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1.
Rev Assoc Med Bras (1992) ; 66(2): 174-179, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32428152

RESUMO

OBJECTIVE: Although estrogen therapy is widely used against post-menopausal symptoms, it can present adverse effects, including endometrial cancer. Soy isoflavones are considered a possible alternative to estrogen therapy. However, there are still concerns whether isoflavones exert trophic effects on the uterine cervix. To evaluate the histomorphometric and immunohistochemical alterations in the uterine cervix of ovariectomized rats treated with soy isoflavones (Iso). METHODS: Fifteen adult Wistar rats were ovariectomized (Ovx) and divided into three groups: Group I (Ovx), administered with vehicle solution; Group II (OVX-Iso), administered with concentrated extract of Iso (150 mg/kg) by gavage; and Group III (OVX-E2), treated with 17ß-estradiol (10 µg/kg), subcutaneously. After 30 days of treatments, the uterine cervix was fixed in 10% formaldehyde and processed for paraffin-embedding. Sections were stained with Hematoxylin and eosin for morphological and morphometric studies or subjected to immunohistochemistry for detections of Ki-67 and vascular endothelial growth factor-A (Vegf-A). The data obtained were subjected to statistical analysis (p ≤ 0.05). RESULTS: We noted an atrophic uterine cervix in GI, whereas it was more voluminous in GII and even more voluminous in GIII. The thickness of the cervical mucosa was significantly higher in GIII, as compared to GI and GII. The cell proliferation (Ki-67) was significantly elevated in the estradiol and isoflavones treated groups, whereas Vegf-A immunoexpression was significantly higher in GIII, as compared to groups GII and GI. CONCLUSIONS: Soy isoflavones cause less trophic and proliferative effects in the uterine cervix of rats as compared to estrogen.


Assuntos
Colo do Útero/efeitos dos fármacos , Estrogênios/farmacologia , Isoflavonas/farmacologia , Fitoestrógenos/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Colo do Útero/patologia , Epitélio/efeitos dos fármacos , Feminino , Imuno-Histoquímica , Antígeno Ki-67/análise , Membrana Mucosa/efeitos dos fármacos , Ovariectomia , Distribuição Aleatória , Ratos Wistar , Reprodutibilidade dos Testes , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular/análise
2.
PLoS One ; 15(5): e0226233, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32379832

RESUMO

Allergic asthma is the most common phenotype of the pathology, having an early-onset in childhood and producing a Th2-driven airways remodeling process that leads to symptoms and pathophysiological changes. The avoidance of aeroallergen exposure in early life has been shown to prevent asthma, but without repeated success and with the underlying preventive mechanisms at the beginning of asthma far to be fully recognized. In the present study, we aimed to evaluate if neonatal LPS-induced boost in epithelial host defenses contribute to prevent OVA-induced asthma in adult mice. To this, we focused on the response of bronchiolar club cells (CC), which are highly specialized in maintaining the epithelial homeostasis in the lung. In these cells, neonatal LPS administration increased the expression of TLR4 and TNFα, as well as the immunodulatory/antiallergic proteins: club cell secretory protein (CCSP) and surfactant protein D (SP-D). LPS also prevented mucous metaplasia of club cells and reduced the epidermal growth factor receptor (EGFR)-dependent mucin overproduction, with mice displaying normal breathing patterns after OVA challenge. Furthermore, the overexpression of the epithelial Th2-related molecule TSLP was blunted, and normal TSLP and IL-4 levels were found in the bronchoalveolar lavage. A lower eosinophilia was detected in LPS-pretreated mice, along with an increase in phagocytes and regulatory cells (CD4+CD25+FOXP3+ and CD4+IL-10+), together with higher levels of IL-12 and TNFα. In conclusion, our study demonstrates stable asthma-preventive epithelial effects promoted by neonatal LPS stimulation, leading to the presence of regulatory cells in the lung. These anti-allergic dynamic mechanisms would be overlaid in the epithelium, favored by an adequate epidemiological environment, during the development of asthma.


Assuntos
Asma/imunologia , Bronquíolos/efeitos dos fármacos , Bronquíolos/imunologia , Citocinas/metabolismo , Epitélio/imunologia , Imunidade Inata , Lipopolissacarídeos/imunologia , Lipopolissacarídeos/farmacologia , Alérgenos/imunologia , Animais , Animais Recém-Nascidos , Asma/prevenção & controle , Modelos Animais de Doenças , Epitélio/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Ovalbumina/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia
3.
Proc Natl Acad Sci U S A ; 117(15): 8515-8523, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32238563

RESUMO

Stromal-epithelial interactions dictate cancer progression and therapeutic response. Prostate cancer (PCa) cells were identified to secrete greater concentration of mitochondrial DNA (mtDNA) compared to noncancer epithelia. Based on the recognized coevolution of cancer-associated fibroblasts (CAF) with tumor progression, we tested the role of cancer-derived mtDNA in a mechanism of paracrine signaling. We found that prostatic CAF expressed DEC205, which was not expressed by normal tissue-associated fibroblasts. DEC205 is a transmembrane protein that bound mtDNA and contributed to pattern recognition by Toll-like receptor 9 (TLR9). Complement C3 was the dominant gene targeted by TLR9-induced NF-κB signaling in CAF. The subsequent maturation complement C3 maturation to anaphylatoxin C3a was dependent on PCa epithelial inhibition of catalase in CAF. In a syngeneic tissue recombination model of PCa and associated fibroblast, the antagonism of the C3a receptor and the fibroblastic knockout of TLR9 similarly resulted in immune suppression with a significant reduction in tumor progression, compared to saline-treated tumors associated with wild-type prostatic fibroblasts. Interestingly, docetaxel, a common therapy for advanced PCa, further promoted mtDNA secretion in cultured epithelia, mice, and PCa patients. The antiapoptotic signaling downstream of anaphylatoxin C3a signaling in tumor cells contributed to docetaxel resistance. The inhibition of C3a receptor sensitized PCa epithelia to docetaxel in a synergistic manner. Tumor models of human PCa epithelia with CAF expanded similarly in mice in the presence or absence of docetaxel. The combination therapy of docetaxel and C3 receptor antagonist disrupted the mtDNA/C3a paracrine loop and restored docetaxel sensitivity.


Assuntos
Anafilatoxinas/metabolismo , Fibroblastos Associados a Câncer/patologia , DNA Mitocondrial/metabolismo , Docetaxel/farmacologia , Resistencia a Medicamentos Antineoplásicos , Epitélio/patologia , Neoplasias da Próstata/patologia , Animais , Antineoplásicos/farmacologia , Apoptose , Fibroblastos Associados a Câncer/efeitos dos fármacos , Fibroblastos Associados a Câncer/metabolismo , Epitélio/efeitos dos fármacos , Epitélio/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Comunicação Parácrina , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Receptor Toll-Like 9/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Clinics (Sao Paulo) ; 75: e1643, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32267395

RESUMO

OBJECTIVES: Aromatase inhibitors are the first-choice drugs for the treatment of hormone sensitive breast cancer. However, in addition to the scarcity of studies, there are controversies about their effects on vaginal epithelial cell proliferation in rats, especially those in persistent estrus. METHODS: To investigate vaginal epithelial cell proliferation by Ki-67 antigen expression, persistent estrus was induced in 42 randomly selected rats. These rats were randomly divided into 2 groups: group I (control, n=21), which received 0.1 mL of propylene glycol (vehicle) daily, and group II (experimental, n=21), which received 0.5 mg/kg or 0.125 mg/day of anastrozole diluted with 0.1 mL of propylene glycol. RESULTS: Light microscopy showed a higher concentration of cells with brown Ki-67 stained nuclei in the control compared to the experimental group. The mean percentage of Ki-67 stained nuclei per 500 cells in the vaginal epithelium was 68.64±2.64 and 30.46±2.00 [mean±standard error of the mean (SEM)] in the control and experimental groups, respectively (p<0.003). CONCLUSION: This study showed that anastrozole, at the dose and treatment duration selected, significantly decreased cell proliferation in the vaginal mucosa of the rats in persistent estrus.


Assuntos
Anastrozol/farmacologia , Epitélio/efeitos dos fármacos , Estro/metabolismo , Antígeno Ki-67/metabolismo , Vagina/efeitos dos fármacos , Animais , Epitélio/metabolismo , Feminino , Antígeno Ki-67/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Wistar , Vagina/metabolismo
5.
Am J Physiol Cell Physiol ; 318(5): C969-C980, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32293931

RESUMO

The porcine lens response to a hyperosmotic stimulus involves an increase in the activity of an ion cotransporter sodium-potassium/two-chloride cotransporter 1 (NKCC1). Recent studies with agonists and antagonists pointed to a mechanism that appears to depend on activation of transient receptor potential vanilloid 1 (TRPV1) ion channels. Here, we compare responses in lenses and cultured lens epithelium obtained from TRPV1-/- and wild type (WT) mice. Hydrostatic pressure (HP) in lens surface cells was determined using a manometer-coupled microelectrode approach. The TRPV1 agonist capsaicin (100 nM) caused a transient HP increase in WT lenses that peaked after ∼30 min and then returned toward baseline. Capsaicin did not cause a detectable change of HP in TRPV1-/- lenses. The NKCC inhibitor bumetanide prevented the HP response to capsaicin in WT lenses. Potassium transport was examined by measuring Rb+ uptake. Capsaicin increased Rb+ uptake in cultured WT lens epithelial cells but not in TRPV1-/- cells. Bumetanide, A889425, and the Akt inhibitor Akti prevented the Rb+ uptake response to capsaicin. The bumetanide-sensitive (NKCC-dependent) component of Rb+ uptake more than doubled in response to capsaicin. Capsaicin also elicited rapid (<2 min) NKCC1 phosphorylation in WT but not TRPV1-/- cells. HP recovery was shown to be absent in TRPV1-/- lenses exposed to hyperosmotic solution. Bumetanide and Akti prevented HP recovery in WT lenses exposed to hyperosmotic solution. Taken together, responses to capsaicin and hyperosmotic solution point to a functional role for TRPV1 channels in mouse lens. Lack of NKCC1 phosphorylation and Rb+ uptake responses in TRPV1-/- mouse epithelium reinforces the notion that a hyperosmotic challenge causes TRPV1-dependent NKCC1 activation. The results are consistent with a role for the TRPV1-activated signaling pathway leading to NKCC1 stimulation in lens osmotic homeostasis.


Assuntos
Cristalino/metabolismo , Membro 2 da Família 12 de Carreador de Soluto/genética , Canais de Cátion TRPV/genética , Animais , Bumetanida/farmacologia , Capsaicina/farmacologia , Linhagem Celular , Epitélio/efeitos dos fármacos , Epitélio/metabolismo , Humanos , Pressão Hidrostática/efeitos adversos , Cristalino/efeitos dos fármacos , Camundongos , Camundongos Knockout , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Suínos
6.
J Fish Biol ; 96(3): 768-781, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32017083

RESUMO

The role of lamprey epithelium tight junctions (TJs) in the regulation of salt and water balance is poorly understood. This study reported on claudin (Cldn) TJ protein transcripts of pre-metamorphic larval and post-metamorphic juvenile sea lamprey (Petromyzon marinus) and the transcriptional response of genes encoding Cldns to changed environmental ion levels. Transcripts encoding Cldn-3b, -4, -5, -10, -14, -18 and -19 were identified, and mRNA expression profiles revealed the organ-specific presence of cldn-5 and -14, broad expression of cldn-3b, -4, -10, -18 and -19 and spatial differences in the mRNA abundance of cldn-4, -3b and -14 along the ammocoete intestine. Expression profiles were qualitatively similar in ammocoetes and juvenile fishes. Transcript abundance of genes encoding Cldns in osmoregulatory organs (gill, kidney, intestine and skin) was subsequently investigated after exposure of ammocoetes to ion-poor water (IPW) and juveniles to hyperosmotic conditions [60% sea water (SW)]. IPW-acclimated ammocoetes increased mRNA abundance of nearly all cldns in the gill. Simultaneously, cldn-10 abundance increased in the skin, whereas cldn-4, -14 and -18 decreased in the kidney. Ammocoete cldn mRNA abundance in the intestine was altered in a region-specific manner. In contrast, cldn transcript abundance was mostly downregulated in osmoregulatory organs of juvenile fish acclimated to SW - cldn-3b, -10 and -19 in the gill; cldn-3b, -4, -10 and -19 in the skin; cldn-3b in the kidney; and cldn-3b and -14 in the intestine. Data support the idea that Cldn TJ proteins play an important role in the osmoregulatory physiology of pre- and post-metamorphic sea lamprey and that Cldn participation can occur across organs, in an organ-specific manner, as well as differ spatially within organs, which contributes to the regulation of salt and water balance in these fishes.


Assuntos
Claudinas/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Íons/farmacologia , Petromyzon/genética , Água/química , Aclimatação/genética , Animais , Epitélio/efeitos dos fármacos , Brânquias/efeitos dos fármacos , Osmorregulação/genética , RNA Mensageiro/genética , Água do Mar , Equilíbrio Hidroeletrolítico/genética
7.
Int. j. morphol ; 38(1): 165-175, Feb. 2020. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1056416

RESUMO

An alternative hyper-ovulator inducer to replace clomiphene citrate (CC) is needed as it is unsuitable for women with polycystic ovarian syndrome and is associated with low pregnancy rates. Anastrozole is an effective hyper-ovulator inducer, but has not been well researched. In order to determine the effectiveness of anastrozole as a hyper-ovulator inducer and to an extent compare it with CC in similar situations, this study ascertained the effects of these drugs on the expression of the focal adhesion proteins, paxillin and FAK, which are uterine receptivity markers in the surface luminal uterine epithelial cells of day 1 and day 6 pregnant Wistar rats. The results show that paxillin is localized in focal adhesions at the base of the uterine epithelial cells at day 1 of pregnancy whereas at day 6, paxillin disassembles from the basal focal adhesions and localizes and increases its expression apically. FAK is faintly expressed at the basal aspect of the uterine epithelial cells while moderately expressed at the cell-to-cell contact at day 1 in all groups from where it disassembles and relocates apically and becomes more intensely expressed at day 6 of pregnancy in untreated and anastrozole treated rats. Although paxillin is localized apically at day 6, its expression is significantly down-regulated with CC treatment suggesting its interference with the implantation process. These findings seem to suggest that anastrozole could favor implantation.


Para reemplazar el citrato de clomifeno (CC) es necesario un inductor de hiperovulación alternativo, ya que no es adecuado para mujeres con síndrome de ovario poliquístico y está asociado con tasas bajas de embarazo. El anastrozol es un inductor eficaz del hiper-ovulador, pero no se ha investigado adecuadamente. Con el fin de determinar la efectividad del anastrozol como inductor del hiper-ovulador y, en cierta medida, compararlo con CC en situaciones similares, este estudio determinó los efectos de estos fármacos en la expresión de las proteínas de adhesión focal, paxillin y FAK, uterinas marcadores de receptividad en la superficie luminal de células uterinas epiteliales, del día 1 y día 6 en ratas Wistar preñadas. Los resultados muestran que la paxilina se localiza en adherencias focales en la base de las células epiteliales uterinas en el día 1 del embarazo, mientras que en el día 6, la paxilina se desmonta de las adherencias focales basales y localiza y aumenta su expresión apicalmente. FAK se expresa débilmente en el aspecto basal de las células epiteliales uterinas, mientras que se expresa moderadamente en el contacto de célula a célula en el día 1 en todos los grupos, donde se separa y se reubica apicalmente y se expresa con mayor intensidad el día 6 de la preñez, en pacientes no tratados y tratados. ratas tratadas con anastrozol. Aunque la paxillina se localiza apicalmente en el día 6, su expresión está significativamente disminuida con el tratamiento con CC, lo que sugiere su interferencia con el proceso de implantación. Estos hallazgos sugieren que el anastrozol podría favorecer el proceso de implantación.


Assuntos
Animais , Feminino , Ratos , Útero/efeitos dos fármacos , Anastrozol/farmacologia , Ovulação/efeitos dos fármacos , Ratos Wistar , Adesões Focais/efeitos dos fármacos , Epitélio/efeitos dos fármacos , Proteína-Tirosina Quinases de Adesão Focal/efeitos dos fármacos , Paxilina/efeitos dos fármacos , Reação em Cadeia da Polimerase em Tempo Real , Microscopia de Fluorescência
8.
FASEB J ; 34(1): 1018-1037, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31914603

RESUMO

Recombinant antimicrobial peptide microcin J25 (MccJ25) causes potent antimicrobial activity against enterotoxigenic Escherichia coli (ETEC) in vitro; however, independently of this activity, its role in suppressing intestinal inflammation and epithelial barrier injury in vivo remains unclear. We investigated the therapeutic effects of MccJ25 on intestinal inflammation and epithelial barrier dysfunction and the underlying mechanism, using gentamicin for comparison. In a mouse model of intestinal inflammation, therapeutic administration of either MccJ25 or gentamicin after ETEC K88 infection attenuated clinical symptoms, reduced intestinal pathogen colonization, improved intestinal morphology, and decreased inflammatory pathologies and intestinal permeability, ultimately improving the hosts' health. MccJ25 also attenuated ETEC-induced mouse intestinal barrier dysfunction by enhancing tight junction proteins (TJPs). Using the human epithelial cell line Caco-2, we verified the epithelial barrier-strengthening and mucosal injury-alleviating effects of MccJ25 on ETEC infection: increased expression of TJPs by activating the p38/MAPK pathway, balancing the microbiota, and improving short-chain fatty acid concentrations in the cecum of ETEC-infected mice. Although gentamicin and MccJ25 had similar effects in the inflamed gut, MccJ25 was superior to gentamicin with regard to defending the host from ETEC infection. Overall, MccJ25 may be a promising therapeutic drug for treating enteric pathogen-induced intestinal inflammation diseases.


Assuntos
Peptídeos Catiônicos Antimicrobianos/farmacologia , Bacteriocinas/farmacologia , Epitélio/efeitos dos fármacos , Infecções por Escherichia coli/imunologia , Inflamação/imunologia , Mucosa Intestinal/efeitos dos fármacos , Animais , Antibacterianos/farmacologia , Células CACO-2 , Citocinas/metabolismo , Escherichia coli Enterotoxigênica , Feminino , Microbioma Gastrointestinal , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Recombinantes/farmacologia
9.
Am J Physiol Lung Cell Mol Physiol ; 318(3): L500-L509, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31913649

RESUMO

Asthma is a common chronic inflammatory disease associated with intermittent airflow obstruction caused by airway inflammation, mucus overproduction, and bronchial hyperresponsiveness. Despite current treatment and management options, a large number of patients with asthma still have poorly controlled disease and are susceptible to acute exacerbations, usually caused by a respiratory virus infection. As a result, there remains a need for novel therapies to achieve better control and prevent/treat exacerbations. Nanoparticles (NPs), including extracellular vesicles (EV) and their synthetic counterparts, have been developed for drug delivery in respiratory diseases. In the case of asthma, where airway epithelium dysfunction, including dysregulated differentiation of epithelial cells, impaired barrier, and immune response, is a driver of disease, targeting airway epithelial cells with NPs may offer opportunities to repair or reverse these dysfunctions with therapeutic interventions. EVs possess multiple advantages for airway epithelial targeting, such as their natural intrinsic cell-targeting properties and low immunogenicity. Synthetic NPs can be coated with muco-inert polymers to overcome biological barriers such as mucus and the phagocytic response of immune cells. Targeting ligands could be also added to enhance targeting specificity to epithelial cells. The review presents current understanding and advances in NP-mediated drug delivery to airway epithelium for asthma therapy. Future perspectives in this therapeutic strategy will also be discussed, including the development of novel formulations and physiologically relevant preclinical models.


Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Antiasmáticos/administração & dosagem , Asma/tratamento farmacológico , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Epitélio/efeitos dos fármacos , Nanopartículas/administração & dosagem , Animais , Antiasmáticos/química , Humanos , Nanopartículas/química
10.
Expert Rev Clin Pharmacol ; 13(2): 163-182, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31975619

RESUMO

Introduction: Steroid hormones are responsible for specific changes in the endometrium during the menstrual cycle, when they are sequentially secreted and, because of this, in the early days sequential combined oral contraceptive regimens were utilized. The same basic concept has been utilized with multi-phasic regimens, in order to produce endometrial pictures mimicking the normal cycle.Areas covered: The Endometrial effects of progestins and estrogens; combined monophasic high- (50 µg), medium- (30 µg), low- (20 µg), ultralow- (15 µg) estrogen content; sequential regimens; multiphasic combinations; treatment schedules.Cervical effects of combined high-dose and sequential combinations, including evidence for an increase in malignant lesions.Expert opinion: Overall, combined oral contraceptives (COCs) inhibit normal proliferative changes and the endometrium becomes thin, narrow, with widely spaced glands and pre-decidual changes in the stroma. During the first few cycles the progestin induces a coexistence of proliferative and secretory features; with time, the picture changes because the progestin induces a down-regulation of estrogen receptors, resulting in tortuous glands similar to those in the secretory phase, but characterized by a quiescent, atrophic glandular epithelium.In the cervical epithelium, under the influence of high-dose COCs, endocervical glands became hypersecretory and in some instances, distinctive type of atypical polypoid endocervical hyperplasia is found.


Assuntos
Anticoncepcionais Orais Combinados/administração & dosagem , Estrogênios/administração & dosagem , Progestinas/administração & dosagem , Animais , Colo do Útero/efeitos dos fármacos , Colo do Útero/metabolismo , Anticoncepcionais Orais Combinados/efeitos adversos , Anticoncepcionais Orais Combinados/farmacologia , Relação Dose-Resposta a Droga , Endométrio/efeitos dos fármacos , Endométrio/metabolismo , Epitélio/efeitos dos fármacos , Epitélio/metabolismo , Estrogênios/efeitos adversos , Estrogênios/farmacologia , Feminino , Humanos , Progestinas/efeitos adversos , Progestinas/farmacologia
11.
Am J Physiol Lung Cell Mol Physiol ; 318(2): L226-L241, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31693394

RESUMO

E-cigarettes are noncombustible, electronic nicotine-delivery devices that aerosolize an e-liquid, i.e., nicotine, in a propylene glycol-vegetable glycerin vehicle that also contains flavors. While the effects of nicotine are relatively well understood, more information regarding the potential biological effects of the other e-liquid constituents is needed. This is a serious concern, because e-liquids are available in >7,000 distinct flavors. We previously demonstrated that many e-liquids affect cell growth/viability through an unknown mechanism. Since Ca2+ is a ubiquitous second messenger that regulates cell growth, we characterized the effects of e-liquids on cellular Ca2+ homeostasis. To better understand the extent of this effect, we screened e-liquids for their ability to alter cytosolic Ca2+ levels and found that 42 of 100 flavored e-liquids elicited a cellular Ca2+ response. Banana Pudding (BP) e-liquid, a representative e-liquid from this group, caused phospholipase C activation, endoplasmic reticulum (ER) Ca2+ release, store-operated Ca2+ entry (SOCE), and protein kinase C (PKCα) phosphorylation. However, longer exposures to BP e-liquid depleted ER Ca2+ stores and inhibited SOCE, suggesting that this e-liquid may alter Ca2+ homeostasis by short- and long-term mechanisms. Since dysregulation of Ca2+ signaling can cause chronic inflammation, ER stress, and abnormal cell growth, flavored e-cigarette products that can elicit cell Ca2+ responses should be further screened for potential toxicity.


Assuntos
Cálcio/metabolismo , Citoplasma/metabolismo , Sistemas Eletrônicos de Liberação de Nicotina , Epitélio/metabolismo , Aromatizantes/efeitos adversos , Sistema Respiratório/metabolismo , Citoplasma/efeitos dos fármacos , Citosol/efeitos dos fármacos , Citosol/metabolismo , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Epitélio/efeitos dos fármacos , Células HEK293 , Humanos , Fosfatos de Inositol/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Musa , Proteína ORAI1/metabolismo , Fosforilação/efeitos dos fármacos , Proteína Quinase C-alfa/metabolismo , Sistema Respiratório/efeitos dos fármacos , Molécula 1 de Interação Estromal/metabolismo , Tapsigargina/farmacologia , Fosfolipases Tipo C/metabolismo , Vaping
13.
Artif Cells Nanomed Biotechnol ; 48(1): 96-106, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31852261

RESUMO

The diabetic foot ulcer (DFU) may be associated with late healing and septic manifestation, subsequently lead to amputation which is an overpriced incident. Neferine is an alkaloid found lotus. Neferine possesses many physiological functions such as anti-inflammatory, antioxidant, antimicrobial activity and anticancer effect. The aim of the present study was to evaluate the effect of topical application based on neferine, in streptozotocin-induced diabetic incision wound models rats. The data demonstrated wound healing activities via macroscopic, biochemical, histological, immuno-histochemical, immunofluorescent and molecular methods. There was significant acceleration in wound closure rate, decrease in the period of re-epitalization, higher amount of collagen and protein content in neferine treated group when compared with diabetic wound control. Histological data evidence collagen formation in skin and marked granulation with more connective tissue markers. The augmentation of serum insulin and HDL was dissimilar with blood glucose reduction and decreased lipid level (TC, TG and LDL). The healing effect was additionally validated by decreased lipid peroxidation and enhanced antioxidants. Concurrently, the mRNA level of Nrf-2, collagen-1, TGF-ß and α-SMA were decreased with Kaep-1 increased significantly. This enhancement was achieved through downregulation of inflammatory mediators such as nuclear factor kappa-light-chain-enhancer of activated B cells, tumour necrosis factor-α, interleukin-1ß, interleukin-8, inducible nitric oxide synthase, and cyclooxygenase-2, and upregulation of growth factor such as in groups treated with neferine. The western blot results reveal the macrophage (CD 68 and CD 163) involved in wound healing markedly elevated. Hence, the results indicate that neferine significantly promotes a fast and efficient wound healing in diabetic rats.


Assuntos
Benzilisoquinolinas/farmacologia , Citocinas/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Transdução de Sinais/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Benzilisoquinolinas/uso terapêutico , Colágeno/metabolismo , Diabetes Mellitus Experimental/patologia , Epitélio/efeitos dos fármacos , Epitélio/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Receptores de Superfície Celular/metabolismo
14.
Sci Adv ; 5(12): eaaw3413, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31844660

RESUMO

The human bronchial epithelium is composed of multiple distinct cell types that cooperate to defend against environmental insults. While studies have shown that smoking alters bronchial epithelial function and morphology, its precise effects on specific cell types and overall tissue composition are unclear. We used single-cell RNA sequencing to profile bronchial epithelial cells from six never and six current smokers. Unsupervised analyses led to the characterization of a set of toxin metabolism genes that localized to smoker ciliated cells, tissue remodeling associated with a loss of club cells and extensive goblet cell hyperplasia, and a previously unidentified peri-goblet epithelial subpopulation in smokers who expressed a marker of bronchial premalignant lesions. Our data demonstrate that smoke exposure drives a complex landscape of cellular alterations that may prime the human bronchial epithelium for disease.


Assuntos
Brônquios/efeitos dos fármacos , Lesões Pré-Cancerosas/genética , Fumar/efeitos adversos , Transcrição Genética/efeitos dos fármacos , Brônquios/metabolismo , Epitélio/efeitos dos fármacos , Epitélio/patologia , Heterogeneidade Genética/efeitos dos fármacos , Células Caliciformes/efeitos dos fármacos , Células Caliciformes/patologia , Humanos , Hiperplasia/induzido quimicamente , Hiperplasia/genética , Hiperplasia/patologia , Lesões Pré-Cancerosas/induzido quimicamente , Lesões Pré-Cancerosas/patologia , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/patologia , Análise de Sequência de RNA , Análise de Célula Única , Transcrição Genética/genética
15.
J Immunol Res ; 2019: 5920620, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31772948

RESUMO

Anesthetics have long been proven to have additional effects other than anesthesia on different organs and tissues of the human body. Barrier tissues play critical roles in human health and diseases, yet the impacts of anesthetics on barrier tissues are still not clear. This review article is aimed at summarizing different effects of anesthetics on the skin, the respiratory, and intestinal membranes from two aspects: inflammation/immunity and ischemia-reperfusion. Among volatile, intravenous, and local anesthetics, volatile anesthetics are less influential on barrier ischemia-perfusion function. Although direct comparisons between volatile and the other two types of anesthetics are still lacking, volatile anesthetics appear to have stronger anti-inflammatory effects on different barrier tissues through various mechanisms. These results suggested that when treating patients with barrier tissue complications, volatile anesthetics can provide better therapeutic outcomes.


Assuntos
Anestésicos/farmacologia , Anestésicos/química , Anestésicos/uso terapêutico , Animais , Epitélio/efeitos dos fármacos , Epitélio/metabolismo , Humanos , Membrana Mucosa/efeitos dos fármacos , Membrana Mucosa/metabolismo
17.
Microb Pathog ; 137: 103781, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31593757

RESUMO

Sub-acute ruminal acidosis (SARA) [1] is one of the most common problems of dairy animals causing great economical loss due to decreased milk production. Here we determined the antioxidant effect of sodium butyrate (NaB) [2] in experimentally induced SARA and its effects on mammary epithelial tissues of goat. Goats (n = 12) were equally divided into two groups: high-concentrate (HC) as control group fed with HC diet (concentrate: forage = 6:4) whereas HC + NaB as treatment group fed HC diet with NaB at 1% by weight for 24 weeks. Mammary epithelial tissue samples were analyzed for the expression of genes and proteins responsible for oxidative stress as well as biochemical markers of antioxidant activity in the form of Reactive Oxygen Species (ROS). The total antioxidant capacity (T-AOC) of antioxidant enzymes was also calculated. Butyrate induced antioxidant effect by increasing mRNA and protein abundance of antioxidants in mammary gland of HC + NaB group compared to HC group. Likewise, the total antioxidant capacity (T-AOC) was significantly increased and Malondialdehyde (MDA) concentration was decreased in HC + NaB group compared to HC group. It is concluded that oxidative stress in mammary gland of goats induced by high concentrate diet was alleviated by NaB supplementation.


Assuntos
Acidose/metabolismo , Acidose/veterinária , Ácido Butírico/administração & dosagem , Doenças das Cabras/tratamento farmacológico , Glândulas Mamárias Animais/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Acidose/tratamento farmacológico , Acidose/fisiopatologia , Animais , Epitélio/efeitos dos fármacos , Epitélio/metabolismo , Feminino , Doenças das Cabras/genética , Doenças das Cabras/metabolismo , Doenças das Cabras/fisiopatologia , Cabras , Lactação/efeitos dos fármacos , Malondialdeído/metabolismo , Glândulas Mamárias Animais/metabolismo , Leite/química , Leite/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo
18.
Acta Pharm ; 69(4): 621-634, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31639085

RESUMO

Oil-in-water nanoemulsions (NEs) represent one of the formulation approaches to improve eye-related bio-availability of lipophilic drugs. The potential of cationic NEs is pronounced due to the electrostatic interaction of positively charged droplets with negatively charged mucins present in the tear film, providing prolonged formulation residence at the ocular surface. The aim of this study was to develop a cationic ophthalmic NE with cationic lipid stearylamine (SA) as a carrier of a positive charge. The addition of a nonionic surfactant provided the dual electro-steric stabilization of NEs and enabled tuning of SA concentration to achieve an optimal balance between its interaction with mucins and biocompatibility. Physicochemical characterization, stability profile, in vitro mucoadhesion study and biocompatibility study employing 3D HCE-T cell-based model of corneal epithelium pointed out the NE with 0.05 % (m/m) SA as the leading formulation. Minimizing SA content while retaining droplet/mucin interactions is of great importance for efficacy and safety of future ophthalmic drug products.


Assuntos
Aminas/química , Cátions/química , Emulsões/química , Nanopartículas/química , Administração Oftálmica , Aminas/administração & dosagem , Materiais Biocompatíveis/administração & dosagem , Materiais Biocompatíveis/química , Disponibilidade Biológica , Cátions/administração & dosagem , Linhagem Celular , Córnea/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Emulsões/administração & dosagem , Epitélio/efeitos dos fármacos , Humanos , Lipídeos/administração & dosagem , Lipídeos/química , Nanopartículas/administração & dosagem
19.
Pflugers Arch ; 471(11-12): 1383-1396, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31654198

RESUMO

The epithelial Na+ channel (ENaC) is essential for Na+/K+ homeostasis and blood pressure control. Its activity is regulated by proteases in rodents. To gain more information on proteolytic ENaC regulation in humans, we tested the hypotheses that (1) human kidney α- and γ-ENaC subunits are furin-cleaved, glycosylated, and altered by medication that change plasma aldosterone; (2) prostasin-cleaved γ-ENaC is increased in proteinuria, and (3) cleaved ENaC moieties prevail at the membranes and in urinary extracellular vesicles (uEVs). We developed three monoclonal antibodies (mAbs) targeting (1) the neo-epitope generated after furin cleavage in γ-ENaC (mAb-furin); (2) the intact prostasin cleavage-site in γ-ENaC (mAb-intactRKRK), and (3) the α-ENaC subunit (mAb-alpha). Nephrectomy tissue and uEVs were used for immunoblotting and -histochemistry. In human kidney tissue, mAb-furin detected a ≈ 65-70 kDa protein, compatible with furin-cleaved γ-ENaC; mAb-intactRKRK detected full-length (≈ 90-100 kDa) and furin-cleaved (≈ 70-75 kDa) γ-ENaC. mAb-alpha detected a ≈ 50 kDa protein compatible with furin-cleaved α-subunit. Furin-cleaved γ-ENaC was detected predominantly within membrane fractions and deglycosylation shifted full-length γ-ENaC migration ~ 20 kDa. While γ-ENaC uEV levels were below the detection limit, α-ENaC migrated as intact (≈ 75 kDa) and furin-cleaved (≈ 50 kDa) in uEVs. Kidney levels of α- and γ-ENaC in diuretic- (n = 3) and ACE-inhibitor-treated (n = 4) patients were not different from controls (n = 4). Proteinuric patients (n = 6) displayed similar level of furin-cleaved γ-ENaC as controls (n = 4). Cleaved α-ENaC abundance was significantly lower in the kidneys from proteinuria patients. In conclusion, the study demonstrates ENaC cleavage as an event in human kidney that could contribute to physiological regulation and pathophysiological activation of ENaC.


Assuntos
Canais Epiteliais de Sódio/metabolismo , Epitélio/metabolismo , Furina/metabolismo , Rim/metabolismo , Subunidades Proteicas/metabolismo , Canais de Sódio/metabolismo , Aldosterona/metabolismo , Animais , Diuréticos/farmacologia , Epitélio/efeitos dos fármacos , Glicosilação , Humanos , Rim/efeitos dos fármacos , Camundongos , Proteinúria/metabolismo , Serina Endopeptidases/metabolismo , Sódio/metabolismo
20.
Gen Comp Endocrinol ; 284: 113268, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31491376

RESUMO

CPFX is a highly effective antibiotic, but it has been reported to significantly impair both testicular function and structure in rats. In this study, we assessed reversal of CPFX-induced variation in mice testicular structure and testosterone synthesis by probiotic microbes in the infected model and normal model. We detected testicular weight, testicular structure and Leydig cell variables in numbers. We detected the levels of serum testosterone and steroidogenic enzymes, as well as DBC1, Sirt1, NF-κB, and related redox state and inflammatory response in the testes. The results showed that probiotic microbes had significantly elevated serum testosterone levels and steroidogenic enzymes, higher Sirt1, anti-oxidative enzymes and anti-inflammatory cytokine expression, and lower NF-κB, DBC1, oxidative damage, pro-inflammatory cytokine expression. The results suggest that the testis-protective, antiinflammatory and antioxidation effects of probiotics largely resulted from its ability to decrease oxidative stress and preserve antioxidant activity by stabilizing antioxidant defense systems, reducing oxidative damage and inflammatory response.


Assuntos
Ciprofloxacino/farmacologia , Probióticos/metabolismo , Testículo/metabolismo , Testículo/microbiologia , Testosterona/metabolismo , Animais , Antioxidantes/metabolismo , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Citocinas/metabolismo , Epitélio/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Células Intersticiais do Testículo/efeitos dos fármacos , Células Intersticiais do Testículo/metabolismo , Masculino , Camundongos , Peso Molecular , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Sirtuína 1/metabolismo , Testículo/efeitos dos fármacos
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