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Hepatopatías , Neutrófilos , Humanos , Inflamación , Infiltración Neutrófila , Enfermedad CrónicaRESUMEN
In response to microbiota colonization, the intestinal epithelia of many animals exhibit increased rates of cell proliferation. We used gnotobiotic larval zebrafish to identify a secreted factor from the mutualist Aeromonas veronii that is sufficient to promote intestinal epithelial cell proliferation. This secreted A. veronii protein is a homologue of the Vibrio cholerae GlcNAc binding protein GbpA, which was identified as a chitin-binding colonization factor in mice. GbpA was subsequently shown to be a lytic polysaccharide monooxygenase (LPMO) that can degrade recalcitrant chitin. Our phenotypic characterization of gbpA deficient A. veronii found no alterations in these cells' biogeography in the zebrafish intestine and only a modest competitive disadvantage in chitin-binding and colonization fitness when competed against the wild-type strain. These results argue against the model of GbpA being a secreted adhesin that binds simultaneously to bacterial cells and GlcNAc, and instead suggests that GbpA is part of a bacterial GlcNAc utilization program. We show that the host proliferative response to GbpA occurs in the absence of bacteria upon exposure of germ-free zebrafish to preparations of native GbpA secreted from either A. veronii or V. cholerae or recombinant A. veronii GbpA. Furthermore, domain 1 of A. veronii GbpA, containing the predicted LPMO activity, is sufficient to stimulate intestinal epithelial proliferation. We propose that intestinal epithelial tissues upregulate their rates of renewal in response to secreted bacterial GbpA proteins as an adaptive strategy for coexisting with bacteria that can degrade glycan constituents of the protective intestinal lining.
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Aeromonas , Microbioma Gastrointestinal , Animales , Ratones , Proteínas Portadoras , Pez Cebra , Intestinos , Proliferación Celular , Proteínas Bacterianas , QuitinaRESUMEN
INTRODUCTION: Since the eight edition of the Union for International Cancer Control and American Joint Committee on Cancer TNM classification system, the primary tumor pT stage is determined on the basis of presence and size of the invasive components. The aim of this study was to identify histologic features in tumors with lepidic growth pattern which may be used to establish criteria for distinguishing invasive from noninvasive areas. METHODS: A Delphi approach was used with two rounds of blinded anonymized analysis of resected nonmucinous lung adenocarcinoma cases with presumed invasive and noninvasive components, followed by one round of reviewer de-anonymized and unblinded review of cases with known outcomes. A digital pathology platform was used for measuring total tumor size and invasive tumor size. RESULTS: The mean coefficient of variation for measuring total tumor size and tumor invasive size was 6.9% (range: 1.7%-22.3%) and 54% (range: 14.7%-155%), respectively, with substantial variations in interpretation of the size and location of invasion among pathologists. Following the presentation of the results and further discussion among members at large of the International Association for the Study of Lung Cancer Pathology Committee, extensive epithelial proliferation (EEP) in areas of collapsed lepidic growth pattern is recognized as a feature likely to be associated with invasive growth. The EEP is characterized by multilayered luminal epithelial cell growth, usually with high-grade cytologic features in several alveolar spaces. CONCLUSIONS: Collapsed alveoli and transition zones with EEP were identified by the Delphi process as morphologic features that were a source of interobserver variability. Definition criteria for collapse and EEP are proposed to improve reproducibility of invasion measurement.
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Adenocarcinoma del Pulmón , Adenocarcinoma , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/patología , Reproducibilidad de los Resultados , Invasividad Neoplásica/patología , Adenocarcinoma del Pulmón/patología , Adenocarcinoma/patología , Estadificación de NeoplasiasRESUMEN
Background: Our study has immunohistochemically examined T cells localization and number as well as proliferative activity level for the bulbourethral gland epithelium in men of different ages, using monoclonal antibodies against CD45RO and proliferating cell nuclear antigen (PCNA). Results: We have found that the T cells have been localized mainly in excretory ducts epithelium of the glands in any age group, meanwhile their relative number varies with age. The excretory ducts epithelium has shown a high proliferative activity when in acini the PCNA index has been low. Postnatal dynamics of the epithelium proliferative activity positively correlates with age-related density fluctuations in lymphocytic infiltration of the glands. Conclusions: We consider that intraepithelial T cells may contribute to the regulation of epithelial cells proliferation in the bulbourethral glands.
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As a microbial tryptophan metabolite, indole-3-carboxaldehyde (ICA) has been suggested to confer benefits to host, such as regulation of intestinal barrier function. This study aimed to elucidate the role of ICA in modulating intestinal homeostasis via using a weaned pig model. Twenty-four weaned piglets were randomly allocated into three groups: the control group (a basal diet), ICA100 group (the basal diet supplemented with 100 mg/kg ICA), and ICA200 group (the basal diet supplemented with 200 mg/kg ICA). The experiment lasted 14 d, and pigs from the control and ICA100 groups were slaughtered. The results showed no significant differences in the average daily gain (ADG) and average daily feed intake (ADFI) among the three groups (P > 0.05). However, the ICA100 group had a lower feed to gain ratio (F:G) (P < 0.05). Dietary ICA supplementation did not alter the villus height, crypt depth, and villus height/crypt depth ratio in the small intestine, and did not change the intestinal permeability and antioxidant parameters (P > 0.05). Intriguingly, ICA treatment significantly increased the jejunal, ileal and colonic indexes in piglets (P < 0.05). Besides, the expression of proliferating cell nuclear antigen (PCNA) in the intestine was up-regulated by ICA treatment. Moreover, in vitro experiments demonstrated that 15 µM ICA significantly accelerated the proliferation activity of IPEC-J2 cells, and increased the expression of the ICA receptor aryl hydrocarbon receptor (AHR) and the proliferation markers PCNA and Cyclin D1 (P < 0.05). In addition, dietary ICA supplementation modulated the intestinal flora, increasing the richness estimators and diversity index, decreasing the abundances of phylum Fibrobacterota and genera Alloprevotella, Prevotella, and Parabacteroides, and enriching the abundance of genera Butyrivibrio. These data reveal a beneficial role for the microbial metabolite ICA on intestinal epithelial proliferation, rather than intestinal barrier function, in weaned piglets.
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INTRODUCTION: Our breast screening unit was identified as high outlier for B3 lesions with a low positive predictive value (PPV) compared to the England average. This prompted a detailed internal audit and review of B3 lesions and their outcomes to identify causes and address any variation in practice. PATIENTS AND METHODS: The B3 rate was calculated in 4168 breast core biopsies from 2019, using the subsequent excision to determine the PPV. Atypical intraductal epithelial proliferation (AIDEP) cases were subject to microscopic review to reassess the presence of atypia against published criteria. The B3 rate was re-audited in 2021, and the results compared. RESULTS: Screening cases had a high B3 rate of 12.4% (30% above the national average), and a PPV of 7.7% (9.7% with atypia). AIDEP was identified as a possible cause of this outlier status. On review and by consensus, AIDEP was confirmed in only 66% of cases reported as such, 17% were downgraded, and 16% did not reach consensus, the latter highlighting the difficulty and subjectivity in diagnosis of these lesions. Repeat audit of B3 rates after this extended review revealed a reduction from 12.4% to 9.11%, which is more in line with national standards. CONCLUSION: Benchmarking against national reporting standards is critical for service improvement. Through a supportive environment, team working, rigorous internal review and adherence to guidelines, interobserver variation and outlier status in breast pathology screening outliers can both be addressed. This study can serve as a model to other outlier units to identify and tackle underlying causes.
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Neoplasias de la Mama , Mamografía , Benchmarking , Biopsia con Aguja Gruesa , Mama/patología , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/patología , Femenino , HumanosRESUMEN
Parkinson's disease (PD) is an age-related neurodegenerative disease, mainly characterized by the loss of dopaminergic (DA) neurons in the substantia nigra. Several non-motor symptoms, including those associated with gastrointestinal dysfunction, precede the classical motor symptoms in PD. However, the mechanisms underlying gastrointestinal dysfunction in the prodromal phase of PD remain elusive. Here, we investigated the contribution of the central DA system to cell proliferation in the colonic epithelium. Degeneration of nigrostriatal DA pathway induced by striatal 6-hydroxydopamine (6-OHDA) injection resulted in a marked reduction in cell proliferation in the colonic epithelium as assessed by Ki-67 and bromodeoxyuridine labeling assays. RNA-sequencing analysis confirmed the suppression of cell cycle-related gene expression in the colonic epithelium of 6-OHDA-lesioned mice. Mesencephalic DA neuron degeneration also caused the gut microbiota dysbiosis. Moreover, 6-OHDA-lesioned mice showed profoundly increased vulnerability to dextran sulfate sodium-induced colitis. Together, our study uncovers a crucial role for the integrity of nigral DA neurons in the maintenance of colonic epithelial cell homeostasis. Our data also provide a new strategy for protecting intestinal homeostasis in PD.
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Enfermedades Neurodegenerativas , Enfermedad de Parkinson , Animales , Proliferación Celular , Modelos Animales de Enfermedad , Dopamina/metabolismo , Neuronas Dopaminérgicas/metabolismo , Epitelio/metabolismo , Ratones , Enfermedades Neurodegenerativas/metabolismo , Oxidopamina , Sustancia Negra/metabolismoRESUMEN
PURPOSE: To compare the clinical, optical coherence tomography (OCT) features, and surgical outcomes of lamellar macular hole (LMH) depending on the presence of epimacular membrane proliferation (EMPF). METHODS: This retrospective chart review included 112 eyes with LMH. The patients were divided into two groups depending on the presence of EMPF. Group 1 had LMH without EMPF and Group 2 had LMH with EMPF. The best-corrected visual acuity was recorded and OCT scans were obtained. RESULTS: Lamellar macular hole without and with EMPF was noted in 62 (55%) and 50 (45%) eyes, respectively. The presence of EMPF was associated with lower presenting visual acuity (P = 0.049), wider LMH size at the largest diameter on the horizontal scan (P = 0.001), thinner residual retinal tissue (P = < 0.0001), and larger IS-OS defects (P = < 0.0001) as compared to the non-EMPF group. Of the 112 eyes, 18 eyes underwent surgery for LMH. Seven eyes had EMPF and the remaining eleven did not have EMPF. The average follow-up time for patients post-surgery and under observation was 16.8 and 24.1 weeks, respectively. A significant improvement in visual acuity was noted in the operated eyes with no EMPF as compared to the eyes with EMPF (P = 0.008). Worsening visual acuity (P = 0.021) was noted in eyes with LMH associated with EMPF which did not undergo surgery. Eyes with LMH and no EMPF, which were not operated on showed a minimal negative change in visual acuity. CONCLUSION: LMH with EMPF showed a higher association with accompanying ellipsoid zone disruption. Better anatomical and functional outcomes were achieved in those eyes that underwent surgery for LMH with no presence of EMPF and ellipsoid zone defect.
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Disturbance in the proteolytic process is one of the malignant signs of tumors. Proteolysis is highly orchestrated by cysteine cathepsin and its inhibitors. Cystatin-B (CSTB) is a general cysteine cathepsin inhibitor that prevents cysteine cathepsin from leaking from lysosomes and causing inappropriate proteolysis. Our study found that CSTB was downregulated in both oral squamous cell carcinoma (OSCC) tissues and cells compared with normal controls. Immunohistochemical analysis showed that CSTB was mainly distributed in the epithelial structure of OSCC tissues, and its expression intensity was related to the grade classification. A correlation analysis between CSTB and clinical prognosis was performed using gene expression data and clinical information acquired from The Cancer Genome Atlas (TCGA) database. Patients with lower expression levels of CSTB had shorter disease-free survival times and poorer clinicopathological features (e.g., lymph node metastases, perineural invasion, low degree of differentiation, and advanced tumor stage). OSCC cell models overexpressing CSTB were constructed to assess the effects of CSTB on malignant biological behaviors and upregulation of CSTB inhibited cell proliferation, migration, and invasion in vitro. Weighted gene correlation network analysis (WGCNA) and gene set enrichment analysis (GSEA) were performed based on the TCGA data to explore potential mechanisms, and CSTB appeared to correlate with squamous epithelial proliferation-differentiation processes, such as epidermal cell differentiation and keratinization. Moreover, in WGCNA, the gene module most associated with CSTB expression (i.e., the brown module) was also the one most associated with grade classification. Upregulation of CSTB promoted the expression levels of markers (LOR, IVL, KRT5/14, and KRT1/10), reflecting a tendency for differentiation and keratinization in vitro. Gene expression profile data of the overexpressed CSTB cell line were obtained by RNA sequencing (RNA-seq) technology. By comparing the GSEA enrichment results of RNA-seq data (from the OSCC models overexpressing CSTB) and existing public database data, three gene sets (i.e., apical junction, G2/M checkpoint, etc.) and six pathways (e.g., NOTCH signaling pathway, glycosaminoglycan degradation, mismatch repair, etc.) were enriched in the data from both sources. Overall, our study shows that CSTB is downregulated in OSCC and might regulate the malignant characteristics of OSCC via the epithelial proliferation/differentiation program.
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BACKGROUND AND PURPOSE: Glucocorticoids are the first line treatment for the flare-ups of inflammatory bowel disease, but they have significant limitations. The objective of this study is to investigate whether glucocorticoid epithelial actions contribute to such limitations. EXPERIMENTAL APPROACH: Intestinal epithelium glucocorticoid receptor knockout mice (Nr3c1ΔIEC ) received dextran sulfate sodium (DSS) to induce colitis. Inflammatory status was assessed by morphological and biochemical methods, and corticoid production was measured in colonic explants. Some mice were administered budesonide. KEY RESULTS: After 7 days of DSS Nr3c1ΔIEC , mice exhibited 23.1% lower disease activity index (DAI) and 37% lower diarrheal score than WT mice, with decreased weight loss in days 5-7 of colitis, attenuated tissue damage, reduced colonic expression of S100A9 and STAT3 phosphorylation, and a better overall state. Ki67 immunoreactivity was increased at the crypt base, indicating enhanced epithelial proliferation. Mice administered budesonide (6 µg·day-1 PO) showed modest antiinflammatory effects but increased weight loss, which was prevented in knockout mice. Epithelial deletion of the glucocorticoid receptor also protected mice in a protracted colitis protocol. Conversely, knockout mice presented a worse status compared to the control group at 1 day post DSS. In a separate experiment, colonic corticosterone production was shown to be significantly increased in knockout mice at 7 days of colitis but not at earlier stages. CONCLUSIONS AND IMPLICATIONS: The intestinal epithelial glucocorticoid receptor has deleterious effects in experimental colitis induced by DSS, probably related to inhibition of epithelial proliferative responses leading to impaired wound healing and reduced endogenous corticosterone production.
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Colitis , Receptores de Glucocorticoides , Animales , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/genética , Colon , Sulfato de Dextran , Modelos Animales de Enfermedad , Inflamación , Mucosa Intestinal , Intestinos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Glucocorticoides/genéticaRESUMEN
BACKGROUND: Sphingosine-1-phosphate receptor 2 (S1PR2) mediates pleiotropic functions encompassing cell proliferation, survival, and migration, which become collectively de-regulated in cancer. Information on whether S1PR2 participates in colorectal carcinogenesis/cancer is scanty, and we set out to fill the gap. METHODS: We screened expression changes of S1PR2 in human CRC and matched normal mucosa specimens [N = 76]. We compared CRC arising in inflammation-driven and genetically engineered models in wild-type (S1PR2+/+) and S1PR2 deficient (S1PR2-/-) mice. We reconstituted S1PR2 expression in RKO cells and assessed their growth in xenografts. Functionally, we mimicked the ablation of S1PR2 in normal mucosa by treating S1PR2+/+ organoids with JTE013 and characterized intestinal epithelial stem cells isolated from S1PR2-/-Lgr5-EGFP- mice. RESULTS: S1PR2 expression was lost in 33% of CRC; in 55%, it was significantly decreased, only 12% retaining expression comparable to normal mucosa. Both colitis-induced and genetic Apc+/min mouse models of CRC showed a higher incidence in size and number of carcinomas and/or high-grade adenomas, with increased cell proliferation in S1PR2-/- mice compared to S1PR2+/+ controls. Loss of S1PR2 impaired mucosal regeneration, ultimately promoting the expansion of intestinal stem cells. Whereas its overexpression attenuated cell cycle progression, it reduced the phosphorylation of AKT and augmented the levels of PTEN. CONCLUSIONS: In normal colonic crypts, S1PR2 gains expression along with intestinal epithelial cells differentiation, but not in intestinal stem cells, and contrasts intestinal tumorigenesis by promoting epithelial differentiation, preventing the expansion of stem cells and braking their malignant transformation. Targeting of S1PR2 may be of therapeutic benefit for CRC expressing high Lgr5.
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Neoplasias Colorrectales/metabolismo , Células Epiteliales/metabolismo , Receptores de Esfingosina-1-Fosfato/metabolismo , Células Madre/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Animales , Proliferación Celular/fisiología , Neoplasias Colorrectales/patología , Femenino , Genes Supresores de Tumor , Humanos , Masculino , Ratones , Persona de Mediana EdadRESUMEN
Inflammatory bowel diseases are debilitating illnesses characterized by severe inflammation of the gastrointestinal tract. Treatments currently available are expensive and ineffective. We here investigated the role of red-light emitting diode (LED) on dextran sodium sulfate (DSS)-induced colitis. DSS was added to the drinking water of male mice at days 0, 2, 4 and withdrawn at day 6. LED irradiation was performed daily for 90s from day 6 to 9 on the right and left sides of the ventral surface and beside the external anal region. LED treatment decreased the amount of crypt dysplasia/edema, inflammatory infiltrates and ulcers, attenuated apoptosis and increased proliferation of crypt cells. Also, LED treatment induced expression of annexin A1 in the damaged epithelium, preserved the organization of claudin-1 and skewed cytokine profiling towards a more anti-inflammatory status. Thus, LED treatment promotes structural protection and modulates the inflammatory response, constituting a potential non-invasive and low-cost combined therapy to help patients achieve disease remission.
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Colitis/patología , Colitis/terapia , Sulfato de Dextran/farmacología , Fototerapia , Animales , Colitis/inducido químicamente , Mucosa Intestinal/patología , Mucosa Intestinal/efectos de la radiación , Masculino , Ratones , Ratones Endogámicos C57BL , Semiconductores , Resultado del TratamientoRESUMEN
OBJECTIVE: Wnt-ß-catenin signalling is essential for intestinal stem cells. Our aim was to investigate the relationship between intestinal stem cells and crypt fission which peaks during infancy. DESIGN: Duodenal biopsies were obtained during endoscopy to assess the severity of reflux oesophagitis of 15 infants, children and teenagers, which would not affect the duodenum. Samples of small intestine were also obtained from rats 7-72 days of life. Crypt fission was assessed using microdissection of 100 whole crypts and recording the percentage of bifid crypts. Intestinal LGR5+ stem cells were identified by in situ hybridisation. Rats were treated with Dickkopf to block Wnt-ß-catenin signalling. RESULTS: Crypt fission peaked during infancy before declining after 3-4 years in humans and after 21 days of life in rats. Occasional mitotic figures were seen in bifid crypts during early fission. Stem cells were elevated for a greater period during infancy and childhood in humans. Clustering of Paneth cells was present around the stem cells at the crypt base. Dickkopf reduced the number of stem cells and crypt fission to 45% and 29%, respectively, of control values, showing dependence of both crypt fission and Lgr5+ stem cells on Wnt signalling. However, Dickkopf did not decrease mitotic count per crypt, indicating a difference in signalling between stem cells and their progeny in the transit amplifying zone. CONCLUSION: Crypt fission peaks during infancy and is dependent on intestinal stem cells. This is relatively hidden by 'a cloak of invisibility' due to the low proliferation of stem cells.
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Mucosa Intestinal/crecimiento & desarrollo , Intestino Delgado/crecimiento & desarrollo , Células Madre/metabolismo , Adolescente , Animales , Biopsia , Proliferación Celular , Niño , Preescolar , Duodeno/patología , Esofagitis Péptica/diagnóstico , Esofagitis Péptica/patología , Humanos , Lactante , Mucosa Intestinal/citología , Mucosa Intestinal/patología , Intestino Delgado/citología , Células de Paneth/patología , Ratas , Índice de Severidad de la Enfermedad , Células Madre/patología , Vía de Señalización Wnt/genéticaRESUMEN
The use of diverse terminology may lead to inconsistent diagnosis and subsequent mistreatment of lesions within the proliferative verrucous leukoplakia (PVL) spectrum. The objectives of this study were: (a) to measure inter-observer variability between a variety of pathologists diagnosing PVL lesions; and (b) to evaluate the impact of diverse terminologies on understanding, interpretation, and subsequent treatment planning by oral and maxillofacial surgeons (OMFS). Six oral pathologists (OP) and six head and neck pathologists (HNP) reviewed 40 digitally scanned slides of PVL-type lesions. Inter-observer agreement on diagnoses was evaluated by Fleiss' kappa analysis. The most commonly used diagnostic terminologies were sent to ten OMFS to evaluate their resulting interpretations and potential follow-up treatment approaches. The overall means of the surgeons' responses were compared by Student t test. There was poor inter-observer agreement between pathologists on the diagnosis of PVL lesions (κ = 0.270), although there was good agreement (κ = 0.650) when diagnosing frankly malignant lesions. The lowest agreement was in diagnosing verrucous hyperplasia (VH) with/without dysplasia, atypical epithelial proliferation (AEP), and verrucous carcinoma (VC). The OMFS showed the lowest agreement on identical categories of non-malignant diagnoses, specifically VH and AEP. This study demonstrates a lack of standardized terminology and diagnostic criteria for the spectrum of PVL lesions. We recommend adopting standardized criteria and terminology, proposed and established by an expert panel white paper, to assist pathologists and clinicians in uniformly diagnosing and managing PVL spectrum lesions.
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Leucoplasia Bucal/diagnóstico , Patología Clínica/normas , Lesiones Precancerosas/diagnóstico , Carcinoma Verrugoso/diagnóstico , Humanos , Neoplasias de la Boca/diagnóstico , Variaciones Dependientes del Observador , Cirujanos Oromaxilofaciales/normas , Proyectos PilotoRESUMEN
Immunopathologic examination of the lungs of mouse models of experimental influenza virus infection provides new insights into the immune response in this disease. First, there is rapidly developing perivascular and peribronchial infiltration of the lung with T-cells. This is followed by invasion of T-cells into the bronchiolar epithelium, and separation of epithelial cells from each other and from the basement membrane leading to defoliation of the bronchial epithelium. The intraepithelial reaction may involve either CD8 or CD4 T-cytotoxic cells and is analogous to a viral exanthema of the skin, such as measles and smallpox, which occur when the immune response against these infections is activated and the infected cells are attacked by T-cytotoxic cells. Then there is formation of B-cell follicles adjacent to bronchi, i.e., induced bronchial associated lymphoid tissue (iBALT). iBALT reacts like the cortex of a lymph node and is a site for a local immune response not only to the original viral infection, but also related viral infections (heterologous immunity). Proliferation of Type II pneumocytes and/or terminal bronchial epithelial cells may extend into the adjacent lung leading to large zones filled with tumor-like epithelial cells. The effective killing of influenza virus infected epithelial cells by T-cytotoxic cells and induction of iBALT suggests that adding the induction of these components might greatly increase the efficacy of influenza vaccination.
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Modelos Animales de Enfermedad , Vacunas contra la Influenza/inmunología , Infecciones por Orthomyxoviridae/inmunología , Linfocitos T Citotóxicos/inmunología , Linfocitos T Reguladores/inmunología , Animales , Anticuerpos Antivirales/sangre , Bronquios/citología , Bronquios/inmunología , Bronquios/virología , Proliferación Celular , Diseño de Fármacos , Inmunidad Mucosa , Ratones , OrthomyxoviridaeRESUMEN
Emerging evidence indicates that gamma-aminobutyric acid (GABA) has many beneficial effects such as ameliorating immune and inflammatory response. But, here we reported that activation of GABAA receptors (GABAA Rs) aggravated dextran sulfate sodium (DSS)-induced colitis, although the expression of pro-inflammatory cytokines was inhibited. By contrast, blocking of GABAA Rs markedly alleviated DSS-induced colitis. Notably, GABAA Rs and glutamic acid decarboxylase 65/67 were significantly increased in colon mucosa of ulcerative colitis patients and the mouse model of colitis. Further studies showed that GABA treatment resulted in an increment of serum FITC-dextran following its oral administration, a decrement of transepithelial electrical resistance, and an increment of bacterial invasion, effects which were blocked by bicuculline. In addition, GABA inhibited the expression of tight junction proteins and mucin secretion in colitis colon. GABA also decreased the expression of ki-67 and increased cleaved-caspase 3 expression in intestinal epithelia. Our data indicate that the GABAA Rs activation within colon mucosa disrupts the intestinal barrier and increases the intestinal permeability which facilitates inflammatory reaction in colon. Meanwhile, the suppression effect of GABA on pro-inflammatory cytokines leads to insufficient bacteria elimination and further aggravated the bacteria invasion and inflammatory damage.
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Enfermedad Aguda , Colitis Ulcerosa/fisiopatología , Colon/inmunología , Progresión de la Enfermedad , Receptores de GABA-A/genética , Animales , Células CACO-2 , Caspasa 3/metabolismo , Colitis/inducido químicamente , Colitis/patología , Colitis Ulcerosa/microbiología , Colon/efectos de los fármacos , Citocinas/antagonistas & inhibidores , Citocinas/inmunología , Sulfato de Dextran , Modelos Animales de Enfermedad , Glutamato Descarboxilasa/metabolismo , Células HT29 , Humanos , Inflamación/patología , Antígeno Ki-67/metabolismo , Ratones , Ratones Endogámicos C57BL , Mucinas/metabolismo , Permeabilidad , Uniones Estrechas/efectos de los fármacos , Ácido gamma-Aminobutírico/administración & dosificaciónRESUMEN
INTRODUCTION: Oral mucositis is known to hamper the quality of life in patients treated for oral cancer. Many pharmacological agents have been tried and tested in its management, especially vitamin supplements including A, E and their combinations. AIM: A Meta-analysis was carried out to evaluate the efficacy of vitamins individually used for prevention or treatment of oral mucositis separately for chemotherapy, concurrent chemo radiotherapy, radiotherapy and Haematopoietic Stem Cell Transplantation (HSCT) individuals. MATERIALS AND METHODS: The literature study was done using PUBMED, MEDLINE, EBSCO, GOOGLE SCHOLAR and COCHRANE data bases with keywords vitamin A, vitamin E, vitamin B, vitamin C, Oral mucositis, Chemotherapy, Radiotherapy, Concurrent chemo radiotherapy and Haematopoietic stem cell transplantation individually, from the year 1980 to 2016. Only randomized controlled trials were included. The data was extracted, tabulated and was subjected to statistical analysis with CI of 95%. RESULTS: Among 201 subjects the analysis clearly demonstrated a male predominance to females in studies where male to female ratio was given. Out of 8 studies, 2 were studies in children and remaining 6 studies concentrated on adult population. WHO and NCI-CTC criteria were followed except for one study which used customised assessment. A meta-analysis was performed regarding usage of topical medication of Vitamin E group in all three cancer treatment modalities, which showed significant reduction in oral mucositis (p < 0.001). There was reduced oral mucositis in a small group of patients with Vitamin A when compared to controls. No information on the agent used for chemotherapy, the dose of radiotherapy and the type of tumours in 4 studies. CONCLUSION: Topical Vitamin E had performed better on oral mucositis than Vitamin E systemic administration. Though the efficacy of topical treatment with Vitamin A showed reduction in oral mucositis, it was evaluated in a very small sample which cannot be attributed to a larger sitting.
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BACKGROUND: The purpose of this study was to examine proliferative and apoptotic activity in relation with BRCA1 expression in ovarian epithelial inclusions (OEIs), the putative precursor lesions of ovarian epithelial cancer (OEC). METHODS: Benign ovaries from 95 patients were examined. Dual immunohistochemical staining for both BRCA1 and MIB-1 were performed to examine the relationship between BRCA1 and MIB-1 in OEI cells. Apoptotic activity was assessed on the parallel tissue sections by using TUNEL assay. Patients' age, menstrual phase and menopausal status were analyzed. RESULTS: OEIs were present in the ovaries of 53% of the patients. OEIs were less frequently found in premenopausal (45%) than postmenopausal women (58%). BRCA1 and MIB-1 were found in 27 and 47% of the OEI-containing ovaries, respectively. All BRCA1 positive OEI cells are MIB-1 positive with dual staining method, although overall the percentage of positive cells was small. No significant difference was found for BRCA1 and MIB-1 expression in OEIs between menopausal status and menstrual phases. Apoptosis containing OEIs were seen in 70% of the ovaries. Compared to OEIs in proliferative menstrual phase and premenopausal status, significantly more apoptosis was found in OEIs from secretory phase and postmenopausal women. A small fraction of the epithelial cells within OEIs are proliferating or dying. CONCLUSIONS: Low estrogen and/or high progesterone levels may promote OEI cell turnover via induction of apoptosis. Imbalance between cell proliferation and death within OEIs under influence of hormones may play a role in the ovarian epithelial tumorigenesis.
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Apoptosis , Proteína BRCA1/metabolismo , Neoplasias Glandulares y Epiteliales/metabolismo , Neoplasias Ováricas/metabolismo , Ovario/metabolismo , Ovario/patología , Lesiones Precancerosas/metabolismo , Adulto , Anciano , Apoptosis/genética , Proteína BRCA1/genética , Biomarcadores , Carcinoma Epitelial de Ovario , Línea Celular Tumoral , Proliferación Celular , Femenino , Expresión Génica , Humanos , Inmunohistoquímica , Antígeno Ki-67/metabolismo , Persona de Mediana Edad , Neoplasias Glandulares y Epiteliales/genética , Neoplasias Glandulares y Epiteliales/patología , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Lesiones Precancerosas/genética , Lesiones Precancerosas/patología , Adulto JovenRESUMEN
OBJECTIVE: We tested the ability of Notch pathway receptors Notch1 and Notch2 to regulate stem and epithelial cell homoeostasis in mouse and human gastric antral tissue. DESIGN: Mice were treated with the pan-Notch inhibitor dibenzazepine (DBZ) or inhibitory antibodies targeting Notch1 and/or Notch2. Epithelial proliferation, apoptosis and cellular differentiation were measured by histological and molecular approaches. Organoids were established from mouse and human antral glands; growth and differentiation were measured after treatment with Notch inhibitors. RESULTS: Notch1 and Notch2 are the predominant Notch receptors expressed in mouse and human antral tissue and organoid cultures. Combined inhibition of Notch1 and Notch2 in adult mice led to decreased epithelial cell proliferation, including reduced proliferation of LGR5 stem cells, and increased apoptosis, similar to the response to global Notch inhibition with DBZ. Less pronounced effects were observed after inhibition of individual receptors. Notch pathway inhibition with DBZ or combined inhibition of Notch1 and Notch2 led to increased differentiation of all gastric antral lineages, with remodelling of cells to express secretory products normally associated with other regions of the GI tract, including intestine. Analysis of mouse and human organoids showed that Notch signalling through Notch1 and Notch2 is intrinsic to the epithelium and required for organoid growth. CONCLUSIONS: Notch signalling is required to maintain gastric antral stem cells. Notch1 and Notch2 are the primary Notch receptors regulating epithelial cell homoeostasis in mouse and human stomach.