RESUMO
Here we introduce a first-in-class microRNA-sensitive oncolytic Zika virus (ZIKV) for virotherapy application against central nervous system (CNS) tumors. The described methodology produced two synthetic modified ZIKV strains that are safe in normal cells, including neural stem cells, while preserving brain tropism and oncolytic effects in tumor cells. The microRNA-sensitive ZIKV introduces genetic modifications in two different virus sites: first, in the established 3'UTR region, and secondly, in the ZIKV protein coding sequence, demonstrating for the first time that the miRNA inhibition systems can be functional outside the UTR RNA sites. The total tumor remission in mice bearing human CNS tumors, including metastatic tumor growth, after intraventricular and systemic modified ZIKV administration, confirms the promise of this virotherapy as a novel agent against brain tumors-highly deadly diseases in urgent need of effective advanced therapies.
Assuntos
Neoplasias do Sistema Nervoso Central , MicroRNAs , Terapia Viral Oncolítica , Vírus Oncolíticos , Infecção por Zika virus , Zika virus , Humanos , Camundongos , Animais , Vírus Oncolíticos/genética , Zika virus/genética , MicroRNAs/genética , Infecção por Zika virus/terapia , Terapia Viral Oncolítica/métodosRESUMO
In the last decades, a group of viruses has received great attention due to its relationship with cancer development and its wide distribution throughout the vertebrates: the papillomaviruses. In this article, we aim to review some of the most relevant reports concerning the use of bovines as an experimental model for studies related to papillomaviruses. Moreover, the obtained data contributes to the development of strategies against the clinical consequences of bovine papillomaviruses (BPV) that have led to drastic hazards to the herds. To overcome the problem, the vaccines that we have been developing involve recombinant DNA technology, aiming at prophylactic and therapeutic procedures. It is important to point out that these strategies can be used as models for innovative procedures against HPV, as this virus is the main causal agent of cervical cancer, the second most fatal cancer in women.
RESUMO
Since the discovery of the double helix and the introduction of genetic engineering, the possibility to develop new strategies to manipulate the genome has fascinated scientists around the world. Currently scientists have the knowledge andabilitytoedit the genomes. Several methodologies of gene editing have been established, all of them working like "scissor", creating double strand breaks at specific spots. The introduction of a new technology, which was adapted from the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas bacterial immune system, has revolutionized the genetic therapy field, as it allows a much more precise editing of gene than the previously described tools and, therefore, to prevent and treat disease in humans. This review aims to revisit the genome editing history that led to the rediscovery of the CRISPR/Cas technology and to explore the technical aspects, applications and perspectives of this fascinating, powerful, precise, simpler and cheaper technology in different fields.
Assuntos
Sistemas CRISPR-Cas/genética , Edição de Genes/métodos , Terapia Genética/métodos , Imunidade Adaptativa/genética , Animais , Bactérias/genética , Bactérias/imunologia , Sistemas CRISPR-Cas/imunologia , Contenção de Riscos Biológicos , Quebras de DNA de Cadeia Dupla , Reparo do DNA , Modelos Animais de Doenças , Terapia Genética/efeitos adversos , Humanos , RNA Guia de Cinetoplastídeos/genéticaRESUMO
Despite the novel diagnostic methods and therapies implemented in oncology, the number of patients that succumb by the cancer remains high globally. Currently studies point out that 20-25% of all human malignancies are related to micro-organism infections. Among these cancer-related pathogens, the human papillomavirus (HPV) has a prominent position, since the virus is responsible for about 30% of all infectious agent-related cancers. Thus, an amount of cancers could be avoided by means prophylactic and/or therapeutic measures. However, these measures required a holistic comprehension about HPV-related cancer biology. Based on this, this review aims to summarize the last evidences of HPV on cancer biology (from initiation to metastasis), focus on molecular and biochemical deregulations associated with viral infection, and discuss the viral etiology in different malignancies.
Assuntos
Transformação Celular Viral , Neoplasias/virologia , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/virologia , Animais , Vacinas Anticâncer/administração & dosagem , Genótipo , Interações Hospedeiro-Patógeno , Humanos , Mutação , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/prevenção & controle , Proteínas Oncogênicas Virais/metabolismo , Papillomaviridae/genética , Papillomaviridae/metabolismo , Infecções por Papillomavirus/metabolismo , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/administração & dosagem , Fenótipo , Prognóstico , Fatores de RiscoRESUMO
Bovine papillomatosis is an infectious disease that is caused by bovine papillomavirus (BPV), which results in important economic losses. However, no BPV vaccines or effective treatment methods are commercially available to date. Moreover, the absence of papillomavirus replication in vitro makes the use of recombinant protein a promising candidate for vaccine formulations. Hence, we developed an integrated study on the L1 capsid protein of BPV-1, obtained from a bacterial expression system, regarding its purification, biosafety, thermostability and immunogenicity. The results indicated an absence of genotoxicity of the purified recombinant L1 protein, ß-sheet prevalence of secondary structure folding, protein stability under high temperatures as well as the presence of capsomeres and VLPs. In addition, preliminary experimental vaccination of calves showed the production of specific antibodies against BPV-1 L1.
Assuntos
Papillomavirus Bovino 1/imunologia , Proteínas do Capsídeo/imunologia , Doenças dos Bovinos/prevenção & controle , Infecções por Papillomavirus/veterinária , Vacinas contra Papillomavirus/imunologia , Animais , Anticorpos Antivirais/sangue , Papillomavirus Bovino 1/genética , Proteínas do Capsídeo/química , Proteínas do Capsídeo/genética , Bovinos , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/administração & dosagem , Vacinas contra Papillomavirus/genética , Conformação Proteica , Dobramento de Proteína , Multimerização Proteica , Estabilidade Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia , Vacinas de Partículas Semelhantes a Vírus/química , Vacinas de Partículas Semelhantes a Vírus/genética , Vacinas de Partículas Semelhantes a Vírus/imunologiaRESUMO
Cancer is a group of highly complex and heterogeneous diseases with several causes. According to the stochastic model, cancer initiates from mutation in somatic cells, leading to genomic instability and cell transformation. This canonical pathway of carcinogenesis is related to the discovery of important mechanisms that regulate cancer initiation. However, there are few studies describing genetic and metabolic alterations that deregulate transformed cells, resulting in epithelial-mesenchymal transition (EMT) and its most dramatic consequence, the metastasis. This review summarizes the main genetics and metabolic changes induced by reactive oxygen species (ROS) that lead to EMT.
Assuntos
Carcinogênese/genética , Carcinogênese/metabolismo , Animais , Metabolismo Energético , Transição Epitelial-Mesenquimal , Humanos , Metástase Neoplásica , Espécies Reativas de Oxigênio/metabolismo , Sistemas do Segundo MensageiroRESUMO
Bovine papillomavirus (BPV) is considered a useful model to study HPV oncogenic process. BPV interacts with the host chromatin, resulting in DNA damage, which is attributed to E5, E6, and E7 viral oncoproteins activity. However, the oncogenic mechanisms of BPV E6 oncoprotein per se remain unknown. This study aimed to evaluate the mutagenic potential of Bos taurus papillomavirus type 1 (BPV-1) E6 recombinant oncoprotein by the cytokinesis-block micronucleus assay (CBMNA) and comet assay (CA). Peripheral blood samples of five calves were collected. Samples were subjected to molecular diagnosis, which did not reveal presence of BPV sequences. Samples were treated with 1 µg/mL of BPV-1 E6 oncoprotein and 50 µg/mL of cyclophosphamide (positive control). Negative controls were not submitted to any treatment. The samples were submitted to the CBMNA and CA. The results showed that BPV E6 oncoprotein induces clastogenesis per se, which is indicative of genomic instability. These results allowed better understanding the mechanism of cancer promotion associated with the BPV E6 oncoprotein and revealed that this oncoprotein can induce carcinogenesis per se. E6 recombinant oncoprotein has been suggested as a possible vaccine candidate. Results pointed out that BPV E6 recombinant oncoprotein modifications are required to use it as vaccine.
Assuntos
Papillomavirus Bovino 1/genética , Proteínas Oncogênicas Virais/genética , Infecções por Papillomavirus/genética , Proteínas Recombinantes/genética , Animais , Papillomavirus Bovino 1/patogenicidade , Carcinogênese/genética , Bovinos , Linhagem Celular , Ciclofosfamida/administração & dosagem , Instabilidade Genômica/efeitos dos fármacos , Humanos , Proteínas Oncogênicas Virais/administração & dosagem , Papillomaviridae/genética , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/virologia , Proteínas Recombinantes/administração & dosagemRESUMO
Abstract In the last decades, a group of viruses has received great attention due to its relationship with cancer development and its wide distribution throughout the vertebrates: the papillomaviruses. In this article, we aim to review some of the most relevant reports concerning the use of bovines as an experimental model for studies related to papillomaviruses. Moreover, the obtained data contributes to the development of strategies against the clinical consequences of bovine papillomaviruses (BPV) that have led to drastic hazards to the herds. To overcome the problem, the vaccines that we have been developing involve recombinant DNA technology, aiming at prophylactic and therapeutic procedures. It is important to point out that these strategies can be used as models for innovative procedures against HPV, as this virus is the main causal agent of cervical cancer, the second most fatal cancer in women.