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1.
Phytomedicine ; 80: 153381, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33086170

RESUMO

BACKGROUND: Hyperactivation of B cells by activators has been demonstrated to play a central role in the pathogenesis of Sjögren's syndrome (SS). In this study, we found that artesunate (ART) can attenuate BAFF-induced B cell hyperactivation and SS-like symptoms in NOD/Ltj mice. PURPOSE: To determine the efficacy of ART in attenuating SS-like symptoms in vivo and explore the underlying mechanism in vitro. STUDY DESIGN: ART was intragastrically injected into SS-like NOD/Ltj mice. The cytokine hsBAFF was used to activate Raji and Daudi B cells to mimic B cell hyperactivation in vitro. METHODS: The efficacy of ART in inhibiting SS progression was studied in NOD/Ltj mice. Salivary flow rate, the number of lymphocytic infiltration foci, the level of autoantibodies and the extent of B cell infiltration were measured in the indicated groups. CCK-8 assays, flow cytometry-based EdU staining and Annexin V/PI staining were also used to detect the effect of ART on the survival and proliferation mechanism in BAFF-induced Raji and Daudi cells. Further studies determined that TRAF6 degradation is a potential mechanism by which ART determines B cell fate. RESULTS: Treatment with ART inhibited lymphocytic foci formation, B cell infiltration and autoantibody secretion in SS-like NOD/Ltj mice. In vitro assay results indicated that ART effectively inhibited BAFF-induced viability, survival and proliferation of neoplastic B cells. Mechanistically, ART targeted BAFF-activated NFκB by regulating the proteasome-mediated degradation of TRAF6 in Raji and Daudi cells. CONCLUSION: ART ameliorated murine SS-like symptoms and regulated TRAF6-NFκB signaling, thus determining survival and proliferation of B cells.


Assuntos
Artesunato/farmacologia , Fator Ativador de Células B/farmacologia , Linfócitos B/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Síndrome de Sjogren/imunologia , Animais , Autoanticorpos/metabolismo , Autoimunidade/efeitos dos fármacos , Fator Ativador de Células B/metabolismo , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linfócitos B/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Linfócitos/efeitos dos fármacos , Camundongos Endogâmicos ICR , Camundongos Endogâmicos NOD , NF-kappa B/metabolismo , Glândulas Salivares/efeitos dos fármacos , Glândulas Salivares/metabolismo , Transdução de Sinais/efeitos dos fármacos , Síndrome de Sjogren/tratamento farmacológico , Síndrome de Sjogren/patologia
2.
PLoS Pathog ; 16(8): e1008710, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32817722

RESUMO

Rice stripe virus (RSV, genus Tenuivirus, family Phenuiviridae) is the causal agent of rice stripe disease transmitted by the small brown planthopper (SBPH, Laodelphax striatellus) in a persistent propagative manner. The midgut and salivary glands of SBPH are the first and last barriers to the viral circulation and transmission processes, respectively; however, the precise mechanisms used by RSV to cross these organs and transmit to rice plants have not been fully elucidated. We obtained the full-length cDNA sequence of L. striatellus α-tubulin 2 (LsTUB) and found that RSV infection increased the level of LsTUB in vivo. Furthermore, LsTUB was shown to co-localize with RSV nonstructural protein 3 (NS3) in vivo and bound NS3 at positions 74-76 and 80-82 in vitro. Transient gene silencing of LsTUB expression caused a significant reduction in detectable RSV loads and viral NS3 expression levels, but had no effect on NS3 silencing suppressor activity and viral replication in insect cells. However, suppression of LsTUB attenuated viral spread in the bodies of SBPHs and decreased RSV transmission rates to rice plants. Electrical penetration graphs (EPG) showed that LsTUB knockdown by RNAi did not impact SBPH feeding; therefore, the reduction in RSV transmission rates was likely caused by a decrease in viral loads inside the planthopper. These findings suggest that LsTUB mediates the passage of RSV through midgut and salivary glands and leads to successful horizontal transmission.


Assuntos
Hemípteros/metabolismo , Proteínas de Insetos/metabolismo , Insetos Vetores/metabolismo , Oryza/virologia , Doenças das Plantas/virologia , Tenuivirus/fisiologia , Tubulina (Proteína)/metabolismo , Animais , Sistema Digestório/metabolismo , Sistema Digestório/virologia , Hemípteros/genética , Hemípteros/virologia , Proteínas de Insetos/genética , Insetos Vetores/genética , Insetos Vetores/virologia , Glândulas Salivares/metabolismo , Glândulas Salivares/virologia , Tubulina (Proteína)/genética
3.
BMC Oral Health ; 20(1): 190, 2020 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-32631313

RESUMO

BACKGROUND: In the last years an increased interest in the use of salivary parameters in connection with caries experience and caries prediction has been shown. In schoolchildren investigations are known, where the relationship between caries prevalence and salivary parameters has been assessed, but in the adolescent population studies are scarce. The aim of the study was evaluate of the association among salivary parameters, oral health status and caries experience in adolescents in Mexico. METHODS: A cross-sectional study was conducted on 256 (DMFT≥5) and 165 (DMFT< 5) 12-to- 14-year-old adolescents. From all the adolescents, unstimulated mid-morning saliva samples were collected, after which the salivary flow rate was calculated, and the salivary pH and buffer capacity was measured. The caries was evaluated via the application of the DMFT score. Clinical variables such as oral hygiene and dental calculus were examined in the adolescent's oral cavity. The adolescents provided data on their personal characteristics by completing a questionnaire, while socioeconomic data were collected from their parents. Descriptive, bivariate and logistic regression model analyses were performed. RESULTS: The prevalence of caries was 61.1% (DMFT≥5) in permanent dentition, with 72.7% of subjects presenting poor oral hygiene. The mean levels of salivary flow rate, pH, and buffer capacity was significantly lower (p < 0.05) in adolescents with caries score of DMFT≥5 than in those with caries score of DMFT < 5. Salivary flow and buffer capacity were higher in boys than in girls. The logistic regression model applied showed that adolescents with a salivary flow rate < 1 ml per min were more likely to present caries [OR = 1.58 (CI95% 1.04-2.40); p = 0.033] than adolescents with a flow rate ≥ 1 ml per-min, and that, for each unit of increased pH, the probability of presenting caries reduced by 76% [OR = 0.24 (CI95% 0.10-0.55); p = 0.001]. CONCLUSION: Significant association was found in salivary flow rate, pH and buffer capacity in adolescents with caries (DMFT≥5). In addition to differences of these parameters by sex, the results suggest saliva parameters may act as indicators of caries in adolescents.


Assuntos
Cárie Dentária/epidemiologia , Saúde Bucal , Higiene Bucal , Saliva/fisiologia , Glândulas Salivares/metabolismo , Taxa Secretória/fisiologia , Adolescente , Tampões (Química) , Criança , Estudos Transversais , Índice CPO , Cárie Dentária/metabolismo , Feminino , Humanos , Masculino , México/epidemiologia , Prevalência
4.
Proc Natl Acad Sci U S A ; 117(29): 16928-16937, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32636269

RESUMO

Whereas most of the arthropod-borne animal viruses replicate in their vectors, this is less common for plant viruses. So far, only some plant RNA viruses have been demonstrated to replicate in insect vectors and plant hosts. How plant viruses evolved to replicate in the animal kingdom remains largely unknown. Geminiviruses comprise a large family of plant-infecting, single-stranded DNA viruses that cause serious crop losses worldwide. Here, we report evidence and insight into the replication of the geminivirus tomato yellow leaf curl virus (TYLCV) in the whitefly (Bemisia tabaci) vector and that replication is mainly in the salivary glands. We found that TYLCV induces DNA synthesis machinery, proliferating cell nuclear antigen (PCNA) and DNA polymerase δ (Polδ), to establish a replication-competent environment in whiteflies. TYLCV replication-associated protein (Rep) interacts with whitefly PCNA, which recruits DNA Polδ for virus replication. In contrast, another geminivirus, papaya leaf curl China virus (PaLCuCNV), does not replicate in the whitefly vector. PaLCuCNV does not induce DNA-synthesis machinery, and the Rep does not interact with whitefly PCNA. Our findings reveal important mechanisms by which a plant DNA virus replicates across the kingdom barrier in an insect and may help to explain the global spread of this devastating pathogen.


Assuntos
Begomovirus/fisiologia , DNA Polimerase III/metabolismo , Hemípteros/virologia , Proteínas de Insetos/metabolismo , Insetos Vetores/virologia , Replicação Viral , Animais , Begomovirus/genética , DNA Polimerase III/genética , Gossypium/parasitologia , Gossypium/virologia , Hemípteros/patogenicidade , Interações Hospedeiro-Patógeno , Proteínas de Insetos/genética , Insetos Vetores/patogenicidade , Glândulas Salivares/metabolismo , Glândulas Salivares/virologia
5.
Med Hypotheses ; 143: 110124, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32721813

RESUMO

Utilising biomarkers for COVID-19 diagnosis, prediction of treatment response and overall prognostication have been investigated recently. However, these ventures have only considered the use of blood-based molecular markers. Saliva is another biofluid that warrants being applied in similar fashion with major advantages that centres on its non-invasive and repeatable collection as well as cost-efficiency. To this end, this article presents a hypothesis for the sources of biomarkers useful clinically for COVID-19 disease outcome estimation and identify the likely implications of their detection in saliva.


Assuntos
Betacoronavirus , Biomarcadores/análise , Infecções por Coronavirus/metabolismo , Modelos Imunológicos , Pandemias , Pneumonia Viral/metabolismo , Saliva/química , Biomarcadores/sangue , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/terapia , Citocinas/análise , Testes Diagnósticos de Rotina , Vesículas Extracelulares , Líquido do Sulco Gengival/química , Humanos , MicroRNAs/análise , Doenças da Boca/complicações , Doenças da Boca/metabolismo , Pneumonia Viral/diagnóstico , Pneumonia Viral/imunologia , Pneumonia Viral/terapia , Saliva/imunologia , Saliva/virologia , Glândulas Salivares/metabolismo , Glândulas Salivares/virologia , Proteínas e Peptídeos Salivares/análise
6.
Clin Nucl Med ; 45(8): e365-e367, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32520511

RESUMO

An 85-year-old woman visited our hospital with repetitive diarrhea, nausea, and anorexia, as well as aggressive behavior. The neurologist decided to perform dopamine transporter imaging (F-FP-CIT PET/CT) for accurate diagnosis, taking into account the potential adverse effects of L-dopa that the patient had been taking for a long time. The uptake of dopamine transporter in the bilateral basal ganglia was well preserved, but reduced uptake in the left parotid gland was incidentally detected. A subsequent salivary scan showed reduced uptake in the left parotid gland with the same pattern as that on F-FP-CIT PET/CT.


Assuntos
Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Glândulas Salivares/diagnóstico por imagem , Glândulas Salivares/metabolismo , Tropanos/metabolismo , Idoso de 80 Anos ou mais , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Feminino , Humanos
7.
Oral Oncol ; 108: 104821, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32474389

RESUMO

Outbreak pneumonia announced in Wuhan, China, in December 2019, had its causative factor classified as a new coronavirus (SARS-CoV-2). Since saliva can host several viruses including SARS-CoV-2, the transmission chance of viruses through saliva, particularly those causing respiratory infections, is unavoidable. COVID-19 can be detected through salivary diagnostic testing which has lots of advantages for medical care professionals and patients. It should be noted that not only does saliva offer an ecological niche for the colonization and development of oral microorganisms, but it also prevents the overgrowth of particular pathogens such as viral factors. The aim of this study is to gather all the information about saliva and its association with COVID-19 for the whole health care professionals across the world.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/transmissão , Pneumonia Viral/epidemiologia , Pneumonia Viral/transmissão , Saliva/imunologia , Saliva/virologia , Sialadenite/diagnóstico , Idoso , Betacoronavirus/genética , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Assistência Odontológica , Odontólogos/psicologia , Testes Diagnósticos de Rotina/métodos , Feminino , Humanos , Imunidade Inata , Controle de Infecções/métodos , Masculino , Pessoa de Meia-Idade , Pandemias , Segurança do Paciente , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , Padrões de Prática Odontológica , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias das Glândulas Salivares/diagnóstico , Glândulas Salivares/metabolismo , Glândulas Salivares/virologia , Proteínas e Peptídeos Salivares/imunologia , Sialadenite/virologia , Telemedicina/métodos , Xerostomia
8.
Arch Oral Biol ; 116: 104765, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32470831

RESUMO

OBJECTIVE: We examined the effects of vitamin C and E supplementation in the prevention of oxidative stress in the salivary glands of STZ-induced diabetic rats. DESIGN: Forty-eight male Wistar rats were divided into six groups (n = 8 in each): control (C), control supplemented with vitamin C (Cvc) and E (Cve), diabetic (D), and diabetic supplemented with vitamin C (Dvc) and E (Dve). Vitamin C (150 mg/kg) and E (300 mg/kg) were daily administered for 21 days. Serum ascorbic acid and α-tocopherol levels were quantified. Glandular levels of hydrogen peroxide (H2O2), superoxide anion (O2-), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT), malondialdehyde (MDA) and the total antioxidant status (TAS) were estimated. RESULTS: Vitamin C and E levels were reduced in D group. Vitamin C decreased the levels of O2- in the salivary gland of diabetic rats. Vitamin E increased the concentration of O2- in PA gland of diabetic animals. In the SM gland of the diabetic group, MDA, SOD, GPx and TAS increased. Dve presented reduced SOD activity and increased GR, GPx, and MDA. Dve increased GPx, Gr and TAS levels. In the PA gland, MDA, SOD, CAT, GPx, GR, and TAS were similar in C and D. TAS, SOD, CAT, GPx, and GR increased in Dvc. Vitamin E supplementation resulted in increased MDA and CAT levels and reduced SOD activity. CONCLUSION: In the SM glands of the diabetic rats, vitamin C supplementation improved the antioxidant system, while vitamin E acted as pro-oxidant.


Assuntos
Antioxidantes , Ácido Ascórbico , Diabetes Mellitus Experimental , Estresse Oxidativo , Vitamina E , Animais , Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Catalase/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Peróxido de Hidrogênio , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Glândulas Salivares/metabolismo , Superóxido Dismutase/metabolismo , Vitamina E/farmacologia
9.
Tissue Cell ; 63: 101319, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32223947

RESUMO

Salivary epidermal growth factor (EGF) plays an important role in the maintenance of the oral and gastro-esophageal mucosa. Sialoadenectomy delays healing of oral wounds and affects lingual papillae. In this work, we aimed to determine the effect of EGF deficiency induced by sialoadenectomy and evaluate the effect of exogenous EGF administration on the lingual papillae and taste buds in rats. Thirty male adult Wistar albino rats were equally divided into 3 groups; sham-operated control group, sialoadenectomy group and group of sialoadenectomy + EGF. EGF was given 8 weeks after sialoadenectomy in a dose of 1 µg /ml/day in drinking water for 2 weeks. The anterior two-thirds of the tongue was dissected and cut longitudinally into two halves; one half for light microscope and the other for electron microscope examinations. Saliva and blood were collected to determine salivary and plasma EGF. Our results revealed that sialoadenectomy significantly reduced plasma and saliva levels of EGF which resulted in severe disruption of the architecture of lingual papillae. These changes were effectively improved by the exogenous EGF administration. In conclusion, EGF supplementation reversed the effects of sialoadenectomy and restored almost normal architecture of lingual papillae and taste buds.


Assuntos
Fator de Crescimento Epidérmico/metabolismo , Glândulas Salivares/metabolismo , Papilas Gustativas/metabolismo , Língua/metabolismo , Animais , Fator de Crescimento Epidérmico/deficiência , Fator de Crescimento Epidérmico/farmacologia , Mucosa Esofágica/efeitos dos fármacos , Mucosa Esofágica/metabolismo , Humanos , Mucosa Bucal/efeitos dos fármacos , Mucosa Bucal/metabolismo , Ratos , Saliva/efeitos dos fármacos , Saliva/metabolismo , Glândulas Salivares/efeitos dos fármacos , Glândulas Salivares/cirurgia , Papilas Gustativas/efeitos dos fármacos , Papilas Gustativas/cirurgia , Língua/efeitos dos fármacos , Língua/patologia , Língua/cirurgia
10.
PLoS One ; 15(4): e0231383, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32302324

RESUMO

Zoological institutions often use immersive, naturalistic exhibits to create an inclusive atmosphere that is inviting for visitors while providing for the welfare of animals in their collections. In this study, we investigated physiological changes in salivary cortisol and blood pressure, as well as psychological changes among visitors before and after a walk through the River's Edge, an immersive, naturalistic exhibit at the Saint Louis Zoo. Study participants had a significant reduction in salivary cortisol and blood pressure after walking through the exhibit. Psychological assessments of mood found that most visitors felt happier, more energized, and less tense after the visit. Additionally, participants who spent more time in River's Edge, had visited River's Edge prior to the study, and had seen more exhibits at the Zoo prior to entering River's Edge experienced greater psychological and/or physiological benefits. We conclude that immersive, naturalistic exhibits in zoos can elicit positive changes in physiological and psychological measures of health and well-being and argue for a greater scientific focus on the role of zoos and other green spaces in human health.


Assuntos
Pressão Sanguínea/fisiologia , Nível de Saúde , Hidrocortisona/análise , Adaptação Psicológica , Adolescente , Adulto , Animais , Animais de Zoológico , Feminino , Felicidade , Humanos , Masculino , Pessoa de Meia-Idade , Glândulas Salivares/química , Glândulas Salivares/metabolismo , Inquéritos e Questionários , Adulto Jovem
12.
Arch Oral Biol ; 113: 104689, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32135333

RESUMO

OBJECTIVE: The aim of this study was to clarify the mechanism of GABA (□-amino butyric acid)-signaling in the salivary glands by localization of vesicular inhibitory amino acid transporter, a key molecule in GABA-synthesis. DESIGN: Parotid, sublingual and submandibular glands of mice at various postnatal stages were examined in immuno-light and electron microscopy as well as immuno-blotting. RESULTS: Expression for vesicular inhibitory amino acid transporter was detected in parotid and sublingual glands of both sexes and female submandibular gland throughout postnatal development, while it was negligible in male submandibular glands at and after puberty. The expression in female submandibular glands attenuated after testosterone injection. The immunoreactivity was localized in striated ductal cells, but not acinar cells, in the salivary glands, and it occurred in association with intracellular and plasma membranes of the cells. It also occurred in myoepithelial and vascular smooth muscle cells. CONCLUSIONS: GABA-signaling was suggested to be a significant signaling pathway in salivary ductal cells, which was suppressed in male submandibular glands at and after puberty. The suppression in the submandibular duct was by testosterone. In addition, the participation of vesicular inhibitory amino acid transporter in GABA signaling through plasma membranes of the ductal cells was suggested. The significance of occurrence of the immunoreactivity in myoepithelial and smooth muscle cells remains to be further elucidated in terms of implication in GABA signaling.


Assuntos
Sistemas de Transporte de Aminoácidos/metabolismo , Glândulas Salivares/metabolismo , Transdução de Sinais , Ácido gama-Aminobutírico/metabolismo , Animais , Feminino , Masculino , Camundongos , Glândula Parótida , Glândula Sublingual , Glândula Submandibular
13.
PLoS One ; 15(3): e0230537, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32208452

RESUMO

During the blood feeding, sand fly females inject saliva containing immunomodulatory and anti-haemostatic molecules into their vertebrate hosts. The saliva composition is species-specific, likely due to an adaptation to particular haemostatic pathways of their preferred host. Research on sand fly saliva is limited to the representatives of two best-studied genera, Phlebotomus and Lutzomyia. Although the members of the genus Sergentomyia are highly abundant in many areas in the Old World, their role in human disease transmission remains uncertain. Most Sergentomyia spp. preferentially attack various species of reptiles, but feeding on warm-blooded vertebrates, including humans and domestic animals, has been repeatedly described, especially for Sergentomyia schwetzi, of which salivary gland transcriptome and proteome is analyzed in the current study. Illumina RNA sequencing and de novo assembly of the reads and their annotation revealed 17,293 sequences homologous to other arthropods' proteins. In the sialome, all proteins typical for sand fly saliva were identified-antigen 5-related, lufaxin, yellow-related, PpSP15-like, D7-related, ParSP25-like, and silk proteins, as well as less frequent salivary proteins included 71kDa-like, ParSP80-like, SP16-like, and ParSP17-like proteins. Salivary enzymes include apyrase, hyaluronidase, endonuclease, amylase, lipase A2, adenosine deaminase, pyrophosphatase, 5'nucleotidase, and ribonuclease. Proteomics analysis of salivary glands identified 631 proteins, 81 of which are likely secreted into the saliva. We also compared two S. schwetzi lineages derived from the same origin. These lineages were adapted for over 40 generations for blood feeding either on mice (S-M) or geckos (S-G), two vertebrate hosts with different haemostatic mechanisms. Altogether, 20 and 40 annotated salivary transcripts were up-regulated in the S-M and S-G lineage, respectively. Proteomic comparison revealed ten salivary proteins more abundant in the lineage S-M, whereas 66 salivary proteins were enriched in the lineage S-G. No difference between lineages was found for apyrase activity; contrarily the hyaluronidase activity was significantly higher in the lineage feeding on mice.


Assuntos
Proteínas de Insetos/genética , Psychodidae/genética , Glândulas Salivares/metabolismo , Transcriptoma , Animais , Apirase/análise , Apirase/genética , Apirase/metabolismo , Hialuronoglucosaminidase/análise , Hialuronoglucosaminidase/genética , Hialuronoglucosaminidase/metabolismo , Proteínas de Insetos/análise , Proteínas de Insetos/metabolismo , Lagartos , Camundongos , Filogenia , Psychodidae/metabolismo , Receptores Odorantes/análise , Receptores Odorantes/genética , Receptores Odorantes/metabolismo
14.
Nucleic Acids Res ; 48(8): 4214-4229, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32182338

RESUMO

Endoreplication, known as endocycle, is a variant of the cell cycle that differs from mitosis and occurs in specific tissues of different organisms. Endoreplicating cells generally undergo multiple rounds of genome replication without chromosome segregation. Previous studies demonstrated that Drosophila fizzy-related protein (Fzr) and its mammalian homolog Cdh1 function as key regulators of endoreplication entrance by activating the anaphase-promoting complex/cyclosome to initiate the ubiquitination and subsequent degradation of cell cycle factors such as Cyclin B (CycB). However, the molecular mechanism underlying Fzr-mediated endoreplication is not completely understood. In this study, we demonstrated that the transcription factor Myc acts downstream of Fzr during endoreplication in Drosophila salivary gland. Mechanistically, Fzr interacts with chromatin-associated histone H2B to enhance H2B ubiquitination in the Myc promoter and promotes Myc transcription. In addition to negatively regulating CycB transcription, the Fzr-ubiquitinated H2B (H2Bub)-Myc signaling cascade also positively regulates the transcription of the MCM6 gene that is involved in DNA replication by directly binding to specific motifs within their promoters. We further found that the Fzr-H2Bub-Myc signaling cascade regulating endoreplication progression is conserved between insects and mammalian cells. Altogether, our work uncovers a novel transcriptional cascade that is involved in Fzr-mediated endoreplication.


Assuntos
Proteínas Cdh1/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Drosophila/metabolismo , Endorreduplicação , Regulação da Expressão Gênica , Fatores de Transcrição/metabolismo , Animais , Linhagem Celular , Ciclina B/genética , Replicação do DNA , Proteínas de Ligação a DNA/genética , Drosophila/genética , Drosophila/metabolismo , Proteínas de Drosophila/genética , Células HEK293 , Histonas/metabolismo , Humanos , Componente 6 do Complexo de Manutenção de Minicromossomo/genética , Regiões Promotoras Genéticas , Glândulas Salivares/metabolismo , Transdução de Sinais , Fatores de Transcrição/genética , Ubiquitinação
15.
PLoS One ; 15(3): e0229761, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32155179

RESUMO

Cyclo-Gly-Pro (CGP) attenuates nociception, however its effects on salivary glands remain unclear. In this study, we investigated the acute effects of CGP on salivary flow and composition, and on the submandibular gland composition, compared with morphine. Besides, we characterized the effects of naloxone (a non-selective opioid receptor antagonist) on CGP- and morphine-induced salivary and glandular alterations in mice. After that, in silico analyses were performed to predict the interaction between CGP and opioid receptors. Morphine and CGP significantly reduced salivary flow and total protein concentration of saliva and naloxone restored them to the physiological levels. Morphine and CGP also reduced several infrared vibrational modes (Amide I, 1687-1594cm-1; Amide II, 1594-1494cm-1; CH2/CH3, 1488-1433cm-1; C = O, 1432-1365cm-1; PO2 asymmetric, 1290-1185cm-1; PO2 symmetric, 1135-999cm-1) and naloxone reverted these alterations. The in silico docking analysis demonstrated the interaction of polar contacts between the CGP and opioid receptor Cys219 residue. Altogether, we showed that salivary hypofunction and glandular changes elicited by CGP may occur through opioid receptor suggesting that the blockage of opioid receptors in superior cervical and submandibular ganglions may be a possible strategy to restore salivary secretion while maintaining antinociceptive action due its effects on the central nervous system.


Assuntos
Gânglios Parassimpáticos/efeitos dos fármacos , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Peptídeos Cíclicos/farmacologia , Glândulas Salivares/efeitos dos fármacos , Analgésicos Opioides/farmacologia , Animais , Sítios de Ligação , Gânglios Parassimpáticos/metabolismo , Gânglios Parassimpáticos/fisiologia , Masculino , Camundongos , Morfina/farmacologia , Nociceptividade , Ligação Proteica , Receptores Opioides/química , Receptores Opioides/metabolismo , Saliva/metabolismo , Glândulas Salivares/metabolismo , Glândulas Salivares/fisiologia
16.
Proc Natl Acad Sci U S A ; 117(12): 6630-6639, 2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32161138

RESUMO

Aging elicits quantitative and qualitative changes in different immune components, leading to disruption of tolerogenic circuits and development of autoimmune disorders. Galectin-1 (Gal1), an endogenous glycan-binding protein, has emerged as a regulator of immune cell homeostasis by shaping the fate of myeloid and lymphoid cells. Here, we demonstrate that aged Gal1-null mutant (Lgals1 -/- ) mice develop a spontaneous inflammatory process in salivary glands that resembles Sjögren's syndrome. This spontaneous autoimmune phenotype was recapitulated in mice lacking ß1,6N-acetylglucosaminyltransferase V (Mgat5), an enzyme responsible for generating ß1,6-branched complex N-glycans, which serve as a major ligand for this lectin. Lack of Gal1 resulted in CD11c+ dendritic cells (DCs) with higher immunogenic potential, lower frequency of Foxp3+ regulatory T cells (Tregs), and increased number of CD8+ T cells with greater effector capacity. Supporting its tolerogenic activity, Gal1 expression decreased with age in autoimmunity-prone nonobese diabetic (NOD) mice. Treatment with recombinant Gal1 restored tolerogenic mechanisms and reduced salivary gland inflammation. Accordingly, labial biopsies from primary Sjögren's syndrome patients showed reduced Gal1 expression concomitant with higher number of infiltrating CD8+ T cells. Thus, endogenous Gal1 serves as a homeostatic rheostat that safeguards immune tolerance and prevents age-dependent development of spontaneous autoimmunity.


Assuntos
Doenças Autoimunes/patologia , Galectina 1/fisiologia , Tolerância Imunológica/imunologia , Glândulas Salivares/patologia , Sialadenite/patologia , Síndrome de Sjogren/patologia , Linfócitos T Reguladores/imunologia , Adulto , Fatores Etários , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Estudos de Casos e Controles , Células Dendríticas/imunologia , Feminino , Glicosilação , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Pessoa de Meia-Idade , N-Acetilglucosaminiltransferases/fisiologia , Polissacarídeos/metabolismo , Glândulas Salivares/imunologia , Glândulas Salivares/metabolismo , Sialadenite/imunologia , Sialadenite/metabolismo , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/metabolismo
17.
J Cell Biol ; 219(3)2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-32045479

RESUMO

Regulated secretion is a fundamental cellular process in which biologically active molecules stored in long-lasting secretory granules (SGs) are secreted in response to external stimuli. Many studies have described mechanisms responsible for biogenesis and secretion of SGs, but how SGs mature remains poorly understood. In a genetic screen, we discovered a large number of endolysosomal trafficking genes required for proper SG maturation, indicating that maturation of SGs might occur in a manner similar to lysosome-related organelles (LROs). CD63, a tetraspanin known to decorate LROs, also decorates SG membranes and facilitates SG maturation. Moreover, CD63-mediated SG maturation requires type II phosphatidylinositol 4 kinase (PI4KII)-dependent early endosomal sorting and accumulation of phosphatidylinositol 4-phosphate (PI4P) on SG membranes. In addition, the PI4P effector Past1 is needed for formation of stable PI4KII-containing endosomal tubules associated with this process. Our results reveal that maturation of post-Golgi-derived SGs requires trafficking via the endosomal system, similar to mechanisms employed by LROs.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Endossomos/metabolismo , Glândulas Salivares/metabolismo , Vesículas Secretórias/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Animais , Animais Geneticamente Modificados , Proteínas de Drosophila/genética , Drosophila melanogaster/embriologia , Drosophila melanogaster/genética , Endossomos/genética , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Menor/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Transporte Proteico , Glândulas Salivares/embriologia , Vesículas Secretórias/genética , Tetraspanina 30/genética , Tetraspanina 30/metabolismo , Fatores de Tempo
18.
Virology ; 543: 1-6, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32056841

RESUMO

Arboviruses are an emerging threat to public health. Arbovirus transmission to vertebrates hinges on dissemination from the arthropod gastrointestinal tract, and ultimately infection of the arthropod salivary glands. Therefore, salivary gland immunity impacts arbovirus transmission; however, these immune responses are poorly understood. Here, we describe the utility of Drosophila melanogaster as a salivary gland infection model. First, we describe the use of a salivary gland-specific driver to launch RNA interference or virus replicon transgenes. Next, we infect flies with an arbovirus panel and find multiple viruses that infect Drosophila salivary glands, albeit inefficiently. We find that this infection is not controlled by antiviral RNA silencing; thus, we silence a panel of immune genes in the salivary glands, but do not observe changes in infection. These data suggest that Drosophila may be used to study salivary gland infection, and that there are likely unexplored pathways controlling infection of this tissue.


Assuntos
Arbovirus , Drosophila melanogaster , Modelos Animais , Animais , Animais Geneticamente Modificados , Proteínas Argonauta/genética , Proteínas Argonauta/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Feminino , Interações Hospedeiro-Patógeno , Imunidade Inata , Interferência de RNA , Glândulas Salivares/imunologia , Glândulas Salivares/metabolismo , Glândulas Salivares/virologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Vesiculovirus , Replicação Viral , Zika virus
19.
Sci Rep ; 10(1): 2967, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32076051

RESUMO

Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease, with only palliative treatments available. Recent work has suggested that increased bone morphogenetic protein 6 (BMP6) expression could alter cell signaling in the salivary gland (SG) and result in the associated salivary hypofunction. We examined the prevalence of elevated BMP6 expression in a large cohort of pSS patients and tested the therapeutic efficacy of BMP signaling inhibitors in two pSS animal models. Increased BMP6 expression was found in the SGs of 54% of pSS patients, and this increased expression was correlated with low unstimulated whole saliva flow rate. In mouse models of SS, inhibition of BMP6 signaling reduced phosphorylation of SMAD1/5/8 in the mouse submandibular glands, and led to a recovery of SG function and a decrease in inflammatory markers in the mice. The recovery of SG function after inhibition of BMP6 signaling suggests cellular plasticity within the salivary gland and a possibility for therapeutic intervention that can reverse the loss of function in pSS.


Assuntos
Receptores de Ativinas Tipo I/antagonistas & inibidores , Proteína Morfogenética Óssea 6/metabolismo , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Quinolinas/administração & dosagem , Glândulas Salivares/patologia , Síndrome de Sjogren/tratamento farmacológico , Receptores de Ativinas Tipo I/metabolismo , Adulto , Idoso , Animais , Proteína Morfogenética Óssea 6/análise , Proteína Morfogenética Óssea 6/genética , Linhagem Celular , Feminino , Voluntários Saudáveis , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Fosforilação/efeitos dos fármacos , Recuperação de Função Fisiológica/efeitos dos fármacos , Saliva/imunologia , Saliva/metabolismo , Glândulas Salivares/efeitos dos fármacos , Glândulas Salivares/metabolismo , Glândulas Salivares/fisiopatologia , Transdução de Sinais/efeitos dos fármacos , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/patologia , Síndrome de Sjogren/fisiopatologia , Proteínas Smad Reguladas por Receptor/metabolismo , Adulto Jovem
20.
Int J Mol Sci ; 21(4)2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32070057

RESUMO

In mammals Homer1, Homer2 and Homer3 constitute a family of scaffolding proteins with key roles in Ca2+ signaling and Ca2+ transport. In rodents, Homer proteins and mRNAs have been shown to be expressed in various postnatal tissues and to be enriched in brain. However, whether the Homers are expressed in developing tissues is hitherto largely unknown. In this work, we used immunohistochemistry and in situ hybridization to analyze the expression patterns of Homer1, Homer2 and Homer3 in developing cephalic structures. Our study revealed that the three Homer proteins and their encoding genes are expressed in a wide range of developing tissues and organs, including the brain, tooth, eye, cochlea, salivary glands, olfactory and respiratory mucosae, bone and taste buds. We show that although overall the three Homers exhibit overlapping distribution patterns, the proteins localize at distinct subcellular domains in several cell types, that in both undifferentiated and differentiated cells Homer proteins are concentrated in puncta and that the vascular endothelium is enriched with Homer3 mRNA and protein. Our findings suggest that Homer proteins may have differential and overlapping functions and are expected to be of value for future research aiming at deciphering the roles of Homer proteins during embryonic development.


Assuntos
Encéfalo/metabolismo , Proteínas de Arcabouço Homer/genética , Animais , Encéfalo/crescimento & desenvolvimento , Diferenciação Celular/genética , Cóclea/crescimento & desenvolvimento , Cóclea/metabolismo , Olho/crescimento & desenvolvimento , Olho/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Camundongos , Glândulas Salivares/crescimento & desenvolvimento , Glândulas Salivares/metabolismo , Transdução de Sinais/genética , Dente/crescimento & desenvolvimento , Dente/metabolismo
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