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1.
J Pharmacol Sci ; 155(2): 21-28, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38677782

RESUMEN

Goblet cell hyperplasia and increased mucus production are features of airway diseases, including asthma, and excess airway mucus often worsens these conditions. Even steroids are not uniformly effective in mucus production in severe asthma, and new therapeutic options are needed. Seihaito is a Japanese traditional medicine that is used clinically as an antitussive and expectorant. In the present study, we examined the effect of Seihaito on goblet cell differentiation and mucus production. In in vitro studies, using air-liquid interface culture of guinea-pig tracheal epithelial cells, Seihaito inhibited IL-13-induced proliferation of goblet cells and MUC5AC, a major component of mucus production. Seihaito suppressed goblet cell-specific gene expression, without changing ciliary cell-specific genes, suggesting that it inhibits goblet cell differentiation. In addition, Seihaito suppressed MUC5AC expression in cells transfected with SPDEF, a transcription factor activated by IL-13. Furthermore, Seihaito attenuated in vivo goblet cell proliferation and MUC5AC mRNA expression in IL-13-treated mouse lungs. Collectively, these findings demonstrated that Seihaito has an inhibitory effect on goblet cell differentiation and mucus production, which is at least partly due to the inhibition of SPDEF.


Asunto(s)
Diferenciación Celular , Proliferación Celular , Células Caliciformes , Interleucina-13 , Medicina Kampo , Metaplasia , Mucina 5AC , Moco , Animales , Células Caliciformes/efectos de los fármacos , Células Caliciformes/patología , Células Caliciformes/metabolismo , Interleucina-13/metabolismo , Mucina 5AC/genética , Mucina 5AC/metabolismo , Moco/metabolismo , Diferenciación Celular/efectos de los fármacos , Cobayas , Proliferación Celular/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Células Cultivadas , Proteínas Proto-Oncogénicas c-ets/genética , Proteínas Proto-Oncogénicas c-ets/metabolismo , Masculino , Expresión Génica/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Ratones , Tráquea/citología , Tráquea/efectos de los fármacos , Tráquea/patología , Tráquea/metabolismo
2.
Cell Death Dis ; 15(4): 301, 2024 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-38684650

RESUMEN

Understanding the mechanisms involved in colonic epithelial differentiation is key to unraveling the alterations causing inflammatory conditions and cancer. Organoid cultures provide an unique tool to address these questions but studies are scarce. We report a differentiation system toward enterocytes and goblet cells, the two major colonic epithelial cell lineages, using colon organoids generated from healthy tissue of colorectal cancer patients. Culture of these organoids in medium lacking stemness agents resulted in a modest ultrastructural differentiation phenotype with low-level expression of enterocyte (KLF4, KRT20, CA1, FABP2) and goblet cell (TFF2, TFF3, AGR2) lineage markers. BMP pathway activation through depletion of Noggin and addition of BMP4 resulted in enterocyte-biased differentiation. Contrarily, blockade of the Notch pathway using the γ-secretase inhibitor dibenzazepine (DBZ) favored goblet cell differentiation. Combination treatment with BMP4 and DBZ caused a balanced strong induction of both lineages. In contrast, colon tumor organoids responded poorly to BMP4 showing only weak signals of cell differentiation, and were unresponsive to DBZ. We also investigated the effects of 1α,25-dihydroxyvitamin D3 (calcitriol) on differentiation. Calcitriol attenuated the effects of BMP4 and DBZ on colon normal organoids, with reduced expression of differentiation genes and phenotype. Consistently, in normal organoids, calcitriol inhibited early signaling by BMP4 as assessed by reduction of the level of phospho-SMAD1/5/8. Our results show that BMP and Notch signaling play key roles in human colon stem cell differentiation to the enterocytic and goblet cell lineages and that calcitriol modulates these processes favoring stemness features.


Asunto(s)
Proteína Morfogenética Ósea 4 , Calcitriol , Proteínas Portadoras , Diferenciación Celular , Colon , Dibenzazepinas , Células Caliciformes , Factor 4 Similar a Kruppel , Organoides , Receptores Notch , Transducción de Señal , Humanos , Organoides/efectos de los fármacos , Organoides/metabolismo , Diferenciación Celular/efectos de los fármacos , Proteína Morfogenética Ósea 4/metabolismo , Colon/efectos de los fármacos , Colon/metabolismo , Colon/citología , Colon/patología , Receptores Notch/metabolismo , Transducción de Señal/efectos de los fármacos , Calcitriol/farmacología , Células Caliciformes/efectos de los fármacos , Células Caliciformes/metabolismo , Dibenzazepinas/farmacología , Linaje de la Célula/efectos de los fármacos , Enterocitos/metabolismo , Enterocitos/efectos de los fármacos , Enterocitos/citología , Vitamina D/farmacología
3.
Vet Ophthalmol ; 27(3): 214-227, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38140703

RESUMEN

OBJECTIVES: The objective of the study was to evaluate whether a twice-daily instillation of 0.45% preservative-free ketorolac tromethamine (FKT) or 0.4% benzalkonium chloride-preserved ketorolac tromethamine (BACKT), every 12 h for 30 days may affect tear film parameters and the meibography in healthy dogs. Additionally, we assessed whether the same treatments irritated the ocular surface, affected goblet cell density (GCD), and the levels of oxidative stress biomarkers (OSB) in the conjunctiva of the same dogs. PROCEDURES: Experimental and masked comparison study. In 11 healthy dogs baseline values of the lipid layer thickness, tear meniscus height, non-invasive tear breakup time (NI-TFBT), and the meibomian gland (MG) loss were assessed by OSAvet®. For each dog, one eye received 40 µL of BACKT, while the other received 40 µL FKT, every 12 h for 30 consecutive days. Tear parameters and meibography were repeated 15, 30, and 60 days post-treatments. Conjunctival hyperemia and blepharospasm were monitored at the same time points. At baseline and Day 30, a conjunctival biopsy was collected for GCD and OSB determination. RESULTS: Conjunctival hyperemia and blepharospasm were not observed. At Day 15, the MG loss increased only in FKT-treated eyes (p < .001). On Day 30, both treatment groups showed increased MG loss, shortened NI-TFBT, and reduced GCD and catalase (p < .05). At Day 30, BACKT-treated eyes showed lower levels of superoxide dismutase (SOD) (p = .006) and higher levels of malondialdehyde (MDA) (p = .02). Differences between treatments were not observed for any parameter at any time point (p > .05). 60 days after treatment, OSAvet® parameters tended to return to values assessed at baseline; however, significant differences remained for MG loss (p < .05). CONCLUSIONS: Twice-daily instillation of KT, containing or not BAC, for 30 consecutive days shortened NI-TFBT, decreased GCD, and increased the MG loss in healthy dogs. KT should be used with caution when prescribed for long periods, particularly in patients with tear film abnormalities. However, future controlled studies using KT, BAC, and other topical NSAIDs are indicated to further support this finding.


Asunto(s)
Conjuntiva , Células Caliciformes , Ketorolaco Trometamina , Estrés Oxidativo , Lágrimas , Animales , Perros , Estrés Oxidativo/efectos de los fármacos , Células Caliciformes/efectos de los fármacos , Lágrimas/efectos de los fármacos , Conjuntiva/efectos de los fármacos , Femenino , Masculino , Ketorolaco Trometamina/administración & dosificación , Ketorolaco Trometamina/farmacología , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/farmacología , Glándulas Tarsales/efectos de los fármacos , Glándulas Tarsales/metabolismo , Soluciones Oftálmicas
4.
PeerJ ; 11: e14695, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36684665

RESUMEN

Solithromycin is a novel fluoroketolide antibiotic belonging to the class of macrolide antibiotics. Activation of the interleukin (IL)-13 receptor leads to STAT6 activation and subsequent induction of SAM pointed domain containing ETS transcription factor (SPDEF), chloride channel accessory 1 (CLCA1), and anoctamin-1 (ANO1), all of which are associated with the induction of MUC5AC. We examined the effects of solithromycin on mucin production led by IL-13 signaling. Normal human bronchial epithelial cells were grown at the air-liquid interface with IL-13 with/without solithromycin for 14 days. Histochemical analysis was performed using hematoxylin and eosin staining and MUC5AC immunostaining. MUC5AC, SPDEF, CLCA1, and ANO1 mRNA expressions were examined using real-time polymerase chain reaction. Western blot analysis was performed to assess CLCA1 and ANO1 proteins, and phosphorylation of STAT6 and ERK. Solithromycin attenuated IL-13 induction of goblet cell hyperplasia and MUC5AC, CLCA1 and ANO1 mRNA and protein expression induced by IL-13, but had no effect on the phosphorylation of STAT6 and ERK. Our results indicate that solithromycin could attenuate goblet cell hyperplasia and MUC5AC induced by IL-13 through inhibition of CLCA1 and ANO1 mRNA and protein expression. However, much more information is required to clarify the molecular mechanisms underlying the inhibition of CLCA1 and ANO1 by solithromycin.


Asunto(s)
Células Caliciformes , Interleucina-13 , Macrólidos , Humanos , Anoctamina-1/genética , Canales de Cloruro/genética , Células Caliciformes/efectos de los fármacos , Células Caliciformes/patología , Hiperplasia , Interleucina-13/genética , Macrólidos/farmacología , Mucina 5AC/genética , Proteínas de Neoplasias/metabolismo , ARN Mensajero/genética
5.
Am J Respir Cell Mol Biol ; 67(3): 360-374, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35679095

RESUMEN

Allergic rhinitis (AR) is a multifactorial airway disease characterized by basal and goblet cell hyperplasia. Hyaluronic acid (HA) is a major component of extracellular matrix and a critical contributor to tissue repair and remodeling after injury. We previously demonstrated that the intermediate progenitor cell (IPC) surface marker CD44v3 is upregulated in the basal and suprabasal layers of well-differentiated primary human nasal epithelial (HNE) cells after stimulation with the Th2 (T-helper cell type 2) cytokine IL-4, and an antibody blocking the CD44v3-HA interaction suppressed IL-4-induced goblet cell hyperplasia. We now show that the expression of HA and two HA synthases, HAS2 and HAS3, was upregulated in both the nasal surface epithelium of subjects with AR and IL-4-stimulated HNE cells. Inhibition of HA synthesis by 4-methylumbelliferone suppressed IL-4-induced goblet cell hyperplasia. Moreover, HAS2 and HAS3 were expressed in IPCs depending on the differentiation events, as follows: the rapid, transient upregulation of HAS2 induced basal IPC proliferation and basal-to-suprabasal transition, whereas the delayed upregulation of HAS3 promoted the transition of suprabasal IPCs to a goblet cell fate. 4-methylumbelliferone treatment in a house dust mite-induced murine AR model attenuated goblet cell metaplasia. Last, HA concentrations in nasal epithelial lining fluids from patients with AR positively correlated with the concentrations of mediators causing allergic inflammation. These data suggest that HA produced after the sequential upregulation of HAS2 and HAS3 contributes to goblet cell hyperplasia in allergic airway inflammation and modulates disease progression.


Asunto(s)
Células Caliciformes , Hialuronano Sintasas , Rinitis Alérgica , Animales , Células Caliciformes/efectos de los fármacos , Células Caliciformes/enzimología , Células Caliciformes/patología , Humanos , Hialuronano Sintasas/metabolismo , Ácido Hialurónico/metabolismo , Himecromona/farmacología , Himecromona/uso terapéutico , Hiperplasia/genética , Hiperplasia/patología , Interleucina-4/metabolismo , Ratones , Rinitis Alérgica/tratamiento farmacológico , Rinitis Alérgica/enzimología , Rinitis Alérgica/patología
6.
Clin Sci (Lond) ; 136(4): 291-307, 2022 02 25.
Artículo en Inglés | MEDLINE | ID: mdl-35194640

RESUMEN

Ulcerative colitis (UC) is majorly associated with dysregulation of the dynamic cross-talk among microbial metabolites, intestinal epithelial cells, and macrophages. Several studies have reported the significant role of butyrate in host-microbiota communication. However, whether butyrate provides anti-inflammatory profiles in macrophages, thus contributing to UC intestinal mucus barrier protection, has currently remained elusive. In the current study, we found that butyrate increased mucin production and the proportion of mucin-secreting goblet cells in the colon crypt in a macrophage-dependent manner by using clodronate liposomes. Furthermore, in vivo and in vitro studies were conducted, validating that butyrate facilitates M2 macrophage polarization with the elevated expressions of CD206 and arginase-1 (Arg1). In macrophages/goblet-like LS174T cells co-culture systems, butyrate-primed M2 macrophages significantly enhanced the expression of mucin-2 (MUC2) and SPDEF (goblet cell marker genes) than butyrate alone, while blockade of WNTs secretion or ERK1/2 activation significantly decreased the beneficial effect of butyrate-primed macrophages on goblet cell function. Additionally, the adoptive transfer of butyrate-induced M2 macrophages facilitated the generation of goblet cells and mucus restoration following dextran sulfate sodium (DSS) insult. Taken together, our results revealed a novel mediator of macrophage-goblet cell cross-talk associated with the regulation of epithelial barrier integrity, implying that the microbial metabolite butyrate may serve as a candidate therapeutic target for UC.


Asunto(s)
Butiratos/farmacología , Colitis Ulcerosa/terapia , Células Caliciformes/efectos de los fármacos , Macrófagos/efectos de los fármacos , Vía de Señalización Wnt , Traslado Adoptivo , Animales , Estudios de Casos y Controles , Línea Celular , Colitis Ulcerosa/inmunología , Microbioma Gastrointestinal , Humanos , Macrófagos/metabolismo , Macrófagos/trasplante , Ratones Endogámicos BALB C
7.
J Ethnopharmacol ; 290: 115093, 2022 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-35149129

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Acalypha indica Linn (Euphorbiaceae), a popular traditional medicine, is an erect herb found throughout various parts of India. In Ayurveda, Acalypha indica was commonly used in asthma and allergy. However, no attempts were made in past to validate the antiasthmatic potential of Acalypha indica. AIM OF THE STUDY: The present study was aimed to assess the anti-asthmatic potential of ethanolic extracts of Acalypha indica leaves (EAIL) using various experimental animal models. MATERIALS AND METHODS: EAIL was analyzed using different screening methods such as acetylcholine and histamine-induced contraction of goat tracheal chain, clonidine-induced catalepsy in mice, milk-induced leucocytosis and eosinophilia in mice, clonidine-induced mast cell degranulation in rats, passive paw anaphylaxis in rats, histamine-induced bronchoconstriction in guinea pigs, and ovalbumin (OVA)-induced histopathological alterations in mice. RESULTS: Data received in the present study showed that EAIL drastically antagonized acetylcholine and histamine-induced contraction of goat tracheal chain, suggesting its anticholinergic and antihistaminic activity respectively. The duration of immobility, produced by clonidine, was found to be decreased in mice which showed its H1 receptor blocking activity. In milk-induced leucocytosis and eosinophilia in mice, EAIL significantly reduced the number of leucocytes and eosinophils suggesting its adaptogenic and anti-allergic potential. Inhibition of clonidine-induced mast cell degranulation in rats displayed its mast cell stabilizing potential. Reduction of paw edema in passive paw anaphylaxis exhibited antianaphylactic activity of EAIL. Guinea pigs were protected from histamine-induced bronchoconstriction by EAIL which revealed its bronchodilator potential. Furthermore, the histopathological architecture of lung tissue was near to normal. CONCLUSION: Our results contribute towards validation of the traditional use of Acalypha indica in the treatment of asthma due to the presence of a wide range of phytoconstituents. Hence our investigation revealed that EAIL possessed strong antiasthmatic property by virtue of various mechanisms.


Asunto(s)
Acalypha , Asma/patología , Broncoconstricción/efectos de los fármacos , Extractos Vegetales/farmacología , Animales , Antialérgicos/farmacología , Antiasmáticos/farmacología , Antiinflamatorios/farmacología , Broncodilatadores/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Células Caliciformes/efectos de los fármacos , Cobayas , Hipersensibilidad/patología , Mediadores de Inflamación/metabolismo , Mastocitos/efectos de los fármacos , Ratones , Hojas de la Planta , Ratas , Ratas Wistar
8.
Laryngoscope ; 132(3): 648-654, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-34599608

RESUMEN

OBJECTIVES: To evaluate histologic changes in middle ear and eustachian tube (ET) mucosa of mice after exposure to tobacco or electronic cigarette (e-cigarette) smoke. To determine whether there were any mitigating effects of middle ear application of anti-IL-13 or the epidermal growth factor receptor antagonist AG1478 on noted changes within ET mucosa. STUDY DESIGN: Controlled animal study. METHODS: Fifty BALB/cJ mice were randomly assigned to one of five groups: A control group with no smoke exposure, two groups exposed to tobacco smoke, and two groups exposed to e-cigarette vapor. Within the exposed groups after 4 weeks of exposure, one ear was infiltrated with a saline hydrogel and the other ear with hydrogel of either Anti-IL-13 or AG1478. After four more weeks of exposure, the animals were euthanized and the ETs were evaluated for mucosal changes. RESULTS: Compared to control animals with no smoke exposure, there were significant decreases in the numbers of goblet cells within the ET mucosa of mice exposed to tobacco smoke and e-cigarette vapor. No significant differences in cilia, mucin, or squamous metaplasia were noted. Neither anti-IL-13 nor AG178 significantly altered goblet cell count in the ET mucosa of mice exposed to tobacco smoke; however, both agents significantly increased goblet cells within the ET mucosa of mice exposed to e-cigarette vapor. CONCLUSION: Short-term tobacco smoke and e-cigarette vapor significantly decrease goblet cell count in mouse ET mucosa. Middle ear application of both anti-IL-13 and AG1478 resulted in an increase in goblet cell count among mice exposed to e-cigarette vapor, but not to tobacco smoke. LEVEL OF EVIDENCE: NA Laryngoscope, 132:648-654, 2022.


Asunto(s)
Cigarrillo Electrónico a Vapor/efectos adversos , Trompa Auditiva/efectos de los fármacos , Membrana Mucosa/efectos de los fármacos , Contaminación por Humo de Tabaco/efectos adversos , Animales , Sistemas Electrónicos de Liberación de Nicotina , Femenino , Células Caliciformes/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB C
9.
BMC Immunol ; 22(1): 78, 2021 12 17.
Artículo en Inglés | MEDLINE | ID: mdl-34920698

RESUMEN

BACKGROUND: Phosphoinositide-3-kinase-delta (PI3Kδ) inhibition is a promising therapeutic approach for inflammatory conditions due to its role in leucocyte proliferation, migration and activation. However, the effect of PI3Kδ inhibition on group 2 innate lymphoid cells (ILC2s) and inflammatory eosinophils remains unknown. Using a murine model exhibiting persistent airway inflammation we sought to understand the effect of PI3Kδ inhibition, montelukast and anti-IL5 antibody treatment on IL33 expression, group-2-innate lymphoid cells, inflammatory eosinophils, and goblet cell metaplasia. RESULTS: Mice were sensitised to house dust mite and after allowing inflammation to resolve, were re-challenged with house dust mite to re-initiate airway inflammation. ILC2s were found to persist in the airways following house dust mite sensitisation and after re-challenge their numbers increased further along with accumulation of inflammatory eosinophils. In contrast to montelukast or anti-IL5 antibody treatment, PI3Kδ inhibition ablated IL33 expression and prevented group-2-innate lymphoid cell accumulation. Only PI3Kδ inhibition and IL5 neutralization reduced the infiltration of inflammatory eosinophils. Moreover, PI3Kδ inhibition reduced goblet cell metaplasia. CONCLUSIONS: Hence, we show that PI3Kδ inhibition dampens allergic inflammatory responses by ablating key cell types and cytokines involved in T-helper-2-driven inflammatory responses.


Asunto(s)
Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Eosinófilos/inmunología , Hipersensibilidad/inmunología , Inflamación/inmunología , Interleucina-33/metabolismo , Linfocitos/inmunología , Sistema Respiratorio/inmunología , Acetatos/uso terapéutico , Animales , Antígenos Dermatofagoides/inmunología , Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Ciclopropanos/uso terapéutico , Citocinas/metabolismo , Femenino , Células Caliciformes/efectos de los fármacos , Células Caliciformes/patología , Hipersensibilidad/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Interleucina-5/antagonistas & inhibidores , Ratones , Ratones Endogámicos BALB C , Pyroglyphidae , Quinolinas/uso terapéutico , Sulfuros/uso terapéutico , Células Th2/inmunología
10.
Biomed Pharmacother ; 144: 112253, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34607106

RESUMEN

Iron supplementation is necessary for the treatment of anemia, one of the most frequent complications in inflammatory bowel disease (IBD). However, oral iron supplementation leads to an exacerbation of intestinal inflammation. Gut barrier plays a key role in the pathogenesis of IBD. The aim of this study was to characterize the interrelationship between systemic iron, intestinal barrier and the development of intestinal inflammation in a dextran sulfate sodium (DSS) induced experimental colitis mice model. We found that DSS-treated mice developed severe inflammation of colon, but became much healthy when intraperitoneal injection with iron. Iron supplementation alleviated colonic and systemic inflammation by lower histological scores, restorative morphology of colonic villi, and reduced expression of pro-inflammatory cytokines. Moreover, intraperitoneal supplementation of iron enhanced intestinal barrier function by upregulating the colonic expressions of tight junction proteins, restoring intestinal immune homeostasis by regulating immune cell infiltration and T lymphocyte subsets, and increasing mucous secretion of goblet cells in the colon. High-throughput sequencing of fecal 16 S rRNA showed that iron injection significantly increased the relative abundance of Bacteroidetes, which was suppressed in the gut microbiota of DSS-induced colitis mice. These results provided evidences supporting the protective effects of systemic iron repletion by intraperitoneal injection of iron on intestinal barrier functions. The finding highlights a novel approach for the treatment of IBD with iron injection therapy.


Asunto(s)
Colitis/tratamiento farmacológico , Colon/efectos de los fármacos , Suplementos Dietéticos , Células Caliciformes/efectos de los fármacos , Mucosa Intestinal/efectos de los fármacos , Complejo Hierro-Dextran/administración & dosificación , Proteínas de Uniones Estrechas/metabolismo , Animales , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/metabolismo , Colitis/inducido químicamente , Colitis/metabolismo , Colitis/microbiología , Colon/metabolismo , Colon/microbiología , Sulfato de Dextran , Modelos Animales de Enfermedad , Disbiosis , Microbioma Gastrointestinal/efectos de los fármacos , Células Caliciformes/metabolismo , Células Caliciformes/microbiología , Inyecciones Intraperitoneales , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Masculino , Ratones Endogámicos C57BL , Permeabilidad , Uniones Estrechas/efectos de los fármacos , Uniones Estrechas/metabolismo , Uniones Estrechas/microbiología , Regulación hacia Arriba
11.
Bull Exp Biol Med ; 171(6): 750-754, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-34709518

RESUMEN

The study examined the effect of H1-receptor antagonist olopatadine on the secretory function of cultured rat conjunctival goblet cells (CGC) assessed by enzyme-linked lectin assay employing UEA-I lectin. The level of mRNA for membrane-bound protein MUC16 in histaminestimulated CGC was assayed by reverse transcription PCR in the control and after preliminary application of olopatadine. The intracellular calcium concentration [Ca2+]i was measured by the calcium colorimetric method using GENMED kits. The effects of histamine and olopatadine on p-ERK level were assessed by Western blotting. Histamine up-regulated secretion of mucin MUC5AC and expression of membrane-bound protein MUC16 in CGC. In addition, it increased both [Ca2+]i and the level of phosphorylated ERK. These effects were diminished by preliminary application of olopatadine that probably acted via the ERK signaling pathway. Thus, olopatadine reduced [Ca2+]i and down-regulated ERK phosphorylation by binding to H1-receptors, thereby inhibiting secretion of mucin from histamine-stimulated CGC.


Asunto(s)
Expresión Génica/efectos de los fármacos , Células Caliciformes/efectos de los fármacos , Antagonistas de los Receptores Histamínicos H1/farmacología , Mucina 5AC/genética , Clorhidrato de Olopatadina/farmacología , Animales , Calcio/metabolismo , Cationes Bivalentes , Conjuntiva/citología , Conjuntiva/metabolismo , Células Caliciformes/citología , Células Caliciformes/metabolismo , Histamina/farmacología , Masculino , Proteína Quinasa 1 Activada por Mitógenos/genética , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Mucina 5AC/antagonistas & inhibidores , Mucina 5AC/metabolismo , Fosforilación/efectos de los fármacos , Cultivo Primario de Células , Ratas , Ratas Sprague-Dawley
12.
Am J Physiol Gastrointest Liver Physiol ; 321(5): G489-G499, 2021 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-34494458

RESUMEN

Goblet cells are specialized for the production and secretion of MUC2 glycoproteins that forms a thick layer covering the mucosal epithelium as a protective barrier against noxious substances and invading microbes. High MUC2 mucin biosynthesis induces endoplasmic reticulum (ER) stress and apoptosis in goblet cells during inflammatory and infectious diseases. Autophagy is an intracellular degradation process required for maintenance of intestinal homeostasis. In this study, we hypothesized that autophagy was triggered during high MUC2 mucin biosynthesis from colonic goblet cells to cope with metabolic stress. To interrogate this, we analyzed the autophagy process in high MUC2-producing human HT29-H and a clone HT29-L silenced for MUC2 expression by lentivirus-mediated shRNA, and WT and CRISPR/Cas9 MUC2 KO LS174T cells. Autophagy was constitutively increased in high MUC2-producing cells characterized by elevated pULK1S555 expression and increased numbers of autophagosomes as compared with MUC2 silenced or gene edited cells. Similarly, colonoids from Muc2+/+ but not Muc2-/- littermates differentiated into goblet cells showed increased autophagy. IL-22 treatment corrected misfolded MUC2 protein and alleviated the autophagy process in LS174T cells. This study highlights that autophagy plays an essential role in goblet cells to survive during high mucin biosynthesis by regulating cellular homeostasis.NEW & NOTEWORTHY It is unclear how colonic goblet cells survive by producing high output MUC2 mucin that triggers endoplasmic stress by misfolded MUC2 proteins. To cope with metabolic stress, we interrogated if autophagy played an essential role in regulating cellular homeostasis. Indeed, high MUC2 mucin biosynthesis dysregulated autophagy processes that was regulated by IL-22 to maintain gut barrier innate host defenses.


Asunto(s)
Autofagia , Colon/metabolismo , Estrés del Retículo Endoplásmico , Metabolismo Energético , Células Caliciformes/metabolismo , Mucina 2/biosíntesis , Animales , Autofagia/efectos de los fármacos , Homólogo de la Proteína 1 Relacionada con la Autofagia/metabolismo , Colon/efectos de los fármacos , Colon/ultraestructura , Estrés del Retículo Endoplásmico/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Femenino , Células Caliciformes/efectos de los fármacos , Células Caliciformes/ultraestructura , Células HT29 , Humanos , Interleucinas/farmacología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Mucina 2/genética , Fosforilación , Pliegue de Proteína , Transducción de Señal , Interleucina-22
13.
Inflammation ; 44(6): 2463-2475, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34420156

RESUMEN

Studies on the bronchial vascular bed have revealed that the number of blood vessels in the lamina propria and under the mucosa of the lung tissue increases in patients suffering from mild to severe asthma. Thus, in this study, a new strategy was employed in respiratory system disorders by angiogenesis inhibition in an ovalbumin (OVA)-induced rat model of asthma. Twenty-one male Wistar albino rats, 8 weeks old, were randomly divided into three groups (n = 7 in each group), including (1) control group, (2) OVA-treated group, and (3) OVA + Bmab (bevacizumab drug). On days 1 and 8, 1 mg of OVA and aluminum hydroxide in sterile phosphate-buffered saline (PBS) were intraperitoneally injected to rats in groups 2 and 3. The control group was only subject to intraperitoneal injection of saline on days 1 and 8. One week after the last injection, the rats (groups 2 and 3) were exposed to OVA inhalation for 30 min at 2-day intervals from days 15 to 25. After sensitization and challenge with OVA, the OVA + Bmab group (group 3) were treated with a 5 mg/kg bevacizumab drug. Genes and protein expression of IL-1ß and TNF-α and the expression of vascular endothelial growth factor (VEGF) protein were assessed by real-time PCR and immunohistochemistry respectively, in lung tissue. OVA exposure increased mucosal secretion and inflammatory cell populations in lung tissue and OVA-specific IgE level in serum. Also, VEGF and cytokine factor expression were significantly elevated in the OVA-induced asthma model (p ≤ 0.05). However, rats in OVA + Bmab group showed significantly a decrease in VEGF and IL-1ß and TNF-α genes as well as proteins (p ≤ 0.05). The results showed that bevacizumab efficiently diminished bronchial inflammation via downregulation of VEGF expression, followed by inflammatory cells population and cytokines reduction. Angiogenesis inhibition in rats with induced asthma not only suppresses the inflammatory process through blocking VEGF expression but also inhibits the development of new blood vessels and progressing asthmatic attacks.


Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Antiasmáticos/farmacología , Asma/tratamiento farmacológico , Bevacizumab/farmacología , Pulmón/irrigación sanguínea , Pulmón/efectos de los fármacos , Neovascularización Patológica , Neumonía/tratamiento farmacológico , Animales , Asma/inducido químicamente , Asma/metabolismo , Asma/patología , Modelos Animales de Enfermedad , Células Caliciformes/efectos de los fármacos , Células Caliciformes/metabolismo , Células Caliciformes/patología , Mediadores de Inflamación/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Pulmón/metabolismo , Pulmón/patología , Masculino , Ovalbúmina , Neumonía/inducido químicamente , Neumonía/metabolismo , Neumonía/patología , Ratas Wistar , Transducción de Señal , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo
14.
Exp Eye Res ; 210: 108685, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34252414

RESUMEN

Dry eye (DE) is a chronic, multifactorial ocular surface disease associated with visual disturbance, tear film instability, hyperosmolarity, ocular surface inflammation and damage. Effective intervention is necessary to control this disease. In this study we topically applied α-melanocyte stimulating hormone (α-MSH) on the ocular surface of scopolamine-induced DE rats and found that it promoted tear secretion, reduced tear breakup time and fluorescein sodium staining and increased the number of conjunctival goblet cells. To investigate the mechanism, protein array was conducted, which showed that α-MSH exerted its effects via epithelial growth factor receptor (EGFR) in the JAK-STAT signaling pathway. Furthermore, in vitro experiments showed that α-MSH protected human corneal epithelial cells (hCECs) by maintaining their migration ability and viability and decreasing apoptosis. However, blockade of EGFR abolished these protective effects. Moreover, α-MSH decreased the level of autophagy in benzalkonium chloride (BAC)-stressed hCECs via EGFR. These results demonstrated that α-MSH ameliorated lesions and restored ocular surface functions by upregulating EGFR expression.


Asunto(s)
Síndromes de Ojo Seco/tratamiento farmacológico , Receptores ErbB/genética , Regulación de la Expresión Génica/fisiología , Hormonas/uso terapéutico , alfa-MSH/uso terapéutico , Administración Oftálmica , Animales , Apoptosis , Autofagia , Línea Celular , Movimiento Celular/fisiología , Supervivencia Celular/fisiología , Modelos Animales de Enfermedad , Síndromes de Ojo Seco/inducido químicamente , Síndromes de Ojo Seco/genética , Síndromes de Ojo Seco/patología , Epitelio Corneal/efectos de los fármacos , Epitelio Corneal/metabolismo , Epitelio Corneal/patología , Femenino , Citometría de Flujo , Células Caliciformes/efectos de los fármacos , Hormonas/administración & dosificación , Humanos , Soluciones Oftálmicas , Interferencia de ARN , Ratas , Ratas Wistar , Escopolamina/toxicidad , Lágrimas/fisiología , alfa-MSH/administración & dosificación
15.
Biomed Pharmacother ; 140: 111746, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-34062412

RESUMEN

BACKGROUND/AIMS: Asthma is a common chronic respiratory disease. It has been reported that Pingchuan formula (PCF) can control asthma attacks by reducing airway inflammation, muscle spasm and mucus secretion. However, PCF's mechanism for reducing airway mucus hypersecretion remains unclear. This study aimed to investigate the effect of PCF on airway mucus secretion in asthmatic mice and to explore changes in the PNEC-GABA-IL13-Muc5ac axis. METHODS: Male Babl/c mice were used to establish the asthma model via sensitisation with OVA. Mice were randomly divided into Normal, OVA, DEX, and PCF groups. After treatment, lung histopathology was observed with H&E and PAS staining. BALF levels of IL-5 and IL-13 were detected using ELISA. The levels of mRNA and protein expression for GAD1, GABAARß1, GABAARα1 and Muc5ac in the lung tissue were measured by RT-PCR and Western blot assays. PNECs were observed with AgNOR staining. RESULTS: PCF treatment effectively reduced goblet cell (P < 0.01) and PNEC (P < 0.05) proliferation, lung tissue inflammation and airway mucus hypersecretion. In addition, PCF also markedly downregulated mRNA and protein expression of GAD1, GABAARß1, GABAARα1 and Muc5ac (P < 0.05, compared with OVA), thus inhibiting the GABA-IL-13 pathway in the lung tissue of asthmatic mice. CONCLUSION: These findings suggest that PCF controls asthma attacks by reducing airway inflammation and mucus hypersecretion via the PNEC-GABA-IL13-Muc5ac axis.


Asunto(s)
Antiasmáticos/uso terapéutico , Asma/tratamiento farmacológico , Medicamentos Herbarios Chinos/uso terapéutico , Animales , Antiasmáticos/farmacología , Asma/inmunología , Asma/metabolismo , Asma/patología , Líquido del Lavado Bronquioalveolar/inmunología , Proliferación Celular/efectos de los fármacos , Citocinas/inmunología , Medicamentos Herbarios Chinos/farmacología , Células Caliciformes/efectos de los fármacos , Interleucina-13/metabolismo , Pulmón/efectos de los fármacos , Pulmón/patología , Masculino , Ratones Endogámicos BALB C , Mucina 5AC/metabolismo , Moco/metabolismo , Células Neuroendocrinas/efectos de los fármacos , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismo
16.
Biomed Pharmacother ; 140: 111726, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-34111725

RESUMEN

Bronchial asthma (BA) is a heterogeneous allergic respiratory disease with diverse inflammatory symptoms, pathology, and responses to treatment. Thyme is a natural product which is consisted of multiple phenolic compounds of therapeutic significance for treatment of cough and bronchitis. This study evaluated the efficacy of thyme oil against ovalbumin (OVA)-induced BA in an experimental rabbit model. Forty male rabbits were divided into four equal groups [control group (G1), OVA (G2), thyme oil (G3), and OVA plus thyme oil (G4)]. Animals were treated for 30 days, and clinical, histopathological (HP), histochemical (HC), immunohistochemical (IHC), morphometric, biochemical and flow cytometry methods were performed, followed by statistical analysis. All used methods revealed normal structure of the lung tissues in rabbits of G1 and G3. In contrast, the clinical examination of G2 rabbits revealed an obvious increase in the respiratory rate, sneezing and wheezing, whereas the HP, HC and IHC techniques exhibited substantial inflammatory changes in the peribronchio-vascular lung tissues with thinning, degeneration, apoptosis (using the TUNEL assay), necrosis, and shedding of the airway epithelium. Furthermore, the morphometric results confirmed significant increases in the numbers of inflammatory cells, goblet cells, eosinophils and apoptotic cells from (12, 0, 2, 2 cells) to (34,10, 16, 18 cells) respectively, as well as the area percentage of collagen fiber deposition and immunoexpression of eotaxin-1/10 high power fields. Additionally, the biochemical results revealed significant increases in the serum levels of TSLP, IL-4, IL-5, IL-9, IL-13, IgE and eotaxin-1 cytokines from (140, 40, 15, 38, 120, 100, 48) pg./ml to (360, 270, 130, 85, 365, 398, 110) pg./ml respectively, while analysis of ROS by flow cytometry revealed remarkable oxidative stress effects in G2 rabbits. On the other hand, treatment of rabbits with thyme oil in G4 substantially alleviated all OVA-induced alterations. Overall, our findings indicate for the first time that thyme oil can ameliorate OVA-induced BA via its immunomodulatory, anti-inflammatory, antiapoptotic, and antioxidant effects on the lung tissues of rabbits.


Asunto(s)
Antiasmáticos/uso terapéutico , Antiinflamatorios/uso terapéutico , Antioxidantes/uso terapéutico , Asma/tratamiento farmacológico , Aceites de Plantas/uso terapéutico , Thymus (Planta) , Alérgenos , Animales , Antiasmáticos/farmacología , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Asma/inmunología , Asma/patología , Citocinas/sangre , Citocinas/inmunología , Células Caliciformes/efectos de los fármacos , Inmunoglobulina E/inmunología , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/patología , Masculino , Ovalbúmina , Aceites de Plantas/farmacología , Conejos , Especies Reactivas de Oxígeno/inmunología , Células Th2/inmunología
17.
Drug Des Devel Ther ; 15: 2357-2373, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34121838

RESUMEN

PURPOSE: To prepare the levocarnitine thermosensitive in situ gel (LCTG) and evaluate its effect on dry eye disease (DED). METHODS: Draize eye irritation test and other examinations were used to evaluate the eye irritation after multiple administration of LCTG. The Schirmer test, fluorescein sodium staining, HE staining and TUNEL staining were used to detect the tear secretion, corneal injury, histopathological changes of the cornea and lacrimal gland, and the apoptosis rate of cornea epithelial cells after 3 days of the administration. The conjunctival goblet cell density was detected by PAS staining, and the expression levels of matrix metalloproteinase-3 (MMP-3) and matrix metalloproteinase-9 (MMP-9) of corneal epithelial cells were detected by immunofluorescence staining after 7 days of the administration. RESULTS: LCTG is non-irritating to rabbit eyes and has good biocompatibility. LCTG administration for 3 days can significantly increase the amount of tear secretion in mice with DED, promote corneal epithelial integrity and central corneal epithelium thickness recovery, and improve the pathological morphology and structure of corneal and lacrimal gland tissues, and reduce the apoptosis rate of the corneal epithelial cells. After 7 days of the administration, the preparation can promote the proliferation of conjunctival goblet cells and down-regulate the cornea expression levels of MMP-3 and MMP-9 in epithelial cells. CONCLUSION: The LCTG has a good curative effect on mice with DED, and the overall curative effect is better than that of levocarnitine solution.


Asunto(s)
Carnitina/administración & dosificación , Córnea/metabolismo , Sistemas de Liberación de Medicamentos , Síndromes de Ojo Seco/tratamiento farmacológico , Administración Oftálmica , Animales , Carnitina/farmacología , Carnitina/toxicidad , Modelos Animales de Enfermedad , Epitelio Corneal/efectos de los fármacos , Epitelio Corneal/metabolismo , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Células Caliciformes/efectos de los fármacos , Células Caliciformes/metabolismo , Metaloproteinasa 3 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/genética , Ratones , Ratones Endogámicos BALB C , Conejos , Temperatura , Resultado del Tratamiento
18.
Exp Mol Pathol ; 121: 104656, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34081961

RESUMEN

Sulfur mustard (SM; bis (2-chloroethyl) sulfide) is a potent vesicant which causes irritation of the conjunctiva and damage to the cornea. In the present studies, we characterized the ocular effects of SM in New Zealand white rabbits. Within one day of exposure to SM, edema and hazing of the cornea were observed, followed by neovascularization which persisted for at least 28 days. This was associated with upper and lower eyelid edema and conjunctival inflammation. The conjunctiva is composed of a proliferating epithelium largely consisting of stratified columnar epithelial cells overlying a well-defined dermis. Superficial layers of the conjunctival epithelium were found to express keratin 1, a marker of differentiating squamous epithelium, while in cells overlying the basement membrane expressed keratin 17, a marker of stratified squamous epithelium. SM exposure upregulated keratin 17 expression. Mucin 5 ac producing goblet cells were interspersed within the conjunctiva. These cells generated both acidic and neutral mucins. Increased numbers of goblet cells producing neutral mucins were evident after SM exposure; upregulation of expression of membrane-associated mucin 1 and mucin 4 in the superficial layers of the conjunctival epithelium were also noted. These data demonstrate that ocular exposure of rabbits to SM causes significant damage not only to the cornea, but to the eyelid and conjunctiva, suggesting multiple targets within the eye that should be assessed when evaluating the efficacy of potential countermeasures.


Asunto(s)
Sustancias para la Guerra Química/toxicidad , Conjuntiva/patología , Córnea/patología , Epitelio/patología , Células Caliciformes/patología , Gas Mostaza/toxicidad , Animales , Conjuntiva/efectos de los fármacos , Conjuntiva/metabolismo , Córnea/efectos de los fármacos , Córnea/metabolismo , Epitelio/efectos de los fármacos , Epitelio/metabolismo , Células Caliciformes/efectos de los fármacos , Células Caliciformes/metabolismo , Masculino , Mucina-1/metabolismo , Mucina 4/metabolismo , Conejos
19.
Biomed Pharmacother ; 139: 111675, 2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-33965725

RESUMEN

We previously profiled the chemical composition of wax apple, Syzygium samarangense, leaf extract using HR-LC-MS/MS and reported its antioxidant, hepatoprotective and antitrypanosomal activities. The plant is widely used in traditional medicine to cure several ailments like bronchitis, asthma, diabetes, fever, pathogenic infections, gut spasms, as well as renal diseases. However, neither the gastroprotective effects nor the underlying mechanisms were explored. Here, we investigated the gastroprotective potential of the leaf extract on indomethacin-induced gastric ulcer in rats and explored the involved mechanism(s) of action. Administration of indomethacin significantly increased the ulcer index, mucosal injury, the gastric levels of the inflammatory markers nuclear factor kabba B-p65(NF-κB p65), myeloperoxidase (MPO), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), lipid peroxidation product, malondialdehyde (MDA) and Caspase-3 expression. It reduced the gastric levels of the endogenous antioxidants glutathione as well peroxidase (GPx), reduced glutathione (GSH) and the gastric mucosal protective factors, mucus secretion and goblet cells. Pretreatment with the leaf extract displayed a prominent decrease in the ulcer index, inflammatory cell infiltration, inflammatory markers, MDA, protein expression of Caspase-3 and a significant increase in the gastric levels of the endogenous antioxidants, mucus content and goblet cell proliferation when compared to the indomethacin group. The individual secondary metabolites of the extract exhibited low binding energy when docked into the prostaglandin receptors EP3 and EP4. This study revealed the gastroprotective effect of S. samarangense on indomethacin-induced gastric ulcer in rats. The gastroprotective effects might be attributed to cytoprotective, antioxidant, anti-inflammatory and antiapoptotic activities with a possible potential of activating EP3 and EP4 receptors. In conclusion, S. samarangense has a promising potential in the prevention of NSAIDs-induced ulcers.


Asunto(s)
Antiinflamatorios no Esteroideos , Indometacina , FN-kappa B/efectos de los fármacos , Extractos Vegetales/uso terapéutico , Hojas de la Planta/química , Transducción de Señal/efectos de los fármacos , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/prevención & control , Syzygium/química , Animales , Antioxidantes/metabolismo , Apoptosis/efectos de los fármacos , Biomarcadores , Células Caliciformes/efectos de los fármacos , Masculino , Simulación del Acoplamiento Molecular , Moco/metabolismo , Estrés Oxidativo/efectos de los fármacos , Sustancias Protectoras/uso terapéutico , Ratas , Ratas Wistar
20.
Front Immunol ; 12: 670279, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34054843

RESUMEN

The inclusion of a medicinal plant leaf extract (MPLE) from sage (Salvia officinalis) and lemon verbena (Lippia citriodora), rich in verbascoside and triterpenic compounds like ursolic acid, was evaluated in gilthead seabream (Sparus aurata) fed a low fishmeal-based diet (48% crude protein, 17% crude fat, 21.7 MJ kg-1, 7% fishmeal, 15% fish oil) for 92 days. In particular, the study focused on the effect of these phytogenic compounds on the gut condition by analyzing the transcriptomic profiling (microarray analysis) and histological structure of the intestinal mucosa, as well as the histochemical properties of mucins stored in goblet cells. A total number of 506 differentially expressed genes (285 up- and 221 down-regulated) were found when comparing the transcriptomic profiling of the intestine from fish fed the control and MPLE diets. The gut transcripteractome revealed an expression profile that favored biological mechanisms associated to the 1) immune system, particularly involving T cell activation and differentiation, 2) gut integrity (i.e., adherens and tight junctions) and cellular proliferation, and 3) cellular proteolytic pathways. The histological analysis showed that the MPLE dietary supplementation promoted an increase in the number of intestinal goblet cells and modified the composition of mucins' glycoproteins stored in goblet cells, with an increase in the staining intensity of neutral mucins, as well as in mucins rich in carboxylated and weakly sulfated glycoconjugates, particularly those rich in sialic acid residues. The integration of transcriptomic and histological results showed that the evaluated MPLE from sage and lemon verbena is responsible for the maintenance of intestinal health, supporting gut homeostasis and increasing the integrity of the intestinal epithelium, which suggests that this phytogenic may be considered as a promising sustainable functional additive for aquafeeds.


Asunto(s)
Inmunidad Mucosa/efectos de los fármacos , Factores Inmunológicos/farmacología , Uniones Intercelulares/efectos de los fármacos , Mucosa Intestinal/efectos de los fármacos , Extractos Vegetales/farmacología , Salvia officinalis , Dorada , Linfocitos T/efectos de los fármacos , Verbenaceae , Uniones Adherentes/efectos de los fármacos , Uniones Adherentes/metabolismo , Animales , Diferenciación Celular/efectos de los fármacos , Células Caliciformes/efectos de los fármacos , Células Caliciformes/inmunología , Células Caliciformes/metabolismo , Factores Inmunológicos/aislamiento & purificación , Uniones Intercelulares/metabolismo , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Activación de Linfocitos/efectos de los fármacos , Mucinas/metabolismo , Permeabilidad/efectos de los fármacos , Extractos Vegetales/aislamiento & purificación , Hojas de la Planta , Salvia officinalis/química , Dorada/genética , Dorada/inmunología , Dorada/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Uniones Estrechas/efectos de los fármacos , Uniones Estrechas/metabolismo , Transcriptoma , Verbenaceae/química
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