to treat. OC has limited treatment options, especially for patients diagnosed with late-stage OC. The dysregulation of miRNAs in OC plays a significant role in tumorigenesis through the alteration of a multitude of molecular processes. The development of OC can also be due to the utilization of endogenously derived reactive oxygen species (ROS) by activating signaling pathways such as PI3K/AKT and MAPK. Both miRNAs and ROS are involved in regulating OC angiogenesis through mediating multiple angiogenic factors such as hypoxia-induced factor (HIF-1) and vascular endothelial growth factor (VEGF). The NAPDH oxidase subunit NOX4 plays an important role in inducing endogenous ROS production in OC. This review will discuss several important miRNAs, NOX4, and ROS, which contribute to therapeutic resistance in OC, highlighting the effective therapeutic potential of OC through these mechanisms.
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Affiliation(s)
- David C. Stieg
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; (D.C.S.); (L.-Z.L.)
| | - Yifang Wang
- Department of Pathology, Anatomy & Cell Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA;
| | - Ling-Zhi Liu
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; (D.C.S.); (L.-Z.L.)
| | - Bing-Hua Jiang
- Department of Pathology, Anatomy & Cell Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA;
- Correspondence:
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Mahajan S, Aalhate M, Guru SK, Singh PK. Nanomedicine as a magic bullet for combating lymphoma. J Control Release 2022; 347:211-236. [PMID: 35533946 DOI: 10.1016/j.jconrel.2022.05.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 04/28/2022] [Accepted: 05/02/2022] [Indexed: 10/18/2022]
Abstract
Hematological malignancy like lymphoma originates in lymph tissues and has a propensity to spread across other organs. Managing such tumors is challenging as conventional strategies like surgery and local treatment are not plausible options and there are high chances of relapse. The advent of novel targeted therapies and antibody-mediated treatments has proven revolutionary in the management of these tumors. Although these therapies have an added advantage of specificity in comparison to the traditional chemotherapy approach, such treatment alternatives suffer from the occurrence of drug resistance and dose-related toxicities. In past decades, nanomedicine has emerged as an excellent surrogate to increase the bioavailability of therapeutic moieties along with a reduction in toxicities of highly cytotoxic drugs. Nanotherapeutics achieve targeted delivery of the therapeutic agents into the malignant cells and also have the ability to carry genes and therapeutic proteins to the desired sites. Furthermore, nanomedicine has an edge in rendering personalized medicine as one type of lymphoma is pathologically different from others. In this review, we have highlighted various applications of nanotechnology-based delivery systems based on lipidic, polymeric and inorganic nanomaterials that address different targets for effectively tackling lymphomas. Moreover, we have discussed recent advances and therapies available exclusively for managing this malignancy.
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Affiliation(s)
- Srushti Mahajan
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India
| | - Mayur Aalhate
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India
| | - Santosh Kumar Guru
- Department of Biological Science, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India
| | - Pankaj Kumar Singh
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India.
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MicroRNAs in Leukemias: A Clinically Annotated Compendium. Int J Mol Sci 2022; 23:ijms23073469. [PMID: 35408829 PMCID: PMC8998245 DOI: 10.3390/ijms23073469] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Revised: 03/17/2022] [Accepted: 03/21/2022] [Indexed: 02/06/2023] Open
Abstract
Leukemias are a group of malignancies of the blood and bone marrow. Multiple types of leukemia are known, however reliable treatments have not been developed for most leukemia types. Furthermore, even relatively reliable treatments can result in relapses. MicroRNAs (miRNAs) are a class of short, noncoding RNAs responsible for epigenetic regulation of gene expression and have been proposed as a source of potential novel therapeutic targets for leukemias. In order to identify central miRNAs for leukemia, we conducted data synthesis using two databases: miRTarBase and DISNOR. A total of 137 unique miRNAs associated with 16 types of leukemia were retrieved from miRTarBase and 86 protein-coding genes associated with leukemia were retrieved from the DISNOR database. Based on these data, we formed a visual network of 248 miRNA-target interactions (MTI) between leukemia-associated genes and miRNAs associated with ≥4 leukemia types. We then manually reviewed the literature describing these 248 MTIs for interactions identified in leukemia studies. This manually curated data was then used to visualize a network of 64 MTIs identified in leukemia patients, cell lines and animal models. We also formed a visual network of miRNA-leukemia associations. Finally, we compiled leukemia clinical trials from the ClinicalTrials database. miRNAs with the highest number of MTIs were miR-125b-5p, miR-155-5p, miR-181a-5p and miR-19a-3p, while target genes with the highest number of MTIs were TP53, BCL2, KIT, ATM, RUNX1 and ABL1. The analysis of 248 MTIs revealed a large, highly interconnected network. Additionally, a large MTI subnetwork was present in the network visualized from manually reviewed data. The interconnectedness of the MTI subnetwork suggests that certain miRNAs represent central disease molecules for multiple leukemia types. Additional studies on miRNAs, their target genes and associated biological pathways are required to elucidate the therapeutic potential of miRNAs in leukemia.
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Szczepanek J, Skorupa M, Tretyn A. MicroRNA as a Potential Therapeutic Molecule in Cancer. Cells 2022; 11:1008. [PMID: 35326459 PMCID: PMC8947269 DOI: 10.3390/cells11061008] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/11/2022] [Accepted: 03/16/2022] [Indexed: 12/11/2022] Open
Abstract
Small noncoding RNAs, as post-translational regulators of many target genes, are not only markers of neoplastic disease initiation and progression, but also markers of response to anticancer therapy. Hundreds of miRNAs have been identified as biomarkers of drug resistance, and many have demonstrated the potential to sensitize cancer cells to therapy. Their properties of modulating the response of cells to therapy have made them a promising target for overcoming drug resistance. Several methods have been developed for the delivery of miRNAs to cancer cells, including introducing synthetic miRNA mimics, DNA plasmids containing miRNAs, and small molecules that epigenetically alter endogenous miRNA expression. The results of studies in animal models and preclinical studies for solid cancers and hematological malignancies have confirmed the effectiveness of treatment protocols using microRNA. Nevertheless, the use of miRNAs in anticancer therapy is not without limitations, including the development of a stable nanoconstruct, delivery method choices, and biodistribution. The aim of this review was to summarize the role of miRNAs in cancer treatment and to present new therapeutic concepts for these molecules. Supporting anticancer therapy with microRNA molecules has been verified in numerous clinical trials, which shows great potential in the treatment of cancer.
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Affiliation(s)
- Joanna Szczepanek
- Centre for Modern Interdisciplinary Technologies, Nicolaus Copernicus University, Ul. Wilenska 4, 87-100 Torun, Poland;
| | - Monika Skorupa
- Centre for Modern Interdisciplinary Technologies, Nicolaus Copernicus University, Ul. Wilenska 4, 87-100 Torun, Poland;
- Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, Ul. Lwowska 1, 87-100 Torun, Poland;
| | - Andrzej Tretyn
- Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, Ul. Lwowska 1, 87-100 Torun, Poland;
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Barghbani M, Sarookhani MR, Abbasi M, Maali A, Hajiaghaei M, Keshavarz Shahbaz S, Foroughi F. Evaluation of serum level of miR-155 and TNF-α in rheumatoid arthritis patients. GENE REPORTS 2022. [DOI: 10.1016/j.genrep.2021.101447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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PDL1-binding peptide/anti-miRNA21 conjugate as a therapeutic modality for PD-L1high tumors and TAMs. J Control Release 2022; 345:62-74. [DOI: 10.1016/j.jconrel.2022.02.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 02/22/2022] [Accepted: 02/23/2022] [Indexed: 11/19/2022]
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Cui Y, Zhou Y, Gan N, Xiang Q, Xia M, Liao W, Zheng XL, Peng J, Tang Z. The Role of Extracellular Non-coding RNAs in Atherosclerosis. J Cardiovasc Transl Res 2022; 15:477-491. [PMID: 35233720 DOI: 10.1007/s12265-022-10218-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 02/09/2022] [Indexed: 12/11/2022]
Abstract
Atherosclerosis (AS) is a complex chronic inflammatory disease that leads to myocardial infarction, stroke, and disabling peripheral artery disease. Non-coding RNAs (ncRNAs) directly participate in various physiological processes and exhibit a wide range of biological functions. The present review discusses how different ncRNAs participate in the process of AS in various carrier forms. We focused on the role and potential mechanisms of extracellular ncRNAs in AS and examined their potential implications for clinical treatment.
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Affiliation(s)
- Yuting Cui
- Institute of Cardiovascular Disease Key Laboratory for Arteriosclerology of Hunan Province School of Basic Medical Sciences Hengyang Medical School, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, University of South China, Hengyang, 421001, Hunan, China
| | - Yating Zhou
- Institute of Cardiovascular Disease Key Laboratory for Arteriosclerology of Hunan Province School of Basic Medical Sciences Hengyang Medical School, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, University of South China, Hengyang, 421001, Hunan, China
| | - Ni Gan
- Hengyang Medical School, The Affiliated Changsha Central Hospital, University of South China, Hengyang, 421001, Hunan, China
| | - Qiong Xiang
- Institute of Cardiovascular Disease Key Laboratory for Arteriosclerology of Hunan Province School of Basic Medical Sciences Hengyang Medical School, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, University of South China, Hengyang, 421001, Hunan, China
| | - Mengdie Xia
- Institute of Cardiovascular Disease Key Laboratory for Arteriosclerology of Hunan Province School of Basic Medical Sciences Hengyang Medical School, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, University of South China, Hengyang, 421001, Hunan, China
| | - Wei Liao
- Institute of Cardiovascular Disease Key Laboratory for Arteriosclerology of Hunan Province School of Basic Medical Sciences Hengyang Medical School, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, University of South China, Hengyang, 421001, Hunan, China
| | - Xi-Long Zheng
- Departments of Biochemistry & Molecular Biology and Physiology & Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4Z6, Canada
| | - Juan Peng
- Institute of Cardiovascular Disease Key Laboratory for Arteriosclerology of Hunan Province School of Basic Medical Sciences Hengyang Medical School, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, University of South China, Hengyang, 421001, Hunan, China.
| | - Zhihan Tang
- Institute of Cardiovascular Disease Key Laboratory for Arteriosclerology of Hunan Province School of Basic Medical Sciences Hengyang Medical School, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, University of South China, Hengyang, 421001, Hunan, China.
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