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1.
J Virol ; 96(17): e0108122, 2022 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-35975996

RESUMO

Following acute infection, herpes simplex virus 1 (HSV-1) establishes lifelong latency in neurons. The latency associated transcript (LAT) is the only viral gene abundantly expressed during latency. Wild-type (WT) HSV-1 reactivates more efficiently than LAT mutants because LAT promotes establishment and maintenance of latency. While sensory neurons in trigeminal ganglia (TG) are important sites for latency, brainstem is also a site for latency and reactivation from latency. The principal sensory nucleus of the spinal trigeminal tract (Pr5) likely harbors latent HSV-1 because it receives afferent inputs from TG. The locus coeruleus (LC), an adjacent brainstem region, sends axonal projections to cortical structures and is indirectly linked to Pr5. Senescent cells accumulate in the nervous system during aging and accelerate neurodegenerative processes. Generally senescent cells undergo irreversible cell cycle arrest and produce inflammatory cytokines and chemokines. Based on these observations, we hypothesized HSV-1 influences senescence and inflammation in Pr5 and LC of latently infected mice. This hypothesis was tested using a mouse model of infection. Strikingly, female but not age-matched male mice latently infected with a LAT null mutant (dLAT2903) exhibited significantly higher levels of senescence markers and inflammation in LC, including cell cycle inhibitor p16, NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3), IL-1α, and IL-ß. Conversely, Pr5 in female but not male mice latently infected with WT HSV-1 or dLAT2903 exhibited enhanced expression of important inflammatory markers. The predilection of HSV-1 to induce senescence and inflammation in key brainstem regions of female mice infers that enhanced neurodegeneration occurs. IMPORTANCE HSV-1 (herpes simplex virus 1), an important human pathogen, establishes lifelong latency in neurons in trigeminal ganglia and the central nervous system. In contrast to productive infection, the only viral transcript abundantly expressed in latently infected neurons is the latency associated transcript (LAT). The brainstem, including principal sensory nucleus of the spinal trigeminal tract (Pr5) and locus coeruleus (LC), may expedite HSV-1 spread from trigeminal ganglia to the brain. Enhanced senescence and expression of key inflammatory markers were detected in LC of female mice latently infected with a LAT null mutant (dLAT2903) relative to age-matched male or female mice latently infected with wild-type HSV-1. Conversely, wild-type HSV-1 and dLAT2903 induced higher levels of senescence and inflammatory markers in Pr5 of latently infected female mice. In summary, enhanced inflammation and senescence in LC and Pr5 of female mice latently infected with HSV-1 are predicted to accelerate neurodegeneration.


Assuntos
Herpes Simples , Herpesvirus Humano 1 , Doenças Neuroinflamatórias , Animais , Tronco Encefálico/virologia , Senescência Celular , Feminino , Herpes Simples/patologia , Herpesvirus Humano 1/patogenicidade , Herpesvirus Humano 1/fisiologia , Inflamação , Masculino , Camundongos , Camundongos Endogâmicos NOD , Doenças Neuroinflamatórias/virologia , Gânglio Trigeminal/virologia , Latência Viral
2.
Am J Physiol Regul Integr Comp Physiol ; 318(2): R435-R444, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31823672

RESUMO

Increases in sympathetic nerve activity (SNA) have been implicated in obesity-induced risk for cardiovascular diseases, especially hypertension. Previous studies indicate that oxidative stress in the rostral ventrolateral medulla (RVLM), a key brain stem region that regulates sympathetic outflow to peripheral tissues, plays a pathogenic role in obesity-mediated sympathoexcitation. However, the molecular mechanisms underlying this phenomenon are not clear. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that regulates the expression of antioxidant and anti-inflammatory genes and confers cytoprotection against oxidative stress. The present study was designed to investigate whether Nrf2 dysfunction was associated with obesity-induced oxidative stress in the RVLM and sympathoexcitation. C57BL/6J mice were fed with chow or a high-fat diet (HFD) for 16 wk. Blood pressure parameters were assessed by radiotelemeters in conscious freely moving mice. SNA was measured by heart rate variability analysis and also through assessment of depressor response to ganglionic blockade. The RVLM was microdissected for gene expression and protein analysis (Western blot analysis and activity assay) related to Nrf2 signaling. Our results showed that HFD-induced obesity resulted in significant increases in SNA, although we only observed a mild increase in mean arterial pressure. Obesity-induced oxidative stress in the RVLM was associated with impaired Nrf2 signaling marked by decreased Nrf2 activity, downregulation of Nrf2 mRNA, its target genes [NAD(P)H quinone dehyrogenase 1 (Nqo1) and superoxide dismutase 2 (Sod2)], and inflammation. Our findings suggest that obesity results in Nrf2 dysfunction, which likely causes maladaptation to oxidative stress and inflammation in the RVLM. These mechanisms could potentially contribute to obesity-induced sympathoexcitation.


Assuntos
Pressão Arterial , Sistema Cardiovascular/inervação , Frequência Cardíaca , Bulbo/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Obesidade/metabolismo , Estresse Oxidativo , Sistema Nervoso Simpático/fisiopatologia , Animais , Citocinas/genética , Citocinas/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Masculino , Bulbo/fisiopatologia , Camundongos Endogâmicos C57BL , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/genética , Obesidade/etiologia , Obesidade/genética , Obesidade/fisiopatologia , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo
3.
Virus Res ; 347: 199420, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38880336

RESUMO

Human alphaherpesvirus 1 (HSV-1) establishes life-long latency in sensory neurons in trigeminal ganglia (TG), brainstem neurons, and other CNS neurons. Two important segments of the brainstem were examined in this study: principal sensory nucleus of the spinal trigeminal tract (Pr5) because it receives direct afferent inputs from TG, and locus coeruleus (LC) because it is indirectly connected to Pr5 and LC sends axonal projections to cortical structures, which may facilitate viral spread from brainstem to the brain. The only viral gene abundantly expressed during latency is the latency associated transcript (LAT). Previous studies revealed 8-week old female C57Bl/6 mice infected with a LAT null mutant (dLAT2903) versus wild-type (wt) HSV-1 exhibit higher levels of senescence markers and inflammation in LC of females. New studies revealed 1-year old mice latently infected with wt HSV-1 or dLAT2903 contained differences in neuroinflammation and senescence in Pr5 and LC versus young mice. In summary, these studies confirm HSV-1 promotes neuro-inflammation in the brainstem, which may accelerate neurodegenerative disease.


Assuntos
Tronco Encefálico , Herpesvirus Humano 1 , Camundongos Endogâmicos C57BL , Doenças Neuroinflamatórias , Latência Viral , Animais , Herpesvirus Humano 1/fisiologia , Herpesvirus Humano 1/genética , Tronco Encefálico/virologia , Tronco Encefálico/patologia , Camundongos , Feminino , Doenças Neuroinflamatórias/virologia , Doenças Neuroinflamatórias/patologia , Herpes Simples/virologia , Herpes Simples/patologia , Envelhecimento , Humanos , Infecção Latente/virologia , Gânglio Trigeminal/virologia , Modelos Animais de Doenças
4.
Aging (Albany NY) ; 13(10): 13460-13473, 2021 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-34038388

RESUMO

Accumulating evidence suggests that the sympathetic nervous system (SNS) overactivity plays a crucial role in age-related increase in the risk for cardiovascular diseases such as hypertension, myocardial infarction, stroke and heart diseases. Previous studies indicate that neuroinflammation in key brainstem regions that regulate sympathetic outflow plays a pathogenic role in aging-mediated sympathoexcitation. However, the molecular mechanisms underlying this phenomenon are not clear. While senescent cells and their secretory phenotype (SASP) have been implicated in the pathogenesis of several age-related diseases, their role in age-related neuroinflammation in the brainstem and SNS overactivity has not been investigated. To test this, we isolated brainstems from young (2-4 months) and aged (24 months) male C57BL/6J mice and assessed senescence using a combination of RNA-in situ hybridization, PCR analysis, multiplex assay and SA-ß gal staining. Our results show significant increases in p16Ink4a expression, increased activity of SA-ß gal and increases in SASP levels in the aged brainstem, suggesting age-induced senescence in the brainstem. Further, analysis of senescence markers in glial cells enriched fraction from fresh brainstem samples demonstrated that glial cells are more susceptible to senesce with age in the brainstem. In conclusion, our study suggests that aging induces glial senescence in the brainstem which likely causes inflammation and SNS overactivity.


Assuntos
Envelhecimento/patologia , Tronco Encefálico/patologia , Senescência Celular , Neuroglia/patologia , Sistema Nervoso Simpático/patologia , Animais , Biomarcadores/sangue , Inflamação/sangue , Inflamação/patologia , Masculino , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Norepinefrina/sangue , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
5.
Sci Rep ; 10(1): 17576, 2020 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-33067477

RESUMO

The anti-inflammatory effects of vagus nerve stimulation are well known. It has recently been shown that low-level, transcutaneous stimulation of vagus nerve at the tragus (LLTS) reduces cardiac inflammation in a rat model of heart failure with preserved ejection fraction (HFpEF). The mechanisms by which LLTS affect the central neural circuits within the brain regions that are important for the regulation of cardiac vagal tone are not clear. Female Dahl salt-sensitive rats were initially fed with either low salt (LS) or high salt (HS) diet for a period of 6 weeks, followed by sham or active stimulation (LLTS) for 30 min daily for 4 weeks. To study the central effects of LLTS, four brainstem (SP5, NAb, NTS, and RVLM) and two forebrain sites (PVN and SFO) were examined. HS diet significantly increased the gene expression of proinflammatory cytokines in the SP5 and SFO. LLTS reversed HS diet-induced changes at both these sites. Furthermore, LLTS augmented the levels of antioxidant Nrf2 in the SP5 and SFO. Taken together, these findings suggest that LLTS has central anti-inflammatory and antioxidant properties that could mediate the neuromodulation of cardiac vagal tone in the rat model of HFpEF.


Assuntos
Antioxidantes/metabolismo , Tronco Encefálico/metabolismo , Citocinas/metabolismo , Inflamação , Prosencéfalo/metabolismo , Estimulação do Nervo Vago/métodos , Animais , Dieta , Feminino , Frequência Cardíaca , Microdissecção , Neurônios/metabolismo , Ratos , Ratos Endogâmicos Dahl , Cloreto de Sódio na Dieta/administração & dosagem , Nervo Vago/fisiologia
6.
Anal Biochem ; 363(1): 97-107, 2007 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-17306205

RESUMO

Using a high-throughput surface discovery approach, we have generated a 1600-member library of metal-containing surfaces and screened them for antibody binding potential. The surface library assembly involved graft modification of argon plasma-treated polyvinylidenedifluoride (PVDF) membranes with alternating maleic anhydride-styrene copolymer followed by anhydride ring opening with a range of secondary amines and microarray contact printing of transition metal complexes. The microarrays of metal-containing surfaces were then tested for their antibody binding capacity by incubation with a biotinylated mouse antibody in a chemiluminescence assay. A total of 11 leads were identified from the first screen, constituting a "hit" rate of 0.7%. A smaller 135-member surface library was then synthesized and screened to optimize existing hits and generate additional leads. To demonstrate the applicability of these surfaces to other formats, high-binding surface leads were then transferred onto Luminex beads for use in a bead flow cytometric immunoassay. The novel one-step antibody coupling process increased assay sensitivity of a Luminex tumor necrosis factor immunoassay. These high-binding surfaces do not require prior incorporation of polyhistidine tags or posttreatments such as oxidation to achieve essentially irreversible binding of immunoglobulin G.


Assuntos
Técnicas Biossensoriais/métodos , Cromo/química , Imunoensaio , Imunoglobulina G/imunologia , Proteínas/imunologia , Animais , Reações Antígeno-Anticorpo , Argônio/química , Humanos , Imunoglobulina G/química , Imunoglobulina G/metabolismo , Membranas Artificiais , Biblioteca de Peptídeos , Poliestirenos/química , Polivinil/química , Análise Serial de Proteínas , Proteínas/metabolismo , Sensibilidade e Especificidade
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