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1.
Medicine (Baltimore) ; 100(1): e24093, 2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33429774

RESUMO

RATIONALE: Henoch-Schönlein Purpura (HSP) is an acute small vessel vasculitis. It is the most common vasculitis in children. In majority of the cases, the disease is self-limited. Relapses can occur, in particular during the first year of the disease. There is no consensus on a specific treatment. The efficacy and safety of steroidal treatment in treating HSP is still controversial. Immunosuppressive treatment of HSP nephritis is used in patients with severe renal involvement (nephrotic range proteinuria and/or progressive renal impairment). The literature on immunosuppressive treatment of severe HSP without kidney involvement is scanty. PATIENTS CONCERNS: We report 2 case reports of 2 adolescents affected from Henoch-Schönlein Purpura and severe gastrointestinal involvement. Both patients presented a poor response to steroids treatment. DIAGNOSES: The diagnosis of HSP was made according to the diagnostic criteria published by European League against Rheumatism and Pediatric Rheumatology European Society in 2006. INTERVENTIONS: In consideration of the recurrence of the Henoch Schönlein Purpura and the gastrointestinal involvement, we decided to start Mycophenolate Mofetil treatment. OUTCOMES: In both patients all clinical manifestations resolved in few days. LESSONS: In our cases of HSP with gastrointestinal involvement Mycophenolate Mofetil treatment has been very effective. This experience teaches us that immunosuppressive agents may be very useful to induce and maintain remission not only in renal involvement, but in all cases of persistent, recurrent, or complicated Henoch Schönlein Purpura in children.


Assuntos
Trato Gastrointestinal/efeitos dos fármacos , Ácido Micofenólico/uso terapêutico , Púrpura de Schoenlein-Henoch/tratamento farmacológico , Adolescente , Criança , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Trato Gastrointestinal/fisiopatologia , Humanos , Masculino , Ácido Micofenólico/farmacologia , Púrpura de Schoenlein-Henoch/fisiopatologia , Recidiva
2.
Nat Rev Endocrinol ; 17(3): 162-175, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33495605

RESUMO

Therapeutic approaches to the treatment of type 2 diabetes mellitus that are designed to increase insulin secretion either directly target ß-cells or indirectly target gastrointestinal enteroendocrine cells (EECs), which release hormones that modulate insulin secretion (for example, incretins). Given that ß-cells and EECs both express a large array of G protein-coupled receptors (GPCRs) that modulate insulin secretion, considerable research and development efforts have been undertaken to design therapeutic drugs targeting these GPCRs. Among them are GPCRs specific for free fatty acid ligands (lipid GPCRs), including free fatty acid receptor 1 (FFA1, otherwise known as GPR40), FFA2 (GPR43), FFA3 (GPR41) and FFA4 (GPR120), as well as the lipid metabolite binding glucose-dependent insulinotropic receptor (GPR119). These lipid GPCRs have demonstrated important roles in the control of islet and gut hormone secretion. Advances in lipid GPCR pharmacology have led to the identification of a number of synthetic agonists that exert beneficial effects on glucose homeostasis in preclinical studies. Yet, translation of these promising results to the clinic has so far been disappointing. In this Review, we present the physiological roles, pharmacology and clinical studies of these lipid receptors and discuss the challenges associated with their clinical development for the treatment of type 2 diabetes mellitus.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Lipídeos de Membrana/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Animais , Sistemas de Liberação de Medicamentos/tendências , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/metabolismo , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/metabolismo
3.
Ecotoxicol Environ Saf ; 210: 111903, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33429322

RESUMO

A diverse and large community of gut microbiota reside in the intestinal tract of various organisms and play important roles in metabolism and immune homeostasis of its host. The disorders of microbiota-host interaction have been closely associated with numerous chronic inflammatory and metabolic diseases, including inflammatory bowel disease and type 2 diabetes. The accumulating evidence has shown that fine particulate matter (PM2.5) exposure contributes to the diabetes, atherosclerosis and inflammatory bowel diseases; however, few studies have explored the impact of inhaled diesel PM2.5 on gut microbiota in vivo. In this study, C57BL/6J mice were exposed to diesel PM2.5 for 14 days via intratracheal instillation, and colon tissues and feces were harvested for microbiota analysis. Using high-throughput sequencing technology, we observed that intratracheally instillated diesel PM2.5 significantly altered the gut microbiota diversity and community. At the phylum and genus levels, principal coordinate analysis (PCoA) and principal component analysis (PCA) indicated pronounced segregation of microbiota compositions, which were further confirmed by ß diversity analysis. As the most affected phylum, Bacteroidetes was greatly diminished by diesel PM2.5. On the genus level, Escherichia, Parabacteroides, Akkermansia, and Oscillibacter were significantly elevated by diesel PM2.5 exposure. Our findings provided clear evidence that exposure to diesel PM2.5 via intratracheal instillation deteriorated the gastrointestinal (GI) tract and significantly altered the structure and composition of gut microbiota, which might subsequently contribute to the developmental abnormalities of inflammation, immunity and metabolism.


Assuntos
Poluentes Atmosféricos/toxicidade , Microbioma Gastrointestinal/efeitos dos fármacos , Material Particulado/toxicidade , Administração por Inalação , Animais , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/microbiologia , Masculino , Camundongos Endogâmicos C57BL
5.
Mutat Res ; 786: 108324, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33339576

RESUMO

Severe gastrointestinal (GI) toxicity is a common side effect after platinum-based chemotherapy. The incidence and severity of GI toxicity vary among patients with the same chemotherapy. Genetic factors involved in platinum transport, metabolism, detoxification, DNA repair, cell cycle control, and apoptosis pathways may account for the interindividual difference in GI toxicity. The influence of gene polymorphisms in the platinum pathway on GI toxicity has been extensively analyzed. Variations in study sample size, ethnicity, design, treatment schedule, dosing, endpoint definition, and assessment of toxicity make it difficult to precisely interpret the results. Hence, we conducted a review to summarize the most recent pharmacogenomics studies of GI toxicity in platinum-based chemotherapy and identify the most promising avenues for further research.


Assuntos
Antineoplásicos/toxicidade , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Trato Gastrointestinal/efeitos dos fármacos , Farmacogenética , Platina/toxicidade , Polimorfismo Genético , Reparo do DNA , Tratamento Farmacológico , Genótipo , Humanos , Testes Farmacogenômicos , Fenótipo
6.
Nat Commun ; 11(1): 5773, 2020 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-33188211

RESUMO

Beneficial modulation of the gut microbiome has high-impact implications not only in humans, but also in livestock that sustain our current societal needs. In this context, we have tailored an acetylated galactoglucomannan (AcGGM) fibre to match unique enzymatic capabilities of Roseburia and Faecalibacterium species, both renowned butyrate-producing gut commensals. Here, we test the accuracy of AcGGM within the complex endogenous gut microbiome of pigs, wherein we resolve 355 metagenome-assembled genomes together with quantitative metaproteomes. In AcGGM-fed pigs, both target populations differentially express AcGGM-specific polysaccharide utilization loci, including novel, mannan-specific esterases that are critical to its deconstruction. However, AcGGM-inclusion also manifests a "butterfly effect", whereby numerous metabolic changes and interdependent cross-feeding pathways occur in neighboring non-mannanolytic populations that produce short-chain fatty acids. Our findings show how intricate structural features and acetylation patterns of dietary fibre can be customized to specific bacterial populations, with potential to create greater modulatory effects at large.


Assuntos
Fibras na Dieta/farmacologia , Microbioma Gastrointestinal , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/microbiologia , Metabolismo Secundário , Acetilação/efeitos dos fármacos , Animais , Butiratos/metabolismo , Ceco/metabolismo , Dieta , Comportamento Alimentar/efeitos dos fármacos , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/efeitos dos fármacos , Genoma , Masculino , Mananas/farmacologia , Redes e Vias Metabólicas/efeitos dos fármacos , Metagenômica , Análise de Componente Principal , Proteoma/metabolismo , RNA Ribossômico 16S/genética , Metabolismo Secundário/efeitos dos fármacos , Suínos , Madeira/química
7.
Life Sci ; 261: 118460, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32961234

RESUMO

AIMS: The hyperpermeability of gut-vascular barrier (GVB) plays a role in gut-derived sepsis. The goal of this study was to evaluate if berberine might improve hepatic apolipoprotein M (ApoM) generation and raise plasma ApoM level to protect the compromised GVB. MATERIALS AND METHODS: The compromised GVB was induced by sepsis. Hepatic ApoM mRNA and phosphoenolpyruvate carboxykinase (PEPCK) mRNA and plasma ApoM level were assayed by qRT-PCR and ELISA, respectively. The permeability of intestinal capillary in vivo and of rat intestinal microvascular endothelial cells (RIMECs) in vitro was assayed by FITC-dextran. The blood glucose was detected by a glucometer. Plasma insulin, TNF-α and IL-1ß were assayed by ELISA. The plasmalemma vesicle-associated protein-1 (PV1), ß-catenin and occludin in RIMECs were assayed by Western blot. KEY FINDINGS: Sepsis decreased hepatic ApoM mRNA and plasma ApoM level, but raised hepatic PEPCK mRNA and plasma glucose, insulin, TNF-α, and IL-1ß levels. The increased vascular endothelial permeability was abrogated by recombinant rat ApoM in vivo or ApoM-bound S1P in vitro. ApoM-bound S1P decreased PV1 but increased occludin and ß-catenin expression in LPS-treated RIMECs. Berberine in a dose-dependent manner raised hepatic ApoM mRNA and plasma ApoM level, but decreased septic hyperglycemia, insulin resistance and plasma TNF-α and IL-1ß levels. Berberine reduced sepsis-induced PEPCK and TLR4 mRNA overexpression in the liver. SIGNIFICANCE: This study demonstrated berberine inhibited TLR4-mediated hyperglycemia, insulin resistance and proinflammatory molecule production, thereby increasing ApoM gene expression and plasma ApoM. Berberine protected the damaged GVB via modulation of ApoM/S1P pathway.


Assuntos
Apolipoproteínas M/metabolismo , Berberina/uso terapêutico , Permeabilidade Capilar/efeitos dos fármacos , Lisofosfolipídeos/metabolismo , Sepse/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Esfingosina/análogos & derivados , Animais , Berberina/farmacologia , Modelos Animais de Doenças , Trato Gastrointestinal/irrigação sanguínea , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/fisiopatologia , Células Hep G2 , Humanos , Masculino , Ratos Wistar , Sepse/metabolismo , Sepse/fisiopatologia , Esfingosina/metabolismo
8.
Medicine (Baltimore) ; 99(35): e21488, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871870

RESUMO

BACKGROUND: Celiac disease is an autoimmune enteropathy characterized by an aberrant immune response to ingested gluten in genetically predisposed individuals. Studies have pointed to a rising prevalence of celiac disease in recent decades. Changes in diet and use of medication that may impact the gut microbiome have been suggested as potential contributors. Exposure to protein pump inhibitors (PPIs) was recently found to be associated with an increased risk for subsequent diagnosis of celiac disease. We aimed to investigate potential mechanisms for this link by examining the relationship between PPI use and gluten-related immune responses in the context of changes in gut microbiome. METHODS: We performed a post hoc analysis of blood and fecal samples from a recent randomized trial in order to assess the potential association between PPI use and development of celiac disease serology in conjunction with alterations in gastrointestinal microbial composition. The study included 12 healthy participants who were administered a PPI (Omeprazole; 40 mg twice daily) for 4 or 8 weeks. RESULTS: The analysis did not reveal an overall significant change in levels of serologic markers of celiac disease for the study cohort in response to PPI treatment. However, one individual developed a marked increase in the celiac disease-specific autoantibody response to transglutaminase 2 in conjunction with enhanced immune reactivity to gluten during the trial. Genotyping revealed positivity for the celiac disease-associated HLA-DQ2 and -DQ8 alleles. Furthermore, the observed elevation in antibody responses was closely associated with a sharp increase in fecal abundance of bacteria of the order Actinomycetales. CONCLUSIONS: The results of this exploratory analysis support further investigation of molecular mechanisms involved in the contribution of PPIs to celiac disease risk through the potential enhancement of gluten immunopathology and changes in gut microbial population.


Assuntos
Doença Celíaca/sangue , Doença Celíaca/induzido quimicamente , Microbioma Gastrointestinal/efeitos dos fármacos , Omeprazol/efeitos adversos , Inibidores da Bomba de Prótons/efeitos adversos , Actinomycetales/crescimento & desenvolvimento , Adulto , Alelos , Doença Celíaca/epidemiologia , Doença Celíaca/metabolismo , Fezes/microbiologia , Feminino , Proteínas de Ligação ao GTP/sangue , Proteínas de Ligação ao GTP/efeitos dos fármacos , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/microbiologia , Genótipo , Glutens/efeitos adversos , Glutens/imunologia , Antígenos HLA-DQ/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Omeprazol/administração & dosagem , Omeprazol/uso terapêutico , Prevalência , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/uso terapêutico , Transglutaminases/sangue , Transglutaminases/efeitos dos fármacos
9.
J Anim Sci ; 98(9)2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32815992

RESUMO

Stress negatively affects the gastrointestinal tract (GIT) barrier function, resulting in compromised animal health. A deeper understanding of how diet and stress impacts the GIT barrier function in feedlot cattle is needed. Aspirin decreases mucus production and mucosal repair in the GIT and could be used as a model for GIT barrier dysfunction research. The objective of this study was to evaluate the effectiveness of aspirin to induce GIT barrier dysfunction in beef cattle. In experiment 1, sixteen crossbred heifers (425.0 ± 8.6 kg) were allotted to 0, 50, 100, or 200 mg/kg body weight (BW) aspirin doses based on BW. Experiment 1 consisted of two periods separated by 4 wk where four heifers per treatment received the same aspirin dose during each period. Heifers were fed a 49.4% corn silage and 50.6% concentrate diet. The 200 mg/kg BW aspirin treatment was dosed as a 100 mg/kg BW aspirin oral bolus 36 and 24 h prior to Cr-ethylenediaminetetraacetic acid (EDTA) dosing (1 liter; 180 mM). The 50 and 100 mg/kg BW aspirin treatments were dosed as an oral bolus 24 h prior to Cr-EDTA dosing. Urine was collected every 3 h for 48 h and analyzed for Cr. Serum was collected at 0 and 48 h and analyzed for lipopolysaccharide-binding protein (LBP), interleukin-6, serum amyloid A (SAA), haptoglobin, and aspartate aminotransferase. In experiment 2, sixteen crossbred steers (576.0 ± 14.2 kg) fed a similar diet were allotted by BW to the 0 and 200 mg/kg BW aspirin treatments (eight steers/treatment) and were slaughtered 24 h after the last dose. Jejunal tissues were collected, and claudin (CLDN) 1, 2, and 3, occludin, and zonula occludens tight junction messenger ribonucleic acid (mRNA) expression was determined. Data were analyzed using the MIXED procedure of SAS. Urinary Cr excretion increased linearly at hours 3, 6, 9, and 12 (P ≤ 0.04) as aspirin dose increased from 0 to 200 mg/kg. Aspirin linearly increased Cr absorption (P = 0.02) and elimination (P = 0.04) rates and linearly decreased mean retention time of Cr (P = 0.02). Aspirin increased SAA (P = 0.04) and tended to increase LBP (P = 0.09) in serum but did not affect any other serum inflammatory marker (P ≥ 0.19). Aspirin tended to increase jejunal CLDN-1 mRNA expression (P = 0.10) but did not affect the mRNA expression of other genes regulating tight junction function (P ≥ 0.20). Results from this study indicate that aspirin disrupts the GIT barrier function in beef cattle and has a potential as a model in GIT permeability research.


Assuntos
Aspirina/efeitos adversos , Doenças dos Bovinos/induzido quimicamente , Inflamação/veterinária , Animais , Biomarcadores/sangue , Peso Corporal/efeitos dos fármacos , Bovinos , Doenças dos Bovinos/patologia , Cromo/urina , Dieta/veterinária , Digestão/efeitos dos fármacos , Feminino , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/patologia , Masculino , Silagem/análise , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/patologia , Zea mays
10.
Commun Biol ; 3(1): 466, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32811894

RESUMO

Chinese herbal formulas including the lung-cleaning and toxicity-excluding (LCTE) soup have played an important role in treating the ongoing COVID-19 pandemic (caused by SARS-CoV-2) in China. Applying LCTE outside of China may prove challenging due to the unfamiliar rationale behind its application in terms of Traditional Chinese Medicine. To overcome this barrier, a biochemical understanding of the clinical effects of LCTE is needed. Here, we explore the chemical compounds present in the reported LCTE ingredients and the proteins targeted by these compounds via a network pharmacology analysis. Our results indicate that LCTE contains compounds with the potential to directly inhibit SARS-CoV-2 and inflammation, and that the compound targets proteins highly related to COVID-19's main symptoms. We predict the general effect of LCTE is to affect the pathways involved in viral and other microbial infections, inflammation/cytokine response, and lung diseases. Our work provides a biochemical basis for using LCTE to treat COVID-19 and its main symptoms.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Medicina Tradicional Chinesa , Pandemias , Pneumonia Viral/tratamento farmacológico , Anti-Inflamatórios/análise , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antivirais/química , Antivirais/uso terapêutico , Sulfato de Cálcio , China/epidemiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/metabolismo , Sistemas de Liberação de Medicamentos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/uso terapêutico , Trato Gastrointestinal/efeitos dos fármacos , Humanos , Redes e Vias Metabólicas/efeitos dos fármacos , Fitoterapia , Plantas Medicinais/química , Pneumonia Viral/epidemiologia , Pneumonia Viral/metabolismo , Sistema Respiratório/efeitos dos fármacos , Proteínas Virais/antagonistas & inibidores
11.
Mol Immunol ; 126: 65-72, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32768860

RESUMO

The insect gut participates in initial local immune responses by producing reactive oxygen and nitrogen species as well as anti-microbial peptides to resist pathogenic invasions. Nitric oxide (NO), a signaling and an immune effector molecule synthesized by the enzyme NO synthase (NOS), mediates an early step of the signal transduction pathway. In this study, we evaluated NO levels after Nosema pernyi infection in Antheraea pernyi gut. NOS activity was higher in the microsporidia-infected gut of A. pernyi than in that of control. Three NOS-related genes were cloned, and their spatio-temporal expression patterns were evaluated. ApNOS2 was expressed quickly in the midgut after N. pernyi infection. Sodium nitroprusside, dihydrate (SNP), or Nω-L-nitro-arginine methyl ester, hydrochloride (L-NAME), altered the NO content in A. pernyi midgut. Anti-microbial peptides (AMPs) in the groups exposed to N. pernyi plus SNP and N. pernyi plus L-NAME exhibited higher and lower expression, respectively, relative to the control. These results indicate that microsporidia infection triggers short-term activation of NO and NOS genes in the A. pernyi gut that is downregulated after 24 h. Notably, infection rates can be influenced by a NOS inhibitor. Furthermore, NO can be induced by pathogens. Similarly, NO content in the A. pernyi gut also influences AMPs in humoral immunity and some immune-related genes. Our results suggest that nitric oxide plays a vital role in A. pernyi gut immunity.


Assuntos
Trato Gastrointestinal/imunologia , Microsporidiose/veterinária , Mariposas/imunologia , Óxido Nítrico/metabolismo , Nosema/imunologia , Animais , Peptídeos Catiônicos Antimicrobianos/metabolismo , Proteínas de Artrópodes/antagonistas & inibidores , Proteínas de Artrópodes/metabolismo , Regulação para Baixo , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/microbiologia , Imunidade Humoral/efeitos dos fármacos , Imunidade nas Mucosas/efeitos dos fármacos , Microsporidiose/imunologia , Mariposas/enzimologia , Mariposas/microbiologia , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Análise Espaço-Temporal
12.
PLoS One ; 15(7): e0234818, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32663210

RESUMO

BACKGROUND: Erlotinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors used to treat EGFR mutation positive non-small-cell lung cancer (NSCLC). Skin rash and diarrhea are well-known and common adverse events in patients receiving erlotinib, whereas other adverse events, including eye, liver, or renal disorders have not been evaluated adequately. This meta-analysis aimed to evaluate the ocular, hepatobiliary, and renal toxicities of erlotinib in patients with NSCLC cancers. METHODS: In total, sixty studies were assessed, and the results of the included studies were quantitatively integrated using meta-analysis. The incidence of ocular, hepatobiliary (alanine aminotransferase [ALT] and bilirubin elevations; other hepatic adverse events), and renal adverse events were estimated. Additionally, the erlotinib-treated groups and the control groups (placebo or other treatment) were compared with respect to ocular disorders and ALT elevation. The study protocol has been registered in the International Prospective Register for Systematic Reviews (PROSPERO) CRD42018093758. RESULTS: The overall incidence of ocular disorders was 3.30% (95% confidence interval [CI] 2.20%-5.00%). The incidence of ALT elevation, bilirubin elevation, and other hepatobiliary disorders was 6.40% (95% CI 3.90%-10.4%), 3.80% (95% CI 2.30%-6.10%), and 1.00% (95% 0.60%-1.80%), respectively. The incidence of renal disorder was 3.10% (95% CI 1.90%-5.00%). The risk of ocular toxicity in the erlotinib treatment group was significantly increased (risk ratio = 2.91; 95% CI 1.70-4.98) compared to that in the control group. ALT elevation was not significantly different between the two groups. CONCLUSION: Based on the results, careful monitoring of ocular toxicity in patients receiving erlotinib should be recommended and closer monitoring of hepatic toxicity should be also recommended in patients with liver-related risk factors.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/fisiopatologia , Cloridrato de Erlotinib/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doenças do Sistema Digestório/etiologia , Intervalo Livre de Doença , Receptores ErbB/genética , Cloridrato de Erlotinib/uso terapêutico , Exantema/etiologia , Olho/efeitos dos fármacos , Oftalmopatias/etiologia , Feminino , Trato Gastrointestinal/efeitos dos fármacos , Humanos , Rim/efeitos dos fármacos , Nefropatias/etiologia , Neoplasias Pulmonares/genética , Masculino , Mutação , Inibidores de Proteínas Quinases/uso terapêutico
13.
J Vis Exp ; (161)2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32716381

RESUMO

Candida albicans hyphal morphogenesis in the gastrointestinal (GI) tract is tightly controlled by various environmental signals, and plays an important role in the dissemination and pathogenesis of this opportunistic fungal pathogen. However, methods to visualize fungal hyphae in the GI tract in vivo are challenging which limits the understanding of environmental signals in controlling this morphogenesis process. The protocol described here demonstrates a novel ex vivo method for visualization of hyphal morphogenesis in gut homogenate extracts. Using an ex vivo assay, this study demonstrates that cecal contents from antibiotic treated mice, but not from untreated control mice, promote C. albicans hyphal morphogenesis in the gut content. Further, adding back specific groups of gut metabolites to the cecal contents from antibiotic-treated mice differentially regulates hyphal morphogenesis ex vivo. Taken together, this protocol represents a novel method to identify and investigate the environmental signals that control C. albicans hyphal morphogenesis in the GI tract.


Assuntos
Bioensaio/métodos , Candida albicans/crescimento & desenvolvimento , Trato Gastrointestinal/microbiologia , Hifas/crescimento & desenvolvimento , Morfogênese , Animais , Candida albicans/efeitos dos fármacos , Ceco/microbiologia , Cefoperazona/farmacologia , Feminino , Proteínas Fúngicas/metabolismo , Trato Gastrointestinal/efeitos dos fármacos , Hifas/efeitos dos fármacos , Masculino , Metaboloma/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Morfogênese/efeitos dos fármacos
14.
Virus Res ; 286: 198103, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32717345

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved into a major pandemic called coronavirus disease 2019 (COVID-19) that has created unprecedented global health emergencies, and emerged as a serious threat due to its strong ability for human-to-human transmission. The reports indicate the ability of SARS-CoV-2 to affect almost any organ due to the presence of a receptor known as angiotensin converting enzyme 2 (ACE2) across the body. ACE2 receptor is majorly expressed in the brush border of gut enterocytes along with the ciliated cells and alveolar epithelial type II cells in the lungs. The amino acid transport function of ACE2 has been linked to gut microbial ecology in gastrointestinal (GI) tract, thereby suggesting that COVID-19 may, to some level, be linked to the enteric microbiota. The significant number of COVID-19 patients shows extra-pulmonary symptoms in the GI tract. Many subsequent studies revealed viral RNA of SARS-CoV-2 in fecal samples of COVID-19 patients. This presents a new challenge in the diagnosis and control of COVID-19 infection with a caution for proper sanitation and hygiene. Here, we aim to discuss the immunological co-ordination between gut and lungs that facilitates SARS-CoV-2 to infect and multiply in the inflammatory bowel disease (IBD) and non-IBD patients.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Disbiose/imunologia , Trato Gastrointestinal/imunologia , Doenças Inflamatórias Intestinais/imunologia , Pulmão/imunologia , Pneumonia Viral/imunologia , Anticorpos Monoclonais/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus/imunologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/microbiologia , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/microbiologia , Síndrome da Liberação de Citocina/virologia , Citocinas/antagonistas & inibidores , Citocinas/genética , Citocinas/imunologia , Disbiose/tratamento farmacológico , Disbiose/microbiologia , Disbiose/virologia , Microbioma Gastrointestinal/imunologia , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/microbiologia , Trato Gastrointestinal/virologia , Expressão Gênica , Interações Hospedeiro-Patógeno/imunologia , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/virologia , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Pulmão/virologia , Pandemias , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/microbiologia , Pneumonia Viral/virologia , Receptores Virais/genética , Receptores Virais/imunologia
15.
J Anim Sci ; 98(6)2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32479635

RESUMO

The objective of this study is to investigate the effect of a maternal antibiotic administration during the last week of gestation on the early life intestinal development in neonatal piglets. Colonization of the gut with bacteria starts during birth and plays a major role in the intestinal and immunological development of the intestine. We demonstrate that maternal interventions induced changes in the sows (n = 6 to 8 per treatment) fecal microbiota diversity around birth (P < 0.001, day 1). Whole-genome microarray analysis in small intestinal samples of 1-d old piglets (n = 6 to 8 per treatment) showed significantly expressed genes (Padj < 0.05) which were involved in processes of tight junction formation and immunoglobulin production. Furthermore, when performing morphometry analysis, the number of goblet cells in jejunum was significantly (P < 0.001) lower in piglets from amoxicillin administered sows compared with the respective control piglets. Both significantly expressed genes (Padj < 0.05) and significant morphometry data (jejunum P < 0.05 and ileum P < 0.01) indicate that the crypts of piglets from amoxicillin administered sows deepen around weaning (day 26) as an effect of the amoxicillin administration in sows. The latter might imply that the intestinal development of piglets was delayed by maternal antibiotic administration. Taken together, these results show that maternally oral antibiotic administration changes in early life can affect intestinal development of the offspring piglets for a period of at least 5 wk after the maternal antibiotic administration was finished. These results show that modulation of the neonatal intestine is possible by maternal interventions.


Assuntos
Antibacterianos/administração & dosagem , Bactérias/efeitos dos fármacos , Microbiota/efeitos dos fármacos , Suínos/fisiologia , Animais , Animais Recém-Nascidos , Bactérias/crescimento & desenvolvimento , Fezes/microbiologia , Feminino , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/crescimento & desenvolvimento , Trato Gastrointestinal/microbiologia , Gravidez , Suínos/crescimento & desenvolvimento , Suínos/microbiologia , Desmame
17.
Sci Rep ; 10(1): 7701, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32382070

RESUMO

Clostridioides difficile is the leading cause of nosocomial infections and a worldwide urgent public health threat. Without doubt, there is an urgent need for new effective anticlostridial agents due to the increasing incidence and severity of C. difficile infection (CDI). The aim of the present study is to investigate the in vivo efficacy of auranofin (rheumatoid arthritis FDA-approved drug) in a CDI mouse model and establish an adequate dosage for treatment. The effects of increased C. difficile inoculum, and pre-exposure to simulated gastric intestinal fluid (SGF) and simulated intestinal fluid (SIF), on the antibacterial activity of auranofin were investigated. Auranofin's in vitro antibacterial activity was stable in the presence of high bacterial inoculum size compared to vancomycin and fidaxomicin. Moreover, it maintained its anti-C. difficile activity after being exposed to SGF and SIF. Upon testing in a CDI mouse model, auranofin at low clinically achievable doses (0.125 mg/kg and 0.25 mg/kg) significantly protected mice against CDI with 100% and 80% survival, respectively. Most importantly, auranofin (0.125 mg/kg and 0.25 mg/kg) significantly prevented CDI recurrence when compared with vancomycin. Collectively, these results indicate that auranofin could potentially provide an effective, safe and quick supplement to the current approaches for treating CDI.


Assuntos
Auranofina/farmacologia , Infecções por Clostridium/tratamento farmacológico , Infecção Hospitalar/tratamento farmacológico , Animais , Antibacterianos/farmacologia , Artrite Reumatoide/tratamento farmacológico , Infecções por Clostridium/microbiologia , Infecções por Clostridium/patologia , Infecção Hospitalar/microbiologia , Infecção Hospitalar/patologia , Reposicionamento de Medicamentos , Fidaxomicina/farmacologia , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/microbiologia , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Recidiva , Vancomicina/farmacologia
18.
Artigo em Inglês | MEDLINE | ID: mdl-32384765

RESUMO

(1) Background: The gastrointestinal tract (GI) tract is one of the main organs exposed to particulate matter (PM) directly through ingestion of contaminated food or indirectly through inhalation. Previous studies have investigated the effects of chronic PM exposure on intestinal epithelia in vitro using Caco-2 cells and in vivo using mice. In this study, we hypothesized that chronic PM exposure would increase epithelial permeability and decrease barrier function due to altered redox homeostasis, which alters levels and/or localization of barrier-associated proteins in human three-dimensional (3D) intestinal tissues. (2) Methods: Transepithelial electrical resistance (TEER) in tissues exposed to 50, 100, 150, 250, and 500 µg/cm2 of PM for 1 week and 2 weeks was analyzed. Levels and localization of tight junction proteins zonula occludens protein 1 (ZO-1) and claudin-1 and desmosome-associated desmocollin were analyzed using immunofluorescence. As a marker of oxidative stress, levels of 4-hydroxy-nonenal (4HNE) adducts were measured. (3) Results: No differences in TEER measurements were observed between exposed and un-exposed tissues. However, increased levels of 4HNE adducts in exposed tissues were observed. Additionally, decreased levels of ZO-1, claudin-1, and desmocollin were demonstrated. (4) Conclusion: These data suggest that chronic PM exposure results in an increase of oxidative stress; modified levels of barrier-associated proteins could possibly link to GI tract inflammatory conditions.


Assuntos
Células CACO-2 , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/metabolismo , Mucosa Intestinal/metabolismo , Material Particulado/farmacologia , Junções Íntimas/metabolismo , Animais , Células CACO-2/efeitos dos fármacos , Células CACO-2/fisiologia , Humanos , Intestinos/fisiopatologia , Proteínas de Membrana/metabolismo , Camundongos , Oxirredução , Material Particulado/administração & dosagem , Proteínas de Junções Íntimas
19.
Food Chem ; 326: 127024, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32428856

RESUMO

This study aimed to analyze the effect of elderly gastrointestinal (GI) conditions on proteolysis, lipolysis and calcium and vitamins A and D3 bioaccessibility in salmon, sardine, sea bass and hake. For this purpose, cooked fishes were in vitro subjected to three elderly in vitro digestion models: E1 (oral elderly conditions), E2 (oral and gastric elderly conditions) and E3 (oral, gastric and intestinal elderly conditions)). In parallel, samples were digested under standardized GI conditions of a healthy adult as a control. Proteolysis was highly affected by elderly GI alterations (p < 0.05) (50% of reduction compared to control), being salmon and sea bass proteolysis extent (40 and 33%, respectively) the most affected with an important descend in leucine release. Calcium and vitamins bioaccessibility seemed to be also compromised for elders; however, the extent of the reduction highly depends on the fish type. Finally, these GI disorders did not negatively influence the bioabsorbable lipids of the fishes.


Assuntos
Cálcio/farmacologia , Trato Gastrointestinal/efeitos dos fármacos , Lipólise/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Vitaminas/farmacologia , Idoso , Animais , Bass , Digestão , Gadiformes , Humanos , Salmão , Alimentos Marinhos/análise
20.
Mol Cell ; 78(4): 570-576, 2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32442503

RESUMO

Co-evolution of gut commensal bacteria and humans has ensured that the micronutrient needs of both parties are met. This minireview summarizes the known molecular mechanisms of iron, zinc, and B vitamin processing by human-associated bacteria, comparing gut pathogens and commensals, and highlights the tension between their roles as competitors versus collaborators with the human host.


Assuntos
Bactérias/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/efeitos dos fármacos , Micronutrientes/farmacologia , Humanos
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