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1.
Microb Biotechnol ; 16(11): 2036-2052, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37740682

RESUMO

The health of the human population has been continuously challenged by viral infections. Herpes simplex virus (HSV) is one of the common causes of illness and can lead to death in immunocompromised patients. Existing anti-HSV therapies are not completely successful in eliminating the infection due to anti-viral drug resistance, ineffectiveness against the latent virus and high toxicity over prolonged use. There is a need to update our knowledge of the current challenges faced in anti-HSV therapeutics and realize the necessity of developing alternative treatment approaches. Protein therapeutics are now being explored as a novel approach due to their high specificity and low toxicity. This review highlights the significance of HSV viral glycoproteins and host receptors in the pathogenesis of HSV infection. Proteins or peptides derived from HSV glycoproteins gC, gB, gD, gH and host cell receptors (HSPG, nectin and HVEM) that act as decoys to inhibit HSV attachment, entry, or fusion have been discussed. Few researchers have tried to improve the efficacy and stability of the identified peptides by modifying them using a peptidomimetic approach. With these efforts, we think developing an alternative treatment option for immunocompromised patients and drug-resistant organisms is not far off.


Assuntos
Glicoproteínas , Simplexvirus , Humanos , Simplexvirus/metabolismo , Linhagem Celular , Glicoproteínas/metabolismo , Peptídeos/farmacologia , Antivirais/farmacologia , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/metabolismo
2.
Cell Oncol (Dordr) ; 46(6): 1747-1762, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37420122

RESUMO

PURPOSE: High-grade glioblastoma is extremely challenging to treat because of its aggressiveness and resistance to conventional chemo- and radio-therapies. On the contrary, genetic and cellular immunotherapeutic strategies based on the stem and immune cells are emerging as promising treatments against glioblastoma (GBM). We aimed to developed a novel combined immunotherapeutic strategy to improve the treatment efficacy using genetically engineered PBMC-derived induced neural stem cells (iNSCs) expressing HSV-TK and second-generation CAR-NK cells against GBM. METHODS: iNSCs cells expressing HSV-TK (iNSCsTK) and GD2-specific CAR-NK92 (GD2NK92) were generated from PBMC-derived iNSCs and NK92 cell lines, respectively. The anti-tumor effect of iNSCsTK and the combinational therapeutics of iNSCsTK and GD2NK92 were evaluated by GBM cell line using in vitro and in vivo experiments. RESULTS: PBMC-derived iNSCsTK possessed tumor-tropism migration ability in vitro and in vivo, which exhibited considerable anti-tumor activity via bystander effect in the presence of ganciclovir (GCV). iNSCsTK/GCV could slow GBM progression and prolong median survival in tumor-bearing mice. However, the anti-tumor effect was limited to single therapy. Therefore, the combinational therapeutic effect of iNSCsTK/GCV and GD2NK92 against GBM was investigated. This approach displayed a more significant anti-tumor effect in vitro and in xenograft tumor mice. CONCLUSIONS: PBMC-derived iNSCsTK showed a significant tumor-tropic migration and an effective anti-tumor activity with GCV in vitro and in vivo. In addition, combined with GD2NK92, iNSCsTK therapeutic efficacy improved dramatically to prolong the tumor-bearing animal model's median survival.


Assuntos
Glioblastoma , Humanos , Animais , Camundongos , Glioblastoma/genética , Simplexvirus/genética , Simplexvirus/metabolismo , Leucócitos Mononucleares/metabolismo , Ganciclovir/farmacologia , Ganciclovir/uso terapêutico , Timidina Quinase/genética
3.
Int J Mol Sci ; 24(14)2023 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-37511481

RESUMO

Previous studies have found that Bifidobacterium infantis-mediated herpes simplex virus-TK/ganciclovir (BF-TK/GCV) reduces the expression of VEGF and CD146, implying tumor metastasis inhibition. However, the mechanism by which BF-TK/GCV inhibits tumor metastasis is not fully studied. Here, we comprehensively identified and quantified protein expression profiling for the first time in gastric cancer (GC) cells MKN-45 upon BF-TK/GCV treatment using quantitative proteomics. A total of 159 and 72 differential expression proteins (DEPs) were significantly changed in the BF-TK/GCV/BF-TK and BF-TK/GCV/BF/GCV comparative analysis. Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis enriched some metastasis-related pathways such as gap junction and cell adhesion molecules pathways. Moreover, the transwell assay proved that BF-TK/GCV inhibited the invasion and migration of tumor cells. Furthermore, immunohistochemistry (IHC) demonstrated that BF-TK/GCV reduced the expression of HIF-1α, mTOR, NF-κB1-p105, VCAM1, MMP13, CXCL12, ATG16, and CEBPB, which were associated with tumor metastasis. In summary, BF-TK/GCV inhibited tumor metastasis, which deepened and expanded the understanding of the antitumor mechanism of BF-TK/GCV.


Assuntos
Ganciclovir , Neoplasias Gástricas , Camundongos , Animais , Ganciclovir/farmacologia , Ganciclovir/uso terapêutico , Simplexvirus/genética , Simplexvirus/metabolismo , Bifidobacterium longum subspecies infantis/metabolismo , Terapia Genética , Modelos Animais de Doenças , Neoplasias Gástricas/terapia , Timidina Quinase/genética , Antivirais/farmacologia
4.
Cancer Sci ; 114(8): 3076-3086, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37322820

RESUMO

Immune cells can recognize tumor-associated antigens released from dead tumor cells, which elicit immune responses, potentially resulting in tumor regression. Tumor cell death induced by chemotherapy has also been reported to activate immunity. However, various studies have reported drug-induced immunosuppression or suppression of inflammation by apoptotic cells. Thus, this study aimed to investigate whether apoptotic tumor cells trigger antitumor immunity independent of anticancer treatment. Local immune responses were evaluated after direct induction of tumor cell apoptosis using a Herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) system. The inflammatory response was significantly altered at the tumor site after apoptosis induction. The expression of cytokines and molecules that activate and suppress inflammation simultaneously increased. The HSV-tk/GCV-induced tumor cell apoptosis resulted in tumor growth suppression and promoted T lymphocyte infiltration into tumors. Therefore, the role of T cells after inducing tumor cell death was explored. CD8 T cell depletion abrogated the antitumor efficacy of apoptosis induction, indicating that tumor regression was mainly dependent on CD8 T cells. Furthermore, CD4 T cell depletion inhibited tumor growth, suggesting the potential role of CD4 T cells in suppressive tumor immunity. Tumor tissues were evaluated after tumor cell apoptosis and CD4 T cell depletion to elucidate this immunological mechanism. Foxp3 and CTLA4, regulatory T-cell markers, decreased. Furthermore, arginase 1, an immune-suppressive mediator induced by myeloid cells, was significantly downregulated. These findings indicate that tumors accelerate CD8 T cell-dependent antitumor immunity and CD4 T cell-mediated suppressive immunity. These findings could be a therapeutic target for immunotherapy in combination with cytotoxic chemotherapy.


Assuntos
Ganciclovir , Neoplasias , Humanos , Ganciclovir/farmacologia , Ganciclovir/uso terapêutico , Timidina Quinase/genética , Timidina Quinase/metabolismo , Simplexvirus/genética , Simplexvirus/metabolismo , Terapia Genética/métodos , Apoptose , Neoplasias/tratamento farmacológico , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Inflamação/tratamento farmacológico , Antivirais/uso terapêutico
5.
Life Sci ; 311(Pt A): 121132, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36309223

RESUMO

AIMS: Glioblastoma multiforme (GBM) is the most malignant type of brain tumor resistant to current treatments. Recently, suicide gene therapy with the Herpex Simplex Virus thymidine kinase (HSV-tk) gene has been developed with high therapeutic potency, even in clinical trials. The primary challenge to establishing a gene therapy strategy is how to transfer the desired gene into the tumor site. The olfactory ensheathing cells (OECs) secreting neurotropic and anti-inflammatory factors have a high migration capacity, making them applicable for gene therapy. We examined our new construct OECs containing the HSV-tk gene for their migration and tumoricidal ability in animal models of GBM. MAIN METHODS: Isolated OECs were transduced by the HSV-tk gene (OEC-tks). OEC-tks or PBS were injected ipsilaterally or contralaterally into the tumor-bearing rats, followed by gancyclovir (GCV) or PBS administration. At the end of the treatment, tumor size, apoptosis, and animal survival were assessed. KEY FINDINGS: Our findings demonstrated that tumor size was significantly decreased in OEC-tks ipsilateral and contralateral groups, followed by GCV injections. Furthermore, both groups' pro-apoptotic protein and gene expressions were up-regulated, whereas Bcl-2 protein expression was down-regulated. Besides, apoptosis in the OEC-tks ipsilateral/GCV group was higher in the intratumoral region, and this percentage was higher in the OEC-tks contralateral/GCV group in the peritumoral region. Interestingly, our new construct increased animal survival rate and reduced body weight loss. SIGNIFICANCE: OECs could serve as a novel carrier for gene therapy, have a high migration capability to the GBM and eventually suppress tumor progression.


Assuntos
Glioblastoma , Ratos , Animais , Glioblastoma/terapia , Glioblastoma/tratamento farmacológico , Timidina Quinase/genética , Células Tumorais Cultivadas , Terapia Genética , Ganciclovir/farmacologia , Ganciclovir/uso terapêutico , Simplexvirus/genética , Simplexvirus/metabolismo , Antivirais/uso terapêutico
6.
Drug Des Devel Ther ; 16: 1515-1530, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35611358

RESUMO

Objective: Gastric cancer is one of the most lethal malignancies in the world. However, the current research on the diagnosis and treatment of nano-ultrasound contrast agents in the field of tumor is mostly focused on breast cancer, ovarian cancer, prostate cancer, liver cancer, etc. Due to the interference of gas in the stomach, there is no report on the treatment of gastric cancer. Herpes simplex virus thymidine kinase/ganciclovir (HSV-TK/GCV) therapy system is the most mature tumor suicide gene in cancer treatment. At the same time, in order to improve its safety and efficiency, we designed a gastric tumor targeted ultrasound-triggered phase-transition nano ultrasound contrast agent PFH/AGM-CBA/HSV-TK/Liposome (PAHL)-Affibody complex. Methods: In our study, guanidinylated SS-PAAs polymer poly(agmatine/N, N'-cystamine-bis-acrylamide) (AGM-CBA) was used as a nuclear localization vector of suicide gene to form a polyplex, perfluorohexane (PFH) was used as ultrasound contrast agent, liposomes were used to encapsulate perfluorohexane droplets and the polyplexes of AGM-CBA/HSV-TK, and affibody molecules were conjugated to the prepared PAHL in order to obtain a specific targeting affinity to human epidermal growth factor receptor type 2 (ErbB2) at gastric cancer cells. With the aid of ultrasound targeted microbubble destruction technology and the nuclear localization effect of AGM-CBA vector, the transfection efficiency of the suicide gene in gastric cancer cells was significantly increased, leading to significant apoptosis of gastric cancer cells. Results: It was shown that PAHL-Affibody complex was nearly spherical with an average diameter of 560 ± 28.9 nm, having higher and specific affinity to ErbB2 (+) gastric cells. In vitro experiments further confirmed that PAHL could target gastric cancer cells expressing ErbB2. In a contrast-enhanced ultrasound scanning study, the prepared ultrasound-triggered phase-change nano-ultrasound contrast agent, PAHL, showed improved ultrasound enhancement effects. With the application of the low-frequency ultrasound, the gene transfection efficiency of PAHL was significantly improved,  thereby inducing significant apoptosis in gastric cancer cells. Conclusion: This study constructs PFH/AGM-CBA/HSV-TK/Liposome-Affibody nano ultrasound contrast agent, which provides new ideas for the treatment strategy of ErbB2-positive gastric cancer and provides some preliminary experimental basis for its inhibitory effect.


Assuntos
Neoplasias Gástricas , Timidina Quinase , Antivirais/farmacologia , Meios de Contraste/farmacologia , Fluorocarbonos , Ganciclovir/farmacologia , Humanos , Lipossomos/farmacologia , Masculino , Receptor ErbB-2 , Simplexvirus/genética , Simplexvirus/metabolismo , Neoplasias Gástricas/diagnóstico por imagem , Neoplasias Gástricas/tratamento farmacológico , Timidina Quinase/genética , Timidina Quinase/metabolismo , Transfecção , Ultrassonografia
7.
Biomed Pharmacother ; 150: 112973, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35468581

RESUMO

Dioscin (Dio), steroid saponin, exists in several medicinal herbs with potent anticancer efficacy. This study aimed to explore the effect of Dio on the immune-related modulation and synergistic therapeutic effects of the herpes simplex virus thymidine kinase/ganciclovir (HSV-Tk/GCV) suicide gene therapy system in murine melanoma, thereby providing a research basis to improve the potential immunomodulatory mechanism underlying combination therapy. Using both in vitro and in vivo experiments, we confirmed the immunocidal effect of Dio-potentiated suicide gene therapy on melanoma. The results showed that Dio upregulated connexin 43 (Cx43) expression and improved gap junction intercellular communication (GJIC) in B16 cells while increasing the cross-presentation of antigens by dendritic cells (DCs), eventually promoting the activation and antitumor immune killing effects of CD8+ T lymphocytes. In contrast, inhibition or blockade of the GJIC function (overexpression of mutant Cx43 tumor cells/Gap26) partially reversed the potentiating effect. The significant synergistic effect of Dio on HSV-Tk/GCV suicide gene therapy was further investigated in a B16 xenograft mouse model. The increased number and activation ratio of CD8+ T lymphocytes and the levels of Gzms-B, IFN-γ, and TNF-α in mice reconfirmed the potential modulatory effects of Dio on the immune system. Taken together, Dio targets Cx43 to enhance GJIC function, improve the antigens cross-presentation of DCs, and activate the antitumor immune effect of CD8+ T lymphocytes, thereby providing insights into the potential immunomodulatory mechanism underlying combination therapy.


Assuntos
Conexina 43 , Melanoma , Animais , Comunicação Celular , Conexina 43/genética , Conexina 43/metabolismo , Apresentação Cruzada , Diosgenina/análogos & derivados , Ganciclovir/farmacologia , Ganciclovir/uso terapêutico , Junções Comunicantes/metabolismo , Terapia Genética/métodos , Humanos , Melanoma/tratamento farmacológico , Melanoma/terapia , Camundongos , Simplexvirus/genética , Simplexvirus/metabolismo , Timidina Quinase/genética , Timidina Quinase/metabolismo , Timidina Quinase/farmacologia
8.
Viruses ; 13(9)2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34578339

RESUMO

Oncolytic virus (OV) as a promising therapeutic agent can selectively infect and kill tumor cells with naturally inherited or engineered properties. Considering the limitations of OVs monotherapy, combination therapy has been widely explored. MEK inhibitor (MEKi) Trametinib is an FDA-approved kinase inhibitor indicated for the treatment of tumors with BRAF V600E or V600K mutations. In this study, the oncolytic activity in vitro and anti-tumor therapeutic efficacy in vivo when combined with oHSV and MEKi Trametinib were investigated. We found: (1) Treatment with MEKi Trametinib augmented oHSV oncolytic activity in BRAF V600E-mutated tumor cells. (2) Combination treatment with oHSV and MEKi Trametinib enhanced virus replication mediated by down-regulation of STAT1 and PKR expression or phosphorylation in BRAF V600E-mutated tumor cells as well as BRAF wt/KRAS-mutated tumor cells. (3) A remarkably synergistic therapeutic efficacy was shown in vivo for BRAF wt/KRAS-mutated tumor models, when a combination of oHSV including PD-1 blockade and MEK inhibition. Collectively, these data provide some new insights for clinical development of combination therapy with oncolytic virus, MEK inhibition, and checkpoint blockade for BRAF or KRAS-mutated tumors.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Piridonas/farmacologia , Pirimidinonas/farmacologia , Simplexvirus/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma/tratamento farmacológico , Linhagem Celular Tumoral , Chlorocebus aethiops , Feminino , Humanos , Pulmão , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Terapia Viral Oncolítica , Vírus Oncolíticos , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Fator de Transcrição STAT1/genética , Células Vero
9.
Cells ; 10(4)2021 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-33800686

RESUMO

Parkinson's disease (PD) is the most common neurodegenerative movement disorder, characterized by progressive loss of dopaminergic neurons in the substantia nigra, intraneuronal deposition of misfolded proteins known as Lewy bodies, and chronic neuroinflammation. PD can arise from monogenic mutations, but in most cases, the etiology is unclear. Viral infection is gaining increasing attentions as a trigger of PD. In this study, we investigated whether the PD-causative 620 aspartate (D) to asparagine (N) mutation in the vacuolar protein sorting 35 ortholog (Vps35) precipitated herpes simplex virus (HSV) infection. We observed that ectopic expression of Vps35 significantly reduced the proliferation and release of HSV-1 virions; the D620N mutation rendered Vps35 a partial loss of such inhibitory effects. Tetherin is a host cell protein capable of restricting the spread of encapsulated viruses including HSV-1 and SARS-Cov-2, both of which are implicated in the development of parkinsonism. Compared with cells overexpressing wildtype Vps35, cells expressing mutant Vps35 with D620N had less Tetherin on cell surfaces. Real-time and static cell imaging revealed that Tetherin recycled through Vps35-positive endosomes. Expression of Vps35 with D620N reduced endosomal dynamics and frequency of motile Tetherin-containing vesicles, a sign of defective production of recycling carriers. Our study suggests that the D620N mutation in Vps35 hinders Tetherin trafficking to cell surfaces and facilitates virus spread.


Assuntos
Antígeno 2 do Estroma da Médula Óssea/metabolismo , Doença de Parkinson/metabolismo , Doença de Parkinson/virologia , Simplexvirus/metabolismo , Proteínas de Transporte Vesicular/metabolismo , COVID-19/virologia , Linhagem Celular Tumoral , Endossomos/metabolismo , Humanos , Mutação , Doença de Parkinson/genética , Transporte Proteico/genética , SARS-CoV-2/crescimento & desenvolvimento , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidade , Simplexvirus/patogenicidade , Transfecção , Proteínas de Transporte Vesicular/genética , Replicação Viral/genética
10.
J Cutan Pathol ; 48(7): 908-910, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33345376

RESUMO

Rett syndrome (RTT) is a progressive neurological disorder, affecting females with mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2). While MECP2 has been implicated in cancers of the breast, colon, and prostrate, cancer in patients with RTT is rare. We present a case of malignant melanoma in a patient with RTT, which additionally, displayed hitherto undescribed nuclear features, resembling herpes simplex virus cytopathic effects.


Assuntos
Efeito Citopatogênico Viral/genética , Melanoma/patologia , Síndrome de Rett/patologia , Simplexvirus/metabolismo , Neoplasias Cutâneas/patologia , Adulto , Progressão da Doença , Feminino , Humanos , Melanoma/diagnóstico , Melanoma/metabolismo , Melanoma/cirurgia , Proteína 2 de Ligação a Metil-CpG/genética , Mutação , Síndrome de Rett/complicações , Síndrome de Rett/genética , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/cirurgia , Melanoma Maligno Cutâneo
11.
Biomed Pharmacother ; 134: 110932, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33370632

RESUMO

Oncolytic viruses have attracted attention as a promising strategy in cancer therapy owing to their ability to selectively infect and kill tumor cells, without affecting healthy cells. They also exert their anti-tumor effects by releasing immunostimulatory molecules from dying cancer cells. Several regulatory mechanisms, such as autophagy, contribute to the anti-tumor properties of oncolytic viruses. Autophagy is a conserved catabolic process in responses to various stresses, such as nutrient deprivation, hypoxia, and infection that produces energy by lysosomal degradation of intracellular contents. Autophagy can support infectivity and replication of the oncolytic virus and enhance their anti-tumor effects via mediating oncolysis, autophagic cell death, and immunogenic cell death. On the other hand, autophagy can reduce the cytotoxicity of oncolytic viruses by providing survival nutrients for tumor cells. In his review, we summarize various types of oncolytic viruses in clinical trials, their mechanism of action, and autophagy machinery. Furthermore, we precisely discuss the interaction between oncolytic viruses and autophagy in cancer therapy and their combinational effects on tumor cells.


Assuntos
Autofagia , Neoplasias/terapia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/metabolismo , Adenoviridae/metabolismo , Animais , Morte Celular Autofágica , Linhagem Celular Tumoral , Ensaios Clínicos como Assunto , Humanos , Morte Celular Imunogênica , Vírus do Sarampo/metabolismo , Camundongos , Neoplasias/metabolismo , Simplexvirus/metabolismo , Vesiculovirus/metabolismo , Replicação Viral
13.
Int J Mol Sci ; 21(21)2020 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-33167582

RESUMO

Oncolytic viruses are smart therapeutics against cancer due to their potential to replicate and produce the needed therapeutic dose in the tumor, and to their ability to self-exhaust upon tumor clearance. Oncolytic virotherapy strategies based on the herpes simplex virus are reaching their thirties, and a wide variety of approaches has been envisioned and tested in many different models, and on a range of tumor targets. This huge effort has culminated in the primacy of an oncolytic HSV (oHSV) being the first oncolytic virus to be approved by the FDA and EMA for clinical use, for the treatment of advanced melanoma. The path has just been opened; many more cancer types with poor prognosis await effective and innovative therapies, and oHSVs could provide a promising solution, especially as combination therapies and immunovirotherapies. In this review, we analyze the most recent advances in this field, and try to envision the future ahead of oHSVs.


Assuntos
Terapia Viral Oncolítica/métodos , Simplexvirus/metabolismo , Terapia Combinada/métodos , Terapia Combinada/tendências , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/metabolismo , Humanos , Terapia Viral Oncolítica/tendências , Vírus Oncolíticos/genética , Vírus Oncolíticos/metabolismo , Simplexvirus/genética
14.
Viruses ; 12(10)2020 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-33096825

RESUMO

Most cells can release extracellular vesicles (EVs), membrane vesicles containing various proteins, nucleic acids, enzymes, and signaling molecules. The exchange of EVs between cells facilitates intercellular communication, amplification of cellular responses, immune response modulation, and perhaps alterations in viral pathogenicity. EVs serve a dual role in inhibiting or enhancing viral infection and pathogenesis. This review examines the current literature on EVs to explore the complex role of EVs in the enhancement, inhibition, and potential use as a nanotherapeutic against clinically relevant viruses, focusing on neurotropic viruses: Zika virus (ZIKV) and human immunodeficiency virus (HIV). Overall, this review's scope will elaborate on EV-based mechanisms, which impact viral pathogenicity, facilitate viral spread, and modulate antiviral immune responses.


Assuntos
Vesículas Extracelulares/metabolismo , Viroses/metabolismo , Antivirais/farmacologia , Comunicação Celular/fisiologia , Coronavirus/metabolismo , Coronavirus/patogenicidade , Exossomos/metabolismo , HIV/metabolismo , HIV/patogenicidade , Infecções por HIV/metabolismo , Humanos , Retroviridae/metabolismo , Simplexvirus/metabolismo , Terapêutica/métodos , Viroses/tratamento farmacológico , Viroses/virologia , Zika virus/metabolismo , Zika virus/patogenicidade , Infecção por Zika virus/metabolismo
15.
J Virol ; 94(23)2020 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-32938770

RESUMO

The herpes simplex virus (HSV) heterodimer gE/gI and another membrane protein, US9, which has neuron-specific effects, promote the anterograde transport of virus particles in neuronal axons. Deletion of both HSV gE and US9 blocks the assembly of enveloped particles in the neuronal cytoplasm, which explains why HSV virions do not enter axons. Cytoplasmic envelopment depends upon interactions between viral membrane proteins and tegument proteins that encrust capsids. We report that tegument protein UL16 is unstable, i.e., rapidly degraded, in neurons infected with a gE-/US9- double mutant. Immunoprecipitation experiments with lysates of HSV-infected neurons showed that UL16 and three other tegument proteins, namely, VP22, UL11, and UL21, bound either to gE or gI. All four of these tegument proteins were also pulled down with US9. In neurons transfected with tegument proteins and gE/gI or US9, there was good evidence that VP22 and UL16 bound directly to US9 and gE/gI. However, there were lower quantities of these tegument proteins that coprecipitated with gE/gI and US9 from transfected cells than those of infected cells. This apparently relates to a matrix of several different tegument proteins formed in infected cells that bind to gE/gI and US9. In cells transfected with individual tegument proteins, this matrix is less prevalent. Similarly, coprecipitation of gE/gI and US9 was observed in HSV-infected cells but not in transfected cells, which argued against direct US9-gE/gI interactions. These studies suggest that gE/gI and US9 binding to these tegument proteins has neuron-specific effects on virus HSV assembly, a process required for axonal transport of enveloped particles.IMPORTANCE Herpes simplex viruses 1 and 2 and varicella-zoster virus cause significant morbidity and mortality. One basic property of these viruses is the capacity to establish latency in the sensory neurons and to reactivate from latency and then cause disease in peripheral tissues, such as skin and mucosal epithelia. The transport of nascent HSV particles from neuron cell bodies into axons and along axons to axon tips in the periphery is an important component of this reactivation and reinfection. Two HSV membrane proteins, gE/gI and US9, play an essential role in these processes. Our studies help elucidate how HSV gE/gI and US9 promote the assembly of virus particles and sorting of these virions into neuronal axons.


Assuntos
Axônios/virologia , Herpes Simples/virologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lipoproteínas/metabolismo , Simplexvirus/metabolismo , Proteínas Virais/metabolismo , Transporte Axonal/fisiologia , Capsídeo/metabolismo , Linhagem Celular , Citoplasma/virologia , Herpesvirus Humano 1/fisiologia , Herpesvirus Humano 2 , Transporte Proteico , Proteínas Virais Reguladoras e Acessórias/metabolismo , Proteínas Estruturais Virais/metabolismo , Vírion/metabolismo , Montagem de Vírus
16.
Int J Mol Sci ; 21(18)2020 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-32967368

RESUMO

Amyotropic lateral sclerosis (ALS) is a lethally progressive and irreversible neurodegenerative disease marked by apparent death of motor neurons present in the spinal cord, brain stem and motor cortex. While more and more gene mutants being established for genetic ALS, the vast majority suffer from sporadic ALS (>90%). It has been challenging, thus, to model sporadic ALS which is one reason why the underlying pathophysiology remains elusive and has stalled the development of therapeutic strategies of this progressive motor neuron disease. To further unravel these pathological signaling pathways, human induced pluripotent stem cell (hiPSCs)-derived motor neurons (MNs) from FUS- and SOD1 ALS patients and healthy controls were systematically compared to independent published datasets. Here through this study we created a gene profile of ALS by analyzing the DEGs, the Kyoto encyclopedia of Genes and Genomes (KEGG) pathways, the interactome and the transcription factor profiles (TF) that would identify altered molecular/functional signatures and their interactions at both transcriptional (mRNAs) and translational levels (hub proteins and TFs). Our findings suggest that FUS and SOD1 may develop from dysregulation in several unique pathways and herpes simplex virus (HSV) infection was among the topmost predominant cellular pathways connected to FUS and not to SOD1. In contrast, SOD1 is mainly characterized by alterations in the metabolic pathways and alterations in the neuroactive-ligand-receptor interactions. This suggests that different genetic ALS forms are singular diseases rather than part of a common spectrum. This is important for patient stratification clearly pointing towards the need for individualized medicine approaches in ALS.


Assuntos
Esclerose Lateral Amiotrófica , Proteína FUS de Ligação a RNA , Superóxido Dismutase-1 , Idoso , Esclerose Lateral Amiotrófica/classificação , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Feminino , Estudo de Associação Genômica Ampla , Herpes Simples/genética , Herpes Simples/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Proteína FUS de Ligação a RNA/genética , Proteína FUS de Ligação a RNA/metabolismo , Simplexvirus/genética , Simplexvirus/metabolismo , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , Transcriptoma
17.
J Virol ; 94(13)2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32295926

RESUMO

Herpes simplex virus (HSV) is among the most prevalent viral infections worldwide and remains incurable. While nucleoside analogs are used to relieve symptoms of infection, they suffer from having serious adverse effects and are unable to abolish the virus from the host. Here, we demonstrate a unique antiviral effect of prodigiosin (PG), a natural secondary metabolite produced by Serratia marcescens, on HSV infection. We show that PG naturally exerts antiviral activity against HSV-1 and HSV-2 infections. PG treatment resulted in robust inhibition of viral replication in vitro and ex vivo in cultured porcine corneas. Additionally, PG protected against HSV-1 infection and disease progression in a murine model of ocular infection. In our quest to determine the molecular mechanisms of its antiviral activity, we show that PG specifically inhibits NF-κB and Akt signaling pathways and promotes accelerated cell death in HSV-infected cells. Our findings reveal novel antiviral properties of PG, suggesting its high potential as an alternative treatment for herpetic diseases. They also provide new information on antiviral effects of HSV-bacterial metabolite interactions.IMPORTANCE In this article, we provide a new role for a commonly found bacterial pigment in controlling herpes simplex virus infection, for which diverse and multimodal antiviral agents are needed to prevent drug resistance. Serratia marcescens is a red pigment (prodigiosin)-producing Gram-negative bacillus that is naturally found in soil and water. It is associated with many kinds of human infections, including wound and eye infections, and meningitis. Taking cues from previous studies on prodigiosin, including possible proapoptotic anticancer properties, we investigated how it might affect HSV infection. Interestingly, we found that it is a potent virucidal compound that disrupts host signaling pathways needed for HSV growth and survival. The mode of antiviral action suggests potentially broad activity against enveloped viruses. Our results also indicate that interactions with commensal bacteria may inhibit HSV infection, underscoring the importance of studying these microbial metabolites and their implications for viral pathogenesis and treatment.


Assuntos
Prodigiosina/farmacologia , Simplexvirus/efeitos dos fármacos , Animais , Antivirais/farmacologia , Linhagem Celular , Córnea/virologia , Células HeLa , Herpes Simples/virologia , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Prodigiosina/metabolismo , Serratia marcescens/metabolismo , Simplexvirus/metabolismo , Simplexvirus/fisiologia , Suínos , Replicação Viral/efeitos dos fármacos
18.
J Cutan Pathol ; 47(1): 6-11, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31441947

RESUMO

BACKGROUND: While usually straightforward, diagnostic features of cutaneous herpes simplex virus and varicella zoster virus infection (HSV/VZV) are not always present in biopsy specimens. Although intuitively the presence of eosinophils may lead the pathologist away from the diagnosis of cutaneous HSV/VZV infection, in our practice we have noted that eosinophils are often encountered in diagnostic specimens. METHODS: To deduce the frequency with which the inflammatory response accompanying cutaneous HSV/VZV infection includes significant numbers of eosinophils, we performed a retrospective review. We included 159 specimens from our database, diagnosed between 2009 and 2017. We determined the number of eosinophils in 10 high-power fields and noted additional histologic factors including presence of follicular involvement, ulceration, and pseudolymphomatous change. RESULTS: Of all included cases, 63% had 0-1 eosinophils, 24% had 2-10 eosinophils, and 13% had more than 10 eosinophils. Statistical analysis did not reveal a significant association between any demographic or histologic features examined and the presence of increased eosinophils. CONCLUSIONS: In this study, more than one-third of biopsy specimens diagnostic of cutaneous HSV/VZV infection had a prominent number of eosinophils. The detection of eosinophils should not be unexpected and should not lessen diagnostic suspicion for cutaneous HSV/VZV infection.


Assuntos
Eosinófilos , Herpes Simples , Herpesvirus Humano 3/metabolismo , Simplexvirus/metabolismo , Pele , Infecção pelo Vírus da Varicela-Zoster , Adolescente , Adulto , Idoso , Biópsia , Criança , Pré-Escolar , Eosinófilos/metabolismo , Eosinófilos/patologia , Eosinófilos/virologia , Feminino , Herpes Simples/metabolismo , Herpes Simples/patologia , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Pele/metabolismo , Pele/patologia , Pele/virologia , Infecção pelo Vírus da Varicela-Zoster/metabolismo , Infecção pelo Vírus da Varicela-Zoster/patologia
19.
Ageing Res Rev ; 48: 145-152, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30391341

RESUMO

Frailty is an emerging geriatric syndrome characterized by decreased physiologic reserve and increased vulnerability to environmental factors. Several studies have examined the association between persistent cytomegalovirus (CMV) infection and poor clinical outcomes in the elderly, but the results are often contradictory. Here, we performed a systematic review and meta-analysis to analyze the association between human herpesvirus seropositivity [CMV, Epstein-Barr virus (EBV), Varicella zoster virus (VZV), and Herpes simplex virus (HSV)] and frailty in elderly people. Searches were performed in PubMed, SCOPUS, Lilacs, IBECS, and Web of Science databases. We used the odds ratio (OR) as a measure of the association between herpesvirus infections and frailty. Summary estimates were calculated using random-effects models. Six studies were included in the present systematic review. The data from 2559 elderly subjects were analyzed; 1571 of the subjects had ages between 60 and 79 years, and 988 of the subjects were older than 80. We found an association between CMV seropositivity and frailty in the elderly aged 60-79 years (OR 2.33, CI 95% 1.48-3.67) but not in the oldest-old subjects (OR 0.67, CI 95% 0.42-1.05). Moreover, no association was found between EBV, VZV, and HSV infections and frailty. Current evidence suggests an association between CMV seropositivity and frailty in individuals aged 60-79 years old.


Assuntos
Fragilidade/sangue , Fragilidade/virologia , Infecções por Herpesviridae/sangue , Herpesvirus Humano 3/metabolismo , Herpesvirus Humano 4/metabolismo , Simplexvirus/metabolismo , Idoso , Idoso de 80 Anos ou mais , Citomegalovirus/metabolismo , Fragilidade/epidemiologia , Infecções por Herpesviridae/epidemiologia , Humanos , Pessoa de Meia-Idade
20.
Anal Cell Pathol (Amst) ; 2018: 8941908, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29854577

RESUMO

Our previous findings showed a good therapeutic effect of the combination of suicide gene HSV-TK, nuclide 131I, and magnetic fluid hyperthermia (MFH) on hepatoma by using magnetic nanoparticles as linkers, far better than any monotherapy involved, with no adverse effects. This combination therapy might be an eligible strategy to treat hepatic cancer. However, it is not clear how the combination regimen took the therapeutic effects. In the current study, to explore the possible mechanisms of radionuclide-gene therapy combined with MFH to treat hepatoma at tissue, cellular, and molecular levels and to provide theoretical and experimental data for its clinical application, we examined the apoptosis induction of the combination therapy and investigated the expression of the proteins related to apoptosis such as survivin, livin, bcl-2, p53, and nucleus protein Ki67 involved in cell proliferation, detected VEGF, and MVD involved in angiogenesis of tumor tissues and analyzed the pathologic changes after treatment. The results showed that the combination therapy significantly induced the hepatoma cell apoptosis. The expression of survivin, VEGF, bcl-2, p53, livin, Ki67, and VEGF proteins and microvascular density (MVD) were all decreased after treatment. The therapeutic mechanisms may be involved in the downregulation of Ki67 expression leading to tumor cell proliferation repression and inhibition of survivin, bcl-2, p53, and livin protein expression inducing tumor cell apoptosis, negatively regulating VEGF protein expression, and reducing vascular endothelial cells, which results in tumor angiogenesis inhibition and microvascular density decrease and tumor cell necrosis. These findings offer another basic data support and theoretical foundation for the clinical application of the combination therapy.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Carcinoma Hepatocelular/terapia , Ganciclovir/uso terapêutico , Hipertermia Induzida , Radioisótopos do Iodo/química , Neoplasias Hepáticas/terapia , Nanosferas/química , Timidina Quinase/metabolismo , Anticorpos Monoclonais/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/ultraestrutura , Proliferação de Células/efeitos dos fármacos , Ganciclovir/farmacologia , Células Hep G2 , Humanos , Proteínas Inibidoras de Apoptose/metabolismo , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/ultraestrutura , Microvasos/efeitos dos fármacos , Microvasos/patologia , Necrose , Proteínas de Neoplasias/metabolismo , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Simplexvirus/metabolismo , Survivina , Ensaios Antitumorais Modelo de Xenoenxerto
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