RESUMO
Breast cancer, specifically metastatic breast, is a leading cause of morbidity and mortality in women. This is mainly due to relapse and reoccurrence of tumor. The primary reason for cancer relapse is the development of multidrug resistance (MDR) hampering the treatment and prognosis. MDR can occur due to a multitude of molecular events, including increased expression of efflux transporters such as P-gp, BCRP, or MRP1; epithelial to mesenchymal transition; and resistance development in breast cancer stem cells. Excessive dose dumping in chemotherapy can cause intrinsic anti-cancer MDR to appear prior to chemotherapy and after the treatment. Hence, novel targeted nanomedicines encapsulating chemotherapeutics and gene therapy products may assist to overcome cancer drug resistance. Targeted nanomedicines offer innovative strategies to overcome the limitations of conventional chemotherapy while permitting enhanced selectivity to cancer cells. Targeted nanotheranostics permit targeted drug release, precise breast cancer diagnosis, and importantly, the ability to overcome MDR. The article discusses various nanomedicines designed to selectively target breast cancer, triple negative breast cancer, and breast cancer stem cells. In addition, the review discusses recent approaches, including combination nanoparticles (NPs), theranostic NPs, and stimuli sensitive or "smart" NPs. Recent innovations in microRNA NPs and personalized medicine NPs are also discussed. Future perspective research for complex targeted and multi-stage responsive nanomedicines for metastatic breast cancer is discussed.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Nanomedicina/métodos , Sistemas de Liberação de Medicamentos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Terapia Genética/métodos , Humanos , Terapia de Alvo Molecular , Nanomedicina/tendências , Nanopartículas/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Células-Tronco Neoplásicas/metabolismo , Medicina de Precisão , Neoplasias de Mama Triplo Negativas/tratamento farmacológicoRESUMO
Methamphetamine (METH) abuse is common among individuals infected with HIV-1 and has been shown to affect HIV replication and pathogenesis. These HIV-1 infected individuals also exhibit greater neuronal injury and higher cognitive decline. HIV-1 proteins, specifically gp120 and HIV-1 Tat, have been earlier shown to affect neurocognition. HIV-1 Tat, a viral protein released early during HIV-1 replication, contributes to HIV-associated neurotoxicity through various mechanisms including production of pro-inflammatory cytokines, reactive oxygen species and dysregulation of neuroplasticity. However, the combined effect of METH and HIV-1 Tat on neurocognition and its potential effect on neuroplasticity mechanisms remains largely unknown. Therefore, the present study was undertaken to investigate the combined effect of METH and HIV-1 Tat on behavior and on the expression of neuroplasticity markers by utilizing Doxycycline (DOX)-inducible HIV-1 Tat (1-86) transgenic mice. Expression of Tat in various brain regions of these mice was confirmed by RT-PCR. The mice were administered with an escalating dose of METH (0.1â¯mg/kg to 6â¯mg/kg, i.p) over a 7-day period, followed by 6â¯mg/kg, i.p METH twice a day for four weeks. After three weeks of METH administration, Y maze and Morris water maze assays were performed to determine the effect of Tat and METH on working and spatial memory, respectively. Compared with controls, working memory was significantly decreased in Tat mice that were administered METH. Moreover, significant deficits in spatial memory were also observed in Tat-Tg mice that were administered METH. A significant reduction in the protein expressions of synapsin 1, synaptophysin, Arg3.1, PSD-95, and BDNF in different brain regions were also observed. Expression levels of Calmodulin kinase II (CaMKII), a marker of synaptodendritic integrity, were also significantly decreased in HIV-1 Tat mice that were treated with METH. Together, this data suggests that METH enhances HIV-1 Tat-induced memory deficits by reducing the expression of pre- and postsynaptic proteins and neuroplasticity markers, thus providing novel insights into the molecular mechanisms behind neurocognitive impairments in HIV-infected amphetamine users.
Assuntos
Transtornos da Memória/fisiopatologia , Transmissão Sináptica/efeitos dos fármacos , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo , Animais , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central , Feminino , Proteína gp120 do Envelope de HIV/metabolismo , Infecções por HIV/metabolismo , Soropositividade para HIV , HIV-1/metabolismo , Humanos , Masculino , Transtornos da Memória/metabolismo , Metanfetamina/efeitos adversos , Metanfetamina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fatores de Crescimento Neural/efeitos dos fármacos , Neurônios/metabolismo , Sinapses/efeitos dos fármacos , Sinapsinas/efeitos dos fármacos , Sinapsinas/metabolismo , Produtos do Gene tat do Vírus da Imunodeficiência Humana/efeitos adversosRESUMO
With increasing survival of patients infected with human immunodeficiency virus type 1 (HIV-1), the manifestation of heterogeneous neurological complications is also increasing alarmingly in these patients. Currently, more than 30% of about 40 million HIV-1 infected people worldwide develop central nervous system (CNS)-associated dysfunction, including dementia, sensory, and motor neuropathy. Furthermore, the highly effective antiretroviral therapy has been shown to increase the prevalence of mild cognitive functions while reducing other HIV-1-associated neurological complications. On the contrary, the presence of neurological disorder frequently affects the outcome of conventional HIV-1 therapy. Although, both the children and adults suffer from the post-HIV treatment-associated cognitive impairment, adults, especially depending on the age of disease onset, are more prone to CNS dysfunction. Thus, addressing neurological complications in an HIV-1-infected patient is a delicate balance of several factors and requires characterization of the molecular signature of associated CNS disorders involving intricate cross-talk with HIV-1-derived neurotoxins and other cellular factors. In this review, we summarize some of the current data supporting both the direct and indirect mechanisms, including neuro-inflammation and genome instability in association with aging, leading to CNS dysfunction after HIV-1 infection, and discuss the potential strategies addressing the treatment or prevention of HIV-1-mediated neurotoxicity.
Assuntos
Envelhecimento , Infecções por HIV/complicações , HIV-1/fisiologia , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/virologia , Animais , HumanosRESUMO
Mild-to-moderate tobacco smoking is highly prevalent in HIV-infected individuals, and is known to exacerbate HIV pathogenesis. The objective of this study was to determine the specific effects of mild-to-moderate smoking on viral load, cytokine production, and oxidative stress and cytochrome P450 (CYP) pathways in HIV-infected individuals who have not yet received antiretroviral therapy (ART). Thirty-two human subjects were recruited and assigned to four different cohorts as follows: a) HIV negative non-smokers, b) HIV positive non-smokers, c) HIV negative mild-to-moderate smokers, and d) HIV positive mild-to-moderate smokers. Patients were recruited in Cameroon, Africa using strict selection criteria to exclude patients not yet eligible for ART and not receiving conventional or traditional medications. Those with active tuberculosis, hepatitis B or with a history of substance abuse were also excluded. Our results showed an increase in the viral load in the plasma of HIV positive patients who were mild-to-moderate smokers compared to individuals who did not smoke. Furthermore, although we did not observe significant changes in the levels of most pro-inflammatory cytokines, the cytokine IL-8 and MCP-1 showed a significant decrease in the plasma of HIV-infected patients and smokers compared with HIV negative non-smokers. Importantly, HIV-infected individuals and smokers showed a significant increase in oxidative stress compared with HIV negative non-smoker subjects in both plasma and monocytes. To examine the possible pathways involved in increased oxidative stress and viral load, we determined the mRNA levels of several antioxidant and cytochrome P450 enzymes in monocytes. The results showed that the levels of most antioxidants are unaltered, suggesting their inability to counter oxidative stress. While CYP2A6 was induced in smokers, CYP3A4 was induced in HIV and HIV positive smokers compared with HIV negative non-smokers. Overall, the findings suggest a possible association of oxidative stress and perhaps CYP pathway with smoking-mediated increased viral load in HIV positive individuals.
Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Citocinas/metabolismo , Infecções por HIV/virologia , Estresse Oxidativo , Fumar , Carga Viral , Adulto , Contagem de Linfócito CD4 , Feminino , Infecções por HIV/enzimologia , Infecções por HIV/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: HIV-associated neurocognitive disorders (HAND) exist in approximately 50% of infected individuals even after the introduction of highly active antiretroviral therapy. HIV-1 Tat has been implicated in HIV-associated neurotoxicity mediated through production of pro-inflammatory cytokines like IL-6 and IL-8 by astrocytes among others as well as oxidative stress. However, the underlying mechanism(s) in the up-regulation of IL-6 and IL-8 are not clearly understood. The present study was designed to determine the mechanism(s) responsible for IL-6 and IL-8 up-regulation by HIV-1 Tat. METHODS: SVG astrocytes were transiently transfected with a plasmid encoding HIV-1 Tat. The HIV-1 Tat-mediated mRNA and protein expression levels of both IL-6 and IL-8 in SVG astrocytes were quantified using real time RT-PCR and multiplex cytokine assay respectively. We also employed immunocytochemistry for staining of IL-6 and IL-8. The underlying signaling mechanism(s) were identified using pharmacological inhibitors and siRNA for different intermediate steps involved in PI3K/Akt, p38 MAPK and JNK MAPK pathways. Appropriate controls were used in the experiments and the effect of pharmacological antagonists and siRNA were observed on both mRNA expression and protein levels. RESULTS: Both IL-6/IL-8 mRNA and protein showed peak expressions at 6 hours and 96 hours post-transfection, respectively. Elevated levels of IL-6/IL-8 were also confirmed by immunocytochemistry. Our studies indicated that both NF-kB and AP-1 transcription factors were involved in IL-6 and IL-8 expression mediated by HIV-1 Tat; however, AP-1 was differentially activated for either cytokine. In the case of IL-6, p38δ activated AP-1 whereas JNK but not p38 MAPK was involved in AP-1 activation for IL-8 production. On the other hand both PI3K/Akt and p38 MAPK (ß subunit) were found to be involved in activation of NF-κB that led to IL-6 and IL-8 production. CONCLUSION: Our results demonstrate HIV-1 Tat-mediated induction of both IL-6 and IL-8 in a time-dependent manner in SVG astrocytes. Furthermore, we also showed the involvement of NF-κB and AP-1 transcription factors regulated by PI3/Akt, p38 MAPK and JNK MAPK upstream signaling molecules. These results present new therapeutic targets that could be used in management of HAND.