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1.
Int J Mol Sci ; 20(19)2019 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-31569415

RESUMO

Campylobacter jejuni (C. jejuni) is the most common cause of foodborne gastroenteritis worldwide. The bacteria induce diarrhea and inflammation by invading the intestinal epithelium. Curcumin is a natural polyphenol from turmeric rhizome of Curcuma longa, a medical plant, and is commonly used in curry powder. The aim of this study was the investigation of the protective effects of curcumin against immune-induced epithelial barrier dysfunction in C. jejuni infection. The indirect C. jejuni-induced barrier defects and its protection by curcumin were analyzed in co-cultures with HT-29/B6-GR/MR epithelial cells together with differentiated THP-1 immune cells. Electrophysiological measurements revealed a reduction in transepithelial electrical resistance (TER) in infected co-cultures. An increase in fluorescein (332 Da) permeability in co-cultures as well as in the germ-free IL-10-/- mouse model after C. jejuni infection was shown. Curcumin treatment attenuated the C. jejuni-induced increase in fluorescein permeability in both models. Moreover, apoptosis induction, tight junction redistribution, and an increased inflammatory response-represented by TNF-α, IL-1ß, and IL-6 secretion-was observed in co-cultures after infection and reversed by curcumin. In conclusion, curcumin protects against indirect C. jejuni-triggered immune-induced barrier defects and might be a therapeutic and protective agent in patients.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Infecções por Campylobacter/imunologia , Campylobacter jejuni/imunologia , Curcumina/farmacologia , Membrana Mucosa/efeitos dos fármacos , Membrana Mucosa/imunologia , Animais , Apoptose , Infecções por Campylobacter/microbiologia , Linhagem Celular , Técnicas de Cocultura , Citocinas/biossíntese , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Interleucina-10/genética , Interleucina-10/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Camundongos , Camundongos Knockout , Membrana Mucosa/microbiologia , Proteínas de Junções Íntimas/genética , Proteínas de Junções Íntimas/metabolismo , Junções Íntimas/genética , Junções Íntimas/metabolismo
2.
Nat Commun ; 10(1): 4739, 2019 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-31628331

RESUMO

HIV viral reservoirs are established very early during infection. Resident memory T cells (TRM) are present in tissues such as the lower female genital tract, but the contribution of this subset of cells to the pathogenesis and persistence of HIV remains unclear. Here, we show that cervical CD4+TRM display a unique repertoire of clusters of differentiation, with enrichment of several molecules associated with HIV infection susceptibility, longevity and self-renewing capacities. These protein profiles are enriched in a fraction of CD4+TRM expressing CD32. Cervical explant models show that CD4+TRM preferentially support HIV infection and harbor more viral DNA and protein than non-TRM. Importantly, cervical tissue from ART-suppressed HIV+ women contain high levels of viral DNA and RNA, being the TRM fraction the principal contributor. These results recognize the lower female genital tract as an HIV sanctuary and identify CD4+TRM as primary targets of HIV infection and viral persistence. Thus, strategies towards an HIV cure will need to consider TRM phenotypes, which are widely distributed in tissues.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Memória Imunológica/imunologia , Adulto , Idoso , Antirretrovirais/uso terapêutico , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/virologia , Colo do Útero/efeitos dos fármacos , Colo do Útero/virologia , Reservatórios de Doenças/virologia , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , Pessoa de Meia-Idade , Membrana Mucosa/efeitos dos fármacos , Membrana Mucosa/virologia , Carga Viral/efeitos dos fármacos , Carga Viral/genética , Carga Viral/imunologia
3.
BMC Vet Res ; 15(1): 330, 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31519215

RESUMO

BACKGROUND: Non-specific immunotherapeutics have been evaluated previously in dogs, primarily for cancer treatment. However, there remains a need for a more broadly targeted, general purpose immunotherapeutic capable of activating innate immune defenses for non-specific protection or early treatment of viral and bacterial infections. To address need, our group has developed a liposomal immune stimulant (liposome-TLR complexes, LTC) containing TLR 3 and 9 agonists specifically designed to activate mucosal immune defenses in sites such as nasal cavity and oropharynx, following topical delivery. In this study, we evaluated the local immune stimulatory properties of LTC in vitro and in healthy purpose-bred dogs, including activation of cellular recruitment and cytokine production. The ability of LTC treatment to elicit effective antiviral immunity was assessed in dogs following a canine herpesvirus outbreak, and the impact of LTC treatment on the local microbiome of the oropharynx was also investigated. RESULTS: These studies revealed that LTC potently activated innate immune responses in vitro and triggered significant recruitment of inflammatory monocytes and T cells into the nasal cavity and oropharynx of healthy dogs. Administration of LTC to dogs shortly after an outbreak of canine herpesvirus infection resulted in significant reduction in clinical signs of infection. Interestingly, administration of LTC to healthy dogs did not disrupt the microbiome in the oropharynx, suggesting resiliency of the microflora to transient immune activation. CONCLUSIONS: Taken together, these results indicate that LTC administration mucosally to dogs can trigger local innate immune activation and activation of antiviral immunity, without significantly disrupting the composition of the local microbiome. Thus, the LTC immune stimulant has potential for use as a non-specific immunotherapy for prevention or early treatment of viral and bacterial infections in dogs.


Assuntos
Cães/imunologia , Imunidade Inata/efeitos dos fármacos , Lipossomos/administração & dosagem , Membrana Mucosa/efeitos dos fármacos , Administração através da Mucosa , Animais , Doenças do Cão/imunologia , Doenças do Cão/virologia , Infecções por Herpesviridae/veterinária , Herpesvirus Canídeo 1 , Membrana Mucosa/imunologia , Ácidos Nucleicos/imunologia , Orofaringe/microbiologia
4.
Environ Toxicol Pharmacol ; 71: 103217, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31284173

RESUMO

Ultrastructural and histopathological reponses in the organs of living organisms are important and useful tools to determine the health condition and the effects of pollutants, such as pesticides, on the organisms. The aim of this study is to determine possible histopathological, cytopathological and ultrastructural alterations in gills of Oreochromis niloticus individuals exposed to 850 µg/L carbaryl standart at 7th, 14th and 21st days with light and electron microscopes. The fish were exposed to carbaryl for 21 days and the histopatological, ultrastructural and cytopathological alterations occuring in the gill tissues of organisms were determined by light, Scanning and Transmission Electron Microscopes (SEM and TEM). At the end of the study, it was observed that carbaryl caused both histopathological and cytopathological changes in the gills of O. niloticus. It has been determined that the most of the pathological changes in the exposed organisms are the metabolic defence reactions.


Assuntos
Carbaril/toxicidade , Ciclídeos , Células Epiteliais/efeitos dos fármacos , Brânquias/efeitos dos fármacos , Inseticidas/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Células Epiteliais/ultraestrutura , Brânquias/ultraestrutura , Hiperplasia , Microscopia Eletroquímica de Varredura , Microscopia Eletrônica de Transmissão , Membrana Mucosa/efeitos dos fármacos , Membrana Mucosa/ultraestrutura
5.
Indian J Dermatol Venereol Leprol ; 85(6): 569-577, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31274470

RESUMO

Introduction: Some viral warts are refractory to treatment, some others tend to recur. Oral isotretinoin is useful against warts to varying degrees. Objective: To determine the efficacy of oral isotretinoin for treating mucocutaneous human papillomavirus infections. Methods: A systematic review and meta-analysis of studies published from the date of inception of the databases to December 30, 2017 were conducted. Randomized controlled trials or case series with ≥10 patients with mucocutaneous human papillomavirus infection who had received oral isotretinoin treatment were analyzed. The meta-analysis estimated the pooled odds ratio and pooled response rate. Results: The review included eight studies. Trials of oral isotretinoin versus placebo treatment revealed that isotretinoin effectively treated mucocutaneous human papillomavirus infections (odds ratio: 43.8, 95% confidence interval: 9.7-198.8). The pooled estimate of the complete response rate of oral isotretinoin to mucocutaneous human papillomavirus was 67.7% (95% confidence interval: 49.5-81.7%). Another pooled estimation revealed that 83.9% (95% confidence interval: 59.7-94.9%) of patients exhibited at least 50% lesion clearance, whereas 12.3% with complete response experienced recurrence. Limitations: This meta-analysis had a small sample size and high inter-study heterogeneity. Conclusion: Oral isotretinoin is superior to placebo for treating mucocutaneous human papillomavirus infections, particularly plane warts. The recurrence rate and risk of severe side effects are low.


Assuntos
Fármacos Dermatológicos/administração & dosagem , Isotretinoína/administração & dosagem , Papillomaviridae , Infecções por Papillomavirus/tratamento farmacológico , Administração Oral , Humanos , Membrana Mucosa/efeitos dos fármacos , Membrana Mucosa/patologia , Membrana Mucosa/virologia , Infecções por Papillomavirus/diagnóstico , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Pele/efeitos dos fármacos , Pele/patologia , Pele/virologia
6.
Environ Sci Pollut Res Int ; 26(26): 27444-27456, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31327144

RESUMO

Air pollution represents a major health problem in megacities, bringing about 8 million deaths every year. The aim of the study was to evaluate in vivo the ocular and respiratory mucosa biological response after chronic exposure to urban air particles from Buenos Aires (UAP-BA). BALB/c mice were exposed to UAP-BA or filtered air for 1, 6, 9, and 12 months. After exposure, histology, histomorphometry, and IL-6 proinflammatory cytokine level were evaluated in the respiratory and ocular mucosa. Total cell number and differential cell count were determined in the brochoalveolar lavage fluid. In the lung, chronic exposure to UAP-BA induced reduction of the alveolar space, polymorhonuclear cell recruitment, and goblet cell hyperplasia. In the ocular surface, UAP-BA induced an initial mucin positive cells rise followed by a decline through time, while IL-6 level increased at the latest point-time assayed. Our results showed that the respiratory and the ocular mucosas respond differently to UAP-BA. Being that lung and ocular mucosa diseases may be triggered and/or exacerbated by chronic exposure to urban air PM, the inhabitants of Buenos Aires whom are chronically exposed to environmental urban air pollution may be considered a subpopulation at risk. Based on our results, we propose the ocular mucosa as a reliable and more accessible surrogate for pulmonary mucosa environmental toxicity that might also serve as an earlier biomarker for air pollution adverse impact on health.


Assuntos
Poluição do Ar/efeitos adversos , Exposição Ambiental/efeitos adversos , Olho/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Membrana Mucosa/efeitos dos fármacos , Poluição do Ar/análise , Animais , Argentina , Biomarcadores/análise , Líquido da Lavagem Broncoalveolar/citologia , Olho/patologia , Feminino , Interleucina-6/análise , Interleucina-6/genética , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Material Particulado/efeitos adversos , Material Particulado/análise , Material Particulado/química , Testes de Toxicidade Crônica , Urbanização
7.
Food Funct ; 10(7): 3965-3976, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31204764

RESUMO

The dry root of Hedysarum polybotrys Hand.-Mazz., commonly known as "Hong Qi", has a variety of health benefits. The present study was undertaken to explore the anti-gastric ulcer potential effect of Hedysarum polysaccharides (HPS; HPS-50, HPS-80), the principal active fraction of Radix Hedysari (RH). The anti-gastric ulcer effects of HPS were evaluated using an animal model of ulcerative lesions induced by acetic acid. The effects of antioxidant factors, anti-inflammatory cytokines, and mucosal blood flow regulatory factor levels in the gastric tissue homogenate of rats were analyzed for the bioactivities of HPS. The results showed that, compared with the acetic acid-induced ulcerated group, the ulcer inhibition rate of HPS-treated rats was significantly increased. The pathological findings suggested that mucosal regeneration, cell migration, and inflammatory cell infiltration were decreased, and collagen fibers were significantly reduced. Extensive granulation tissue proliferation indicated the healing stage was initiated, suggesting a good prognosis. The oxidative stress status of the gastric ulcer rats was improved, the levels of TNF-α and IL-6 were significantly decreased, and the levels of PGE-2 and NO were increased (P < 0.05). HPS-80-H may be a promising ingredient for incorporation into functional foods or nutritional supplements for the prevention of gastric ulcers.


Assuntos
Ácido Acético/efeitos adversos , Antiulcerosos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Polissacarídeos/farmacologia , Ranunculaceae/química , Úlcera Gástrica/tratamento farmacológico , Úlcera Gástrica/prevenção & controle , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , China , Citocinas/metabolismo , Dinoprostona/metabolismo , Modelos Animais de Doenças , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Interleucina-6/metabolismo , Masculino , Membrana Mucosa/efeitos dos fármacos , Estresse Oxidativo , Extratos Vegetais/farmacologia , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Estômago/efeitos dos fármacos , Estômago/patologia , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/patologia , Fator de Necrose Tumoral alfa/metabolismo , Cicatrização/efeitos dos fármacos
8.
Bull Exp Biol Med ; 167(1): 47-49, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31177448

RESUMO

We studied the influence of synthetic indolicidin analogues on the development of acute periodontitis. The corrective effect was found in indolicidin analogues Nos. 7 and 8; it manifested in a decrease in the edema of gingival epithelium and lamina propria, a decrease in the relative area of inflammatory infiltrates, and a significant increase in the relative area of normal connective tissue. These changes were revealed as soon as on day 14 and were most pronounced in 21 days after the removal of the ligature. Indolicidin analogues Nos. 7 and 8 demonstrated similar effectiveness on the model of acute periodontitis.


Assuntos
Peptídeos Catiônicos Antimicrobianos/uso terapêutico , Periodontite/tratamento farmacológico , Animais , Peptídeos Catiônicos Antimicrobianos/química , Tecido Conjuntivo/efeitos dos fármacos , Tecido Conjuntivo/metabolismo , Gengiva/citologia , Gengiva/metabolismo , Membrana Mucosa/efeitos dos fármacos , Membrana Mucosa/metabolismo , Ratos Wistar
9.
Tohoku J Exp Med ; 248(1): 37-43, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31105123

RESUMO

The antibodies targeting programmed death 1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) have provided survival benefits in patients with advanced malignant melanoma. The anti-PD-1 antibodies nivolumab and pembrolizumab are considered superior to the anti-CTLA-4 antibody ipilimumab as first-line therapy, suggesting that ipilimumab should be administered to patients with anti-PD-1 antibody-refractory melanoma in the second-line setting. However, there is limited evidence regarding the efficacy and safety of ipilimumab after disease progression on anti-PD-1 antibody therapy. Moreover, in patients with mucosal melanoma, a rare and aggressive subtype, evidence is extremely poor. This study aimed to clarify the efficacy and safety of ipilimumab among Japanese patients with nivolumab-refractory advanced mucosal melanoma. We retrospectively analyzed the seven patients with advanced mucosal melanoma who were treated with ipilimumab after disease progression on nivolumab at our hospital between September 2015 and December 2017. No patient achieved complete response or partial response to ipilimumab therapy. However, six patients achieved stable disease, and of these patients, three achieved a decline in the tumor size. All the three patients with a decline in tumor size developed grade 3 toxicity: two patients developed colitis and one patient experienced alanine aminotransferase elevation. The median progression-free survival (PFS) for prior nivolumab therapy was 148 days. The median PFS for ipilimumab therapy after disease progression with nivolumab was 193 days. The median overall survival was 661 days. In conclusion, although even partial response was undetectable with ipilimumab therapy, ipilimumab could produce additional PFS among nivolumab-refractory advanced mucosal melanoma patients.


Assuntos
Grupo com Ancestrais do Continente Asiático , Resistencia a Medicamentos Antineoplásicos , Ipilimumab/uso terapêutico , Melanoma/tratamento farmacológico , Membrana Mucosa/patologia , Nivolumabe/uso terapêutico , Idoso , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Ipilimumab/efeitos adversos , Ipilimumab/farmacologia , Estimativa de Kaplan-Meier , Masculino , Melanoma/diagnóstico por imagem , Melanoma/patologia , Pessoa de Meia-Idade , Membrana Mucosa/efeitos dos fármacos , Metástase Neoplásica , Nivolumabe/efeitos adversos , Resultado do Tratamento
10.
PLoS One ; 14(5): e0217229, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31107913

RESUMO

Recent data support that the vaginal microbiota may alter mucosal pharmacokinetics (PK) of topically delivered microbicides. Our team developed an intravaginal ring (IVR) that delivers tenofovir (TFV) (8-10 mg/day) alone or with levonorgestrel (LNG) (20 ug/day). We evaluated the effect of IVRs on the vaginal microbiota, and describe how the vaginal microbiota impacts mucosal PK of TFV. CONRAD A13-128 was a randomized, placebo controlled phase I study. We randomized 51 women to TFV, TFV/LNG or placebo IVR. We assessed the vaginal microbiota by sequencing the V3-V4 regions of 16S rRNA genes prior to IVR insertion and after approximately 15 days of use. We measured the concentration of TFV in the cervicovaginal (CV) aspirate, and TFV and TFV-diphosphate (TFV-DP) in vaginal tissue at the end of IVR use. The change in relative or absolute abundance of vaginal bacterial phylotypes was similar among active and placebo IVR users (all q values >0.13). TFV concentrations in CV aspirate and vaginal tissue, and TFV-DP concentrations in vaginal tissue were not significantly different among users with community state type (CST) 4 versus those with Lactobacillus dominated microbiota (all p values >0.07). The proportions of participants with CV aspirate concentrations of TFV >200,000 ng/mL and those with tissue TFV-DP concentrations >1,000 fmol/mg were similar among women with anaerobe versus Lactobacillus dominated microbiota (p = 0.43, 0.95 respectively). There were no significant correlations between the CV aspirate concentration of TFV and the relative abundances of Gardnerella vaginalis or Prevotella species. Tissue concentrations of TFV-DP did not correlate with any the relative abundances of any species, including Gardnerella vaginalis. In conclusion, active IVRs did not differ from the placebo IVR on the effect on the vaginal microbiota. Local TFV and TFV-DP concentrations were high and similar among IVR users with Lactobacillus dominated microbiota versus CST IV vaginal microbiota. Trial registration: ClinicalTrials.gov NCT02235662.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Dispositivos Anticoncepcionais Femininos , Levanogestrel/administração & dosagem , Microbiota/efeitos dos fármacos , Tenofovir/administração & dosagem , Tenofovir/farmacocinética , Vagina/metabolismo , Vagina/microbiologia , Adenina/análogos & derivados , Adenina/farmacocinética , Adulto , Antivirais/administração & dosagem , Antivirais/farmacocinética , Remoção de Dispositivo , Feminino , Infecções por HIV/prevenção & controle , Herpes Genital/prevenção & controle , Humanos , Microbiota/genética , Pessoa de Meia-Idade , Membrana Mucosa/efeitos dos fármacos , Membrana Mucosa/metabolismo , Organofosfatos/farmacocinética , Vagina/efeitos dos fármacos , Adulto Jovem
12.
Urol Int ; 102(4): 468-475, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30889607

RESUMO

BACKGROUND: A medical device containing xyloglucan-gelose-hibiscus-propolis (referred to hereafter as xyloglucan + gelose) acts as a mucosal barrier protector and urinary acidifier. The safety and efficacy of this device were investigated as adjuvant therapy to first-line antimicrobials for treatment of uncomplicated urinary tract infection (UTI) in adults. PATIENTS AND METHODS: In this multicentre, randomised, parallel group, double-blind, phase IV study, xyloglucan + gelose (n = 20) or placebo (n = 20) were administered orally in combination with an antimicrobial agent (e.g., ciprofloxacin) for 5 days, then alone for 5 days, then beginning on Day 30 of the study for 15 days per month for 2 months. RESULTS: Frequency of adverse events (AEs) was 5 and 45% in the xyloglucan + gelose and placebo groups respectively. All AEs were unrelated to study products. Xyloglucan + gelose reduced uroculture positivity (defined as a bacterial count ≥103 CFU/mL) from 100% of patients at baseline to 0% at Day 11, with recurrence in 3 patients (15%) by Day 76. Corresponding results with placebo were 100% uroculture positive patients at baseline reduced to 45% at Day 11, with recurrence in 14 patients (70%) by Day 76. Xyloglucan + gelose significantly reduced the frequency of urinary incontinence and urgency of micturition compared with placebo (both p < 0.05), with symptom resolution in all patients by Day 90. CONCLUSIONS: The xyloglucan + gelose medical device was safe, well tolerated, and it reduced bacteriological and symptomatic parameters in adults with uncomplicated UTI.


Assuntos
Anti-Infecciosos/administração & dosagem , Quimioterapia Adjuvante/métodos , Glucanos/administração & dosagem , Infecções Urinárias/tratamento farmacológico , Xilanos/administração & dosagem , Adolescente , Adulto , Idoso , Ciprofloxacino/administração & dosagem , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Membrana Mucosa/efeitos dos fármacos , Segurança do Paciente , Recidiva , Resultado do Tratamento , Micção/efeitos dos fármacos , Adulto Jovem
13.
Int J Pharm ; 562: 241-248, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30880105

RESUMO

Eudragit® E PO (EPO) is a terpolymer based on N,N-dimethylaminoethyl methacrylate with methylmethacrylate and butylmethacrylate, produced by Evonik Industries AG as a pharmaceutical excipient. In this work, EPO was chemically modified through reaction with acryloyl chloride. The successful modification of EPO was confirmed by FTIR, NMR-spectroscopy, elemental and thermal analysis. The degree of acrylation was determined by permanganatometric titration. The slug mucosal irritation test was used to demonstrate non-irritant nature of EPO and its acrylated derivatives (AEPO). The mucoadhesive properties of EPO and AEPO were evaluated using freshly excised sheep nasal mucosa and it was demonstrated that acrylated polymers facilitated greater retention of sodium fluorescein on mucosal surfaces compared to solution mixture of this dye solution with EPO as well as free dye.


Assuntos
Acrilatos/química , Excipientes/química , Membrana Mucosa/química , Ácidos Polimetacrílicos/química , Adesividade , Administração Intranasal , Animais , Excipientes/toxicidade , Gastrópodes , Membrana Mucosa/efeitos dos fármacos , Ácidos Polimetacrílicos/toxicidade , Ovinos
14.
Klin Lab Diagn ; 64(2): 78-82, 2019.
Artigo em Russo | MEDLINE | ID: mdl-30917247

RESUMO

This study is devoted to assessing the state of the mucous membrane of the upper respiratory tract of the workers of chemical production of methanol and formaldehyde. A total of 450 workers were examined by rhinocytogram (RCH) evaluation. As a result of the study, studies have found that people with work experience of up to 10 years in the production of methanol and formaldehyde in the RCH the siggns of chronic inflammation is more likely to be detected. More experienced patients (more than 10 years of work experience) studies have found the establishment of morphological signs of protective and degenerative changes in ciliated epithelium, and there is a high degree of connection between the development of protective changes and the exposure to chemicals (RR = 2.71, etiological share, EF = 56.4%) and the development of degenerative changes (RR = 3.28, EF = 65.4%). These results are considered by the authors as the biomarkers of the development of a professionally conditioned lesion of the upper respiratory tract.


Assuntos
Formaldeído/efeitos adversos , Metanol/efeitos adversos , Membrana Mucosa/patologia , Exposição Ocupacional/efeitos adversos , Humanos , Inflamação/patologia , Membrana Mucosa/efeitos dos fármacos
15.
Curr Protoc Pharmacol ; 84(1): e55, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30786171

RESUMO

Pemphigoid diseases (PDs) are a group of autoimmune bullous diseases characterized and caused by autoantibodies targeting structural proteins of the skin and mucous membranes. Chronic inflammation, subepidermal blistering, and often scaring are the clinical characteristics of PDs. Itching and, in severe cases, disabilities resulting from scaring (i.e., blindness, esophageal strictures) are the leading subjective symptoms. Treatment of PDs, which is based on nonspecific immunosuppression, is challenging because of frequent relapses, lack of efficacy, and numerous adverse events. In addition, the incidence of PDs is increasing. Given the high morbidity, limited therapeutic options, and increasing incidence, there is a growing urgency for drug discovery to help treat this condition. The recent development of PD model systems has added to the understanding of PD pathogenesis and, based on these insights, new clinical trials will soon be launched. The (auto-)antibody transfer PD models allow for investigations into autoantibody-mediated tissue pathology, while immunization-induced PD models more closely resemble the clinical situation. The latter duplicate all aspects of the human disease and are useful for investigating PD pathogenesis and testing therapeutic interventions. This article describes antibody transfer and immunization-induced PD mouse models currently employed for translational PD research. © 2019 by John Wiley & Sons, Inc.


Assuntos
Penfigoide Bolhoso/tratamento farmacológico , Animais , Autoanticorpos/imunologia , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Vesícula/tratamento farmacológico , Vesícula/imunologia , Modelos Animais de Doenças , Descoberta de Drogas/métodos , Camundongos , Membrana Mucosa/efeitos dos fármacos , Membrana Mucosa/imunologia , Penfigoide Bolhoso/imunologia , Pele/efeitos dos fármacos , Pele/imunologia , Dermatopatias Vesiculobolhosas/tratamento farmacológico , Dermatopatias Vesiculobolhosas/imunologia
16.
Reprod Fertil Dev ; 31(5): 915-919, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30625114

RESUMO

The status of the testicular lamina propria (LP) is associated with spermatogenesis. The aim of this study was to determine whether Raman spectroscopy (RS) could detect material components within the LP and predict spermatogenesis. Twenty adult male mice were divided into a busulfan-treated group (n=16 mice receiving a single injection of 50mgkg-1, i.p., busulfan) and a control group (n=4 mice receiving an equivalent volume of 0.9% saline solution injected i.p.). Mice were killed 2, 4, 6 and 8 weeks after injection of busulfan or saline solution (n=1 control and 4 busulfan-treated mice at each time point). The testicular tubules were assessed by RS and compared with histopathological observations. Control tubules had raw spectral intensities below 2000 arbitrary units, whereas busulfan tubules had strengthened intensities that peaked at Week 4 (absent spermatogenesis) and returned to normal levels at Week 8 (restored spermatogenesis). The change in the LP revealed by RS occurred before the change in spermatogenesis detected by histopathology. Correspondingly, the sensitivity/specificity of RS for distinguishing busulfan-treated and control tubules at 2, 4, 6 and 8 weeks were 65.00%/70.00%, 95.00%/100.00%, 40.00%/100.00% and 25.00%/95.00% respectively. Collectively, RS could be used to evaluate the status of the LP and as a complement to histopathological evaluation to predict tubules with the potential to develop spermatogenesis for infertile patients.


Assuntos
Infertilidade Masculina/metabolismo , Membrana Mucosa/metabolismo , Espermatogênese/fisiologia , Espermatozoides/metabolismo , Testículo/metabolismo , Animais , Bussulfano/farmacologia , Modelos Animais de Doenças , Masculino , Camundongos , Membrana Mucosa/efeitos dos fármacos , Túbulos Seminíferos/efeitos dos fármacos , Túbulos Seminíferos/metabolismo , Análise Espectral Raman , Espermatogênese/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Testículo/efeitos dos fármacos
17.
Intern Med ; 58(8): 1049-1056, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30626809

RESUMO

Objective The incidence of osteoporosis is increasing with the rapid aging of the Japanese population. Bisphosphonates are first-line agents used for the treatment of osteoporosis, but they can cause upper gastrointestinal mucosal injury. This study investigated symptoms and upper gastrointestinal mucosal injury associated with oral bisphosphonates. Methods Symptoms were evaluated using the F-scale questionnaire, and esophageal mucosal injury and gastroduodenal ulceration were assessed by endoscopy. Patients were stratified by the type of bisphosphonate (alendronate, risedronate, or minodronate), treatment schedule (once weekly or every four weeks), and the concomitant use of other medications [antithrombotic agents, nonsteroidal anti-inflammatory drugs (NSAIDs), or acid suppressants]. Patients The subjects included 221 patients treated with oral bisphosphonates for at least one month. Results The median F-scale total score was 4 (0-34), reflux score was 2 (0-20), and the mean dyspepsia score was 2 (0-16). Endoscopy showed esophageal mucosal injury of Grade A or worse (Los Angeles classification) in 22/221 patients (10.0%) and gastroduodenal ulcers in 9 patients (4.1%). The dyspepsia score in patients who took minodronate every four weeks was significantly lower (p<0.05) in comparison to patients who took other bisphosphonates. The dyspepsia score was significantly higher (p<0.05) and mucosal injury was significantly more frequent in patients who also used antithrombotic agents and NSAIDs. Conclusion Symptoms and upper gastrointestinal mucosal damage were not necessarily frequent or severe in patients treated with bisphosphonates. However, the concomitant use of bisphosphonates with antithrombotic agents and NSAIDs increased both symptoms and mucosal injury. The symptoms were milder in patients using minodronate once monthly.


Assuntos
Alendronato/efeitos adversos , Conservadores da Densidade Óssea/efeitos adversos , Trato Gastrointestinal/efeitos dos fármacos , Membrana Mucosa/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Ácido Risedrônico/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Alendronato/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Feminino , Trato Gastrointestinal/lesões , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Membrana Mucosa/lesões , Ácido Risedrônico/uso terapêutico
18.
FASEB J ; 33(2): 2435-2450, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30260705

RESUMO

Increased colonic bile acid (BA) exposure, frequent in diarrhea-predominant irritable bowel syndrome (IBS-D), can affect gut function. Nerve growth factor (NGF) is implicated in the development of visceral hypersensitivity (VH). In this study, we tested the hypothesis that BAs cause VH via mucosal mast cell (MMC)-to-nociceptor signaling, which involves the farnesoid X receptor (FXR)/NGF/transient receptor potential vanilloid (TRPV)1 axis. BAs were intracolonically administered to rats for 15 d. Visceral sensitivity to colorectal distention and colonic NGF expression were examined. BAs caused VH, an effect that involved MMC-derived NGF and was accompanied by enhanced TRPV1 expression in the dorsal root ganglia. Anti-NGF treatment and TRPV1 antagonism inhibited BA-induced VH. BAs induced NGF mRNA and protein expression and release in cultured mast cells. Colonic supernatants from patients with IBS-D with elevated colonic BA content transcriptionally induced NGF expression. In FXR-/- mice, visceral sensitivity and colonic NGF expression were unaltered after BA treatment. Pharmacological antagonism and FXR silencing suppressed BA-induced NGF expression and release in mast cells. Mitogen-activated protein kinase kinase (MKK) 3/6/p38 MAPK/NF-κB signaling was mechanistically responsible for FXR-mediated NGF expression and secretion. The findings show an MMC-dependent and FXR-mediated pronociceptive effect of BAs and identify the BA/FXR/NGF/TRPV1 axis as a key player in MMC-to-neuron communication during pain processing in IBS.-Li, W.-T., Luo, Q.-Q., Wang, B., Chen, X., Yan, X.-J., Qiu, H.-Y., Chen, S.-L. Bile acids induce visceral hypersensitivity via mucosal mast cell-to-nociceptor signaling that involves the farnesoid X receptor/nerve growth factor/transient receptor potential vanilloid 1 axis.


Assuntos
Ácidos e Sais Biliares/toxicidade , Hipersensibilidade/patologia , Síndrome do Intestino Irritável/patologia , Mastócitos/imunologia , Fator de Crescimento Neural/metabolismo , Nociceptores/imunologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Canais de Cátion TRPV/metabolismo , Adulto , Animais , Estudos de Casos e Controles , Células Cultivadas , Feminino , Fármacos Gastrointestinais/toxicidade , Humanos , Hipersensibilidade/etiologia , Hipersensibilidade/metabolismo , Síndrome do Intestino Irritável/induzido quimicamente , Síndrome do Intestino Irritável/metabolismo , Masculino , Mastócitos/metabolismo , Mastócitos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Membrana Mucosa/efeitos dos fármacos , Membrana Mucosa/imunologia , Membrana Mucosa/metabolismo , Nociceptores/metabolismo , Nociceptores/patologia , Ratos , Ratos Sprague-Dawley , Dor Visceral/induzido quimicamente , Dor Visceral/metabolismo , Dor Visceral/patologia
19.
Inflamm Bowel Dis ; 25(3): 580-586, 2019 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-30165638

RESUMO

BACKGROUND/AIMS: The clinical utility of vedolizumab (VDZ) trough levels (VTLs) in inflammatory bowel disease (IBD) is not well defined. The aims of this study are to determine the median VTLs and frequency of detected antibodies, the correlation of VTLs with C-reactive protein (CRP) and mucosal healing (MH), and the change in clinical management based on VTLs. METHODS: A cross-sectional study of IBD patients treated with VDZ with VTLs checked between July 1, 2016, and March 1, 2017, was conducted. Mucosal healing was defined as absence of mucosal ulcers in Crohn's disease (CD) and Mayo endoscopic score ≤1 for ulcerative colitis (UC). Normal CRP was defined as ≤8 mg/L. RESULTS: A total of 171 patients (62% CD, 31% UC, 7% indeterminate colitis) were included. Median VTLs was 15.3 ug/mL (range, 0-60), and 1 patient had detectable antibodies to VDZ. Patients with a normal CRP had a median VTLs of 17.3 ug/mL vs 10.7 ug/mL in high CRP patients (P = 0.046). This was noted in CD (20.3 vs 10.4 ug/mL; P = 0.005) but not in UC patients (14.4 vs 20.8; P = 0.72). Mucosal healing was achieved in 35% of patients (37 of 105); among these, median VTLs was 13.7 ug/mL vs 16.1 ug/mL in patients who did not achieve MH (P = 0.64). Vedolizumab trough levels resulted in a change in clinical management in 73%. CONCLUSIONS: Our cohort showed a low rate of immunogenicity to VDZ and an association between VTLs and CRP in CD but not in UC patients. No relationship between VTLs and MH was detected. Vedolizumab trough level measurements altered management in approximately three fourths of patients.


Assuntos
Anticorpos Monoclonais Humanizados/sangue , Biomarcadores/sangue , Fármacos Gastrointestinais/sangue , Doenças Inflamatórias Intestinais/sangue , Membrana Mucosa/metabolismo , Cicatrização , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/uso terapêutico , Criança , Pré-Escolar , Estudos Transversais , Feminino , Seguimentos , Fármacos Gastrointestinais/uso terapêutico , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Membrana Mucosa/efeitos dos fármacos , Prognóstico , Estudos Retrospectivos , Adulto Jovem
20.
Colloids Surf B Biointerfaces ; 175: 166-174, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30530002

RESUMO

Clotrimazole (CLT) was formulated in a multiple W/O/W emulsion (ME) with the aim of evaluating its potential as topical anticandidal agent and comparing with marketed products. A previously evaluated CLT-ME was selected and physicochemically characterized. The in vitro release behavior and the ex vivo permeation profiles were assessed using Franz diffusion cells using three different types of biological membranes: human skin and porcine buccal, sublingual and vaginal mucosae. The antifungal activity against Candida strains was also tested. Results showed CLT-MEs sizes of 29.206 and 47.678 µm with skin compatible pH values of 6.47 and 6.42 exhibiting high zeta potential values of -55.13 and -55.59 mV with dependence on the pH variation. The physicochemical stability was kept for a period of 180 days of storage at room temperature. CLT-MEs exhibited pseudoplastic behavior with hysteresis areas and viscosities of 286 and 331 mPa⋅s showing higher spreadability properties than commercial counterparts. An improved CLT release pattern was supplied by the ME system following a hyperbolic model. Likewise, ME system gave higher skin permeation flux of CLT than commercial reference. CLT amounts retained in the skin and mucosae were also higher than commercial references, which coupled with the higher antimycotic efficacy make CLT-MEs a great tool for clinical investigation of topical candidiasis treatments.


Assuntos
Candida/efeitos dos fármacos , Candidíase/tratamento farmacológico , Clotrimazol/farmacologia , Membrana Mucosa/efeitos dos fármacos , Pele/efeitos dos fármacos , Animais , Antifúngicos/química , Antifúngicos/farmacocinética , Antifúngicos/farmacologia , Candida/classificação , Candida/fisiologia , Candidíase/microbiologia , Clotrimazol/química , Clotrimazol/farmacocinética , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Emulsões/química , Feminino , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Testes de Sensibilidade Microbiana/métodos , Membrana Mucosa/metabolismo , Membrana Mucosa/microbiologia , Pele/metabolismo , Pele/microbiologia , Absorção Cutânea , Especificidade da Espécie , Suínos
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