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2.
Nature ; 596(7871): 262-267, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34349263

RESUMO

Regulated cell death is an integral part of life, and has broad effects on organism development and homeostasis1. Malfunctions within the regulated cell death process, including the clearance of dying cells, can manifest in diverse pathologies throughout various tissues including the gastrointestinal tract2. A long appreciated, yet elusively defined relationship exists between cell death and gastrointestinal pathologies with an underlying microbial component3-6, but the direct effect of dying mammalian cells on bacterial growth is unclear. Here we advance a concept that several Enterobacteriaceae, including patient-derived clinical isolates, have an efficient growth strategy to exploit soluble factors that are released from dying gut epithelial cells. Mammalian nutrients released after caspase-3/7-dependent apoptosis boosts the growth of multiple Enterobacteriaceae and is observed using primary mouse colonic tissue, mouse and human cell lines, several apoptotic triggers, and in conventional as well as germ-free mice in vivo. The mammalian cell death nutrients induce a core transcriptional response in pathogenic Salmonella, and we identify the pyruvate formate-lyase-encoding pflB gene as a key driver of bacterial colonization in three contexts: a foodborne infection model, a TNF- and A20-dependent cell death model, and a chemotherapy-induced mucositis model. These findings introduce a new layer to the complex host-pathogen interaction, in which death-induced nutrient release acts as a source of fuel for intestinal bacteria, with implications for gut inflammation and cytotoxic chemotherapy treatment.


Assuntos
Apoptose , Enterobacteriaceae/crescimento & desenvolvimento , Enterobacteriaceae/metabolismo , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Intestinos/citologia , Intestinos/microbiologia , Acetiltransferases/genética , Acetiltransferases/metabolismo , Animais , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular , Modelos Animais de Doenças , Células Epiteliais/patologia , Feminino , Doenças Transmitidas por Alimentos/microbiologia , Vida Livre de Germes , Interações Hospedeiro-Patógeno , Inflamação/metabolismo , Inflamação/microbiologia , Inflamação/patologia , Masculino , Camundongos , Mucosite/induzido quimicamente , Salmonella/enzimologia , Salmonella/genética , Salmonella/crescimento & desenvolvimento , Salmonella/metabolismo , Transcriptoma , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
3.
AAPS PharmSciTech ; 22(5): 200, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34212283

RESUMO

Mucositis is one of the most adverse effects of 5-fluorouracil (5-FU) and had no standard drug for treatment. Melatonin is a neurohormone, and can ameliorate radiotherapy-induced small intestinal mucositis. Melatonin encapsulated in niosomes improved its poor bioavailability. Succinyl melatonin, a melatonin derivative, showed prolonged release compared with melatonin. This study investigated the efficacy of melatonin niosome gel (MNG) and succinyl melatonin niosome gel (SNG) in 5-FU-induced small intestinal mucositis treatment in mice. MNG and SNG with particle sizes of 293 and 270 nm were shown to have mucoadhesive potentials. The effect of a daily oral application of MNG, SNG, or fluocinolone acetonide gel (FAG, positive control) was compared to that of the normal group. The body weight, food consumption, histology, Fourier transform infrared (FTIR) spectroscopy, inflammatory cytokines (tumor necrosis factor (TNF)-α and interleukin (IL)-1ß), and malondialdehyde (MDA) in the small intestine were monitored. The results showed decreased %body weight and food consumption in all 5-FU-injected groups compared with the normal group. The MNG and SNG treatments maintained the food consumption and the normal integrity of the small intestines, as evidenced by villus length and crypt depth, similar to the observations in the normal groups. The FTIR spectra showed no change in lipids of the MNG and SNG groups compared with the normal group. Moreover, SNG could reduce IL-1ß content to a level that was not different from the level in the normal groups. Therefore, the oral application of MNG and SNG could protect against 5-FU-induced small intestinal mucositis in mice.


Assuntos
Lipossomos/química , Melatonina/administração & dosagem , Mucosite/tratamento farmacológico , Administração Oral , Animais , Fluoruracila/toxicidade , Interleucina-1beta/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Intestino Delgado/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Melatonina/química , Melatonina/farmacologia , Camundongos , Camundongos Endogâmicos ICR , Mucosite/induzido quimicamente , Mucosite/patologia , Tamanho da Partícula , Fator de Necrose Tumoral alfa/metabolismo
5.
Bull Cancer ; 108(7-8): 761-770, 2021.
Artigo em Francês | MEDLINE | ID: mdl-33933290

RESUMO

Mucositis is defined as inflammatory and/or ulcerative lesions of the oral and/or gastrointestinal tract. It occurs in approximately 40% to 50% of adults patients receiving conventional chemotherapy and up to 75% of patients receiving high dose chemotherapy as conditioning for hematopoietic stem cell transplantation. It is a toxic side effect, which strongly impairs quality of life and leads to refractory pain, increasing risk of infection and even therapeutic modifications. Despite improvements made, the management of mucositis remains a challenge and is still not consensual. A multicentric survey of practices concerning the preventive and curative management of chemo-induced mucositis in pediatric oncology department in France was carried out using a standardized questionnaire. Results confirm heterogeneous practices and the small progress made during the last decade. This national survey and an analysis of the recent literature leads to propose guidelines for the prevention and treatment of oral mucositis in children receiving treatment for cancer.


Assuntos
Antineoplásicos/efeitos adversos , Mucosite/induzido quimicamente , Padrões de Prática Médica/normas , Institutos de Câncer/estatística & dados numéricos , Criança , França , Pesquisas sobre Serviços de Saúde/estatística & dados numéricos , Transplante de Células-Tronco Hematopoéticas , Humanos , Terapia a Laser/métodos , Mucosite/complicações , Mucosite/microbiologia , Mucosite/prevenção & controle , Higiene Bucal , Manejo da Dor , Qualidade de Vida , Condicionamento Pré-Transplante/efeitos adversos
6.
In Vivo ; 35(3): 1485-1497, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33910826

RESUMO

BACKGROUND/AIM: Intestinal mucositis with diarrhea is a dose-limiting toxicity of 5-fluorouracil (5-FU). M40403, a superoxide dismutase mimetic, was evaluated on whether it improves the mucositis with diarrhea. MATERIALS AND METHODS: BALB/c mice were treated with daily intraperitoneal injections of 5-FU±M40403 for five consecutive days. Following treatment, light microscopy (apoptosis), electron microscopy (autophagy), and analyses for the expression of apoptosis/autophagy-related proteins were performed in analysing small intestinal samples. Body weight, diarrhea score, blood cytokine levels, complete blood count, and blood chemistries were measured. The in vivo anti-tumor activity of 5-FU±M40403 was also evaluated. RESULTS: M40403 improved 5-FU-induced intestinal mucositis (apoptosis and autophagy) and attenuated 5-FU-induced changes in the expression of apoptosis/autophagy-related proteins, weight loss, diarrhea score, and serum TNF-α levels. M40403 neither added further adverse effects nor compromised the anti-tumor activity during 5-FU treatment. CONCLUSION: M40403 can be useful in improving 5-FU-induced intestinal mucositis with diarrhea.


Assuntos
Fluoruracila , Mucosite , Animais , Fluoruracila/efeitos adversos , Mucosa Intestinal , Manganês , Camundongos , Camundongos Endogâmicos BALB C , Mucosite/induzido quimicamente , Mucosite/tratamento farmacológico , Compostos Organometálicos , Superóxido Dismutase
7.
Crit Rev Oncol Hematol ; 161: 103312, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33794308

RESUMO

Methotrexate (MTX), an important chemotherapeutic agent, is often accompanied with mucositis. The occurrence and severity are unpredictable and show large interindividual variability. In this study, we review and meta-analyze previously studied genetic variants in relation to MTX-induced mucositis. We conducted a systematic search in Medline and Embase. We included genetic association studies of MTX-induced mucositis in cancer patients. A meta-analysis was conducted for single nucleotide polymorphisms (SNPs) for which at least two studies found a statistically significant association. A total of 34 SNPs were associated with mucositis in at least one study of the 57 included studies. Two of the seven SNPs included in our meta-analysis were statistically significantly associated with mucositis: MTHFR c.677C > T (recessive, grade ≥3 vs grade 0-2, OR 2.53, 95 %CI [1.48-4.32], False Discovery Rate[FDR]-corrected p-value 0.011) and MTRR c.66A > G (overdominant, grade ≥1 vs grade 0, OR 2.08, 95 %CI [1.16-3.73], FDR-corrected p-value 0.042).


Assuntos
Mucosite , Neoplasias , Antimetabólitos Antineoplásicos/efeitos adversos , Humanos , Metotrexato/efeitos adversos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Mucosite/induzido quimicamente , Mucosite/genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Polimorfismo de Nucleotídeo Único
8.
Nutrients ; 13(3)2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33801889

RESUMO

Background: The aim of this study was to examine the anti-inflammatory and anti-apoptotic patterns of omega-3 polyunsaturated fatty acids (n-3 PUFAs) during methotrexate (MTX) induced intestinal damage in cell culture and in a rat model. Methods: Non-treated and treated with MTX HT 29 and HCT116cells were exposed to increasing doses of n-3 PUFAs and cell viability was evaluated using PrestoBlue® assay. Male Sprague-Dawley rats were divided into 4 experimental groups: Control rats, CONTR+n-3 PUFA rats that were treated with oral n-3 PUFA, MTX rats were treated with MTX given IP, and MTX+n-3 PUFA rats were treated with oral n-3 PUFA before and following injection of MTX. Intestinal mucosal parameters and mucosal inflammation, enterocyte proliferation and apoptosis, TNF-α in mucosal tissue and plasma (ELISA), NF-κB, COX-2, TNF-α, Fas, FasL, Fadd, Bid, Bax and Bcl-2gene and protein levels were determined 72 h following MTX injection. Results: Exposure of HT 29 and HCT116cells to n-3 PUFA attenuated inhibiting effects of MTX on cell viability. MTX-n-3 PUFA rats demonstrated a lower intestinal injury score and enhanced intestinal repair. A significant decrease in enterocyte apoptosis in MTX+n-3 PUFA rats was accompanied by decreased TNF-α, FAS, FasL, FADD and BID mRNA levels. Decreased NF-κB, COX-2 and TNF-α levels in mucosa was accompanied by a decreased number of IELs and macrophages. Conclusions: n-3 PUFAs inhibit NF-κB/COX-2 induced production of pro-inflammatory cytokines and inhibit cell apoptosis mainly by extrinsic pathway in rats with MTX-induced intestinal damage.


Assuntos
Anti-Inflamatórios/administração & dosagem , Apoptose/efeitos dos fármacos , Citocinas/metabolismo , Ácidos Graxos Ômega-3/administração & dosagem , Mucosa Intestinal/citologia , Metotrexato/toxicidade , Mucosite/terapia , Animais , Anti-Inflamatórios/farmacologia , Proliferação de Células , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Enterócitos/citologia , Enterócitos/efeitos dos fármacos , Ácidos Graxos Ômega-3/farmacologia , Células HCT116 , Células HT29 , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Masculino , Mucosite/induzido quimicamente , Mucosite/metabolismo , Mucosite/patologia , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley
9.
Support Care Cancer ; 29(10): 5701-5709, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33649918

RESUMO

PURPOSE: To discuss the role of benzydamine in the prevention and treatment of radiation-induced oral mucositis (OM) in head and neck (H&N) cancer patients. This document represents an expert opinion paper on indications and key-role aspects in OM pathogenesis, prevention and treatment. ORAL MUCOSITIS: OM represents a common side effect of chemotherapy (CHT) and radiotherapy (RT). It consists in a painful erythema involving the oral cavity mucosa, which may progress to ulceration. Five biologically dynamic phases are considered crucial in mucositis: "initiation, signalling, amplification, ulceration and healing". Oral environment and microbiota are fundamental in mucositis development being involved in susceptibility to infections and in ulceration consequences. Different agents against mucositis have been studied and the use of benzydamine is strongly supported in literature. The Multinational Association of Supportive Care in Cancer and International Society for Oral Oncology (MASCC/ISOO) guidelines recommend its use for the prevention of OM in H&N patients undergoing RT and RT/CHT. BENZYDAMINE: Benzydamine is a local anti-inflammatory drug with analgesic properties. It can decrease TNF-α, IL-1ß and prostaglandin synthesis, also inhibiting leukocyte-endothelial interactions, neutrophil degranulation, vasodilation and vascular permeability. Literature agrees on the beneficial effects of benzydamine in preventing and reducing oral mucositis severity in H&N cancer patients undergoing RT/CHT. CONCLUSIONS: Mucositis represents a major concern in H&N cancer patients and a clinical and economical issue. A multimodal and multidisciplinary approach is needed for its management. International guidelines recommend benzydamine for OM prevention and treatment in H&N cancer patients, but further "real world" trials should be designed.


Assuntos
Benzidamina , Neoplasias de Cabeça e Pescoço , Mucosite , Estomatite , Benzidamina/uso terapêutico , Quimiorradioterapia , Humanos , Mucosite/induzido quimicamente , Mucosite/prevenção & controle , Estomatite/induzido quimicamente , Estomatite/prevenção & controle
10.
J Ethnopharmacol ; 271: 113912, 2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-33567307

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: 5-Fluorouracil (5-FU) is a chemotherapy agent that is widely used in clinical oncologic practice. However, intestinal mucositis is the most frequently occurring side effect of cancer therapy with 5-FU. Based on a literature survey, Radix Aucklandiae herbal preparation potentially ameliorates intestinal mucositis in 5-FU-treated mice. AIM OF THE STUDY: The aim of this study was to investigate the inflammation and gastrointestinal regulation of intestinal mucositis induced by 5-FU, including the intestinal morphology, as well as the reduction in food intake, body weight loss, and diarrhea. MATERIALS AND METHODS: Intestinal mucositis was induced in mice by 5-FU (30 mg/kg, i.p., for 5 consecutive days). The dose-dependent Radix Aucklandiae herbal preparation (0.3, 1, and 3 g/kg/day, p.o.), loperamide (3 mg/kg/day, p.o.) or celecoxib (40 mg/kg/day, p.o.) was concurrently administered until the 7th day. Physical status observation, diarrhea assessment, serum proinflammatory cytokine levels, intestinal villus height and crypt depth, and total goblet cells from tissues were assessed. RESULTS: The dosage regimen of 5-FU administration caused severe intestinal mucositis in mice, including damage to the intestinal morphology, accompanied by a reduction in food intake, body weight loss, and diarrhea. The high-dose Radix Aucklandiae herbal preparation significantly relieves 5-FU-induced intestinal mucositis by enhancing proliferative activity in epithelial crypts; improving anepithymia, body weight loss, and diarrhea; and displaying protective effects on goblet cells in intestinal mucosal epithelia. Activation of NF-κB in the intestinal mucositis model was also suppressed by the Radix Aucklandiae herbal preparation, suggesting that it is a potent inhibitor of NF-κB and proinflammatory cytokines, such as IL-1ß, IL-6, TNF-α, and COX-2. CONCLUSIONS: Our data support the conclusion that the Radix Aucklandiae herbal preparation could effectively ameliorate 5-FU-induced gastrointestinal toxicity and be applied clinically for the prevention of intestinal mucositis during chemotherapy.


Assuntos
Anti-Inflamatórios/farmacologia , Asteraceae/química , Mucosite/prevenção & controle , Preparações de Plantas/farmacologia , Animais , Anti-Inflamatórios/uso terapêutico , Peso Corporal/efeitos dos fármacos , Citocinas/sangue , Diarreia/induzido quimicamente , Diarreia/tratamento farmacológico , Modelos Animais de Doenças , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Fluoruracila/toxicidade , Células Caliciformes/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Intestinos/efeitos dos fármacos , Jejuno/efeitos dos fármacos , Masculino , Camundongos Endogâmicos BALB C , Mucosite/induzido quimicamente , Mucosite/patologia , Preparações de Plantas/uso terapêutico , Fator de Transcrição RelA/metabolismo
11.
Cancer Med ; 10(6): 1944-1954, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33638305

RESUMO

BACKGROUND: Temsirolimus is an mTOR antagonist with proven anticancer efficacy. Preclinical data suggest greater anticancer effect when mTOR inhibitors are combined with cytotoxic chemotherapy. We performed a Phase I assessment of the combination of temsirolimus and capecitabine in patients with advanced solid tumors. METHODS: Patients were enrolled in an alternating dose escalation of temsirolimus (at 15 or 25 mg IV weekly) and capecitabine (at 750, 1000, and 1250 mg/m2 twice daily) in separate Q2-week and Q3-week cohorts. At the recommended Phase II doses (RP2Ds) of temsirolimus and capecitabine (Q2), seven patients were also treated with oxaliplatin (85 mg/m2 , day 1) to determine triplet combination safety and efficacy. RESULTS: Forty-five patients were enrolled and 41 were evaluable for dose-limiting toxicities (DLTs). The most common adverse events (AEs) were mucositis, fatigue, and thrombocytopenia. The most common grade 3/4 AEs were hypophosphatemia and anemia. Five patients had DLTs, including hypophosphatemia, mucositis, and thrombocytopenia. The RP2Ds were temsirolimus 25 mg +capecitabine 1000 mg/m2 (Q2); and temsirolimus 25 mg +capecitabine 750 mg/m2  (Q3). Of the 38 patients evaluable for response, one had a partial response (PR) and 19 had stable disease (SD). The overall disease control rate was 52%. Five of the 20 patients with SD/PR maintained disease control for >6 months. CONCLUSIONS: The combination of temsirolimus and capecitabine is safe on both a Q2-week and a Q3-week schedule. The combination demonstrated promising evidence of disease control in this highly refractory population and could be considered for testing in disease-specific phase II trials.


Assuntos
Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Capecitabina/administração & dosagem , Neoplasias/tratamento farmacológico , Sirolimo/análogos & derivados , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adulto , Idoso , Anemia/induzido quimicamente , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Esquema de Medicação , Fadiga/induzido quimicamente , Feminino , Febre/induzido quimicamente , Humanos , Hipofosfatemia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Mucosite/induzido quimicamente , Neoplasias/patologia , Oxaliplatina/administração & dosagem , Oxaliplatina/efeitos adversos , Sirolimo/administração & dosagem , Sirolimo/efeitos adversos , Trombocitopenia/induzido quimicamente , Resultado do Tratamento
12.
BMC Cancer ; 21(1): 206, 2021 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-33639888

RESUMO

BACKGROUND: The adverse reactions (ADRs) of targeted therapy were closely associated with treatment response, clinical outcome, quality of life (QoL) of patients with cancer. However, few studies presented the correlation between ADRs of targeted therapy and treatment effects among cancer patients. This study was to explore the characteristics of ADRs with targeted therapy and the prognosis of cancer patients based on the clinical data. METHODS: A retrospective secondary data analysis was conducted within an ADR data set including 2703 patients with targeted therapy from three Henan medical centers of China between January 2018 and December 2019. The significance was evaluated with chi-square test between groups with or without ADRs. Univariate and multivariate logistic regression with backward stepwise method were applied to assess the difference of pathological characteristics in patients with cancer. Using the univariate Cox regression method, the actuarial probability of overall survival was performed to compare the clinical outcomes between these two groups. RESULTS: A total of 485 patients were enrolled in this study. Of all patients, 61.0% (n = 296) occurred ADRs including skin damage, fatigue, mucosal damage, hypertension and gastrointestinal discomfort as the top 5 complications during the target therapy. And 62.1% of ADRs were mild to moderate, more than half of the ADRs occurred within one month, 68.6% ADRs lasted more than one month. Older patients (P = 0.022) and patients with lower education level (P = 0.036), more than 2 comorbidities (P = 0.021), longer medication time (P = 0.022), drug combination (P = 0.033) and intravenous administration (P = 0.019) were more likely to have ADRs. Those with ADRs were more likely to stop taking (P = 0.000), change (P = 0.000), adjust (P = 0.000), or not take the medicine on time (P = 0.000). The number of patients with recurrence (P = 0.000) and metastasis (P = 0.006) were statistically significant difference between ADRs and non-ADRs group. And the patients were significantly poor prognosis in ADRs groups compared with non-ADRs group. CONCLUSION: The high incidence of ADRs would affect the treatment and prognosis of patients with cancer. We should pay more attention to these ADRs and develop effective management strategies.


Assuntos
Terapia de Alvo Molecular/efeitos adversos , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , China/epidemiologia , Erupção por Droga/epidemiologia , Erupção por Droga/etiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Fadiga/induzido quimicamente , Fadiga/epidemiologia , Feminino , Gastroenteropatias/induzido quimicamente , Gastroenteropatias/epidemiologia , Registros Hospitalares , Humanos , Hipertensão/induzido quimicamente , Hipertensão/epidemiologia , Incidência , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mucosite/induzido quimicamente , Mucosite/epidemiologia , Metástase Neoplásica , Recidiva Local de Neoplasia/epidemiologia , Neoplasias/mortalidade , Prognóstico , Modelos de Riscos Proporcionais , Qualidade de Vida , Estudos Retrospectivos , Fatores Socioeconômicos , Resultado do Tratamento , Adulto Jovem
13.
Am J Physiol Gastrointest Liver Physiol ; 320(5): G712-G719, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33471628

RESUMO

Intestinal mucositis remains one of the most debilitating side effects related to chemotherapy. The onset and persistence of mucositis is an intricate physiological process involving cross-communication between the specific chemotherapeutic drug, the immune system, and gut microbes that results in a loss of mucosal integrity leading to gut-barrier dysfunction. Intestinal mucositis has a severe impact on a patient's quality of life and negatively influences the outcome of treatment. Most importantly, intestinal mucositis is a major contributor to the decreased survival rates and early onset of death associated with certain chemotherapy treatments. Understanding the pathophysiology and symptomology of intestinal mucositis is important in reducing the negative consequences of this condition. Prophylaxis, early diagnosis, and proper symptom management are essential to improved survival outcomes in patients with cancer. This review focuses on the pathobiology of intestinal mucositis that accompanies chemotherapy treatments. In addition, we will discuss the therapeutic potential of select strategies that have shown promise in mitigating chemotherapies' off-target effects without hampering their anticancer efficacy.NEW & NOTEWORTHY Intestinal mucositis, or damage to the intestinal mucosa, is a common side effect of chemotherapy. In this review, we describe the pathobiology of intestinal mucositis that is associated with chemotherapy treatments. In addition, we discuss the efficacy of several potential therapeutic strategies that have shown some potential in alleviating chemotherapies' off-target effects.


Assuntos
Antineoplásicos/efeitos adversos , Mucosa Intestinal/efeitos dos fármacos , Mucosite/induzido quimicamente , Humanos
14.
Support Care Cancer ; 29(5): 2415-2421, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-32918133

RESUMO

PURPOSE: Chemotherapy-induced gastrointestinal toxicity is a common adverse event during chemotherapeutic treatment. No uniformly applicable strategies exist to predict, prevent, or treat gastrointestinal toxicity. Thus, a goal of mucositis research is to identify targets for therapeutic interventions and individualized risk prediction. Fibrinogen C domain containing 1 (FIBCD1) is a transmembrane protein expressed in human intestinal epithelial cells with functions in the innate immune system. Previous observations have shown that FIBCD1 ameliorates dextran sulfate sodium (DSS)-induced intestinal inflammation in vivo. We evaluated the effect of FIBCD1 in a murine model of chemotherapy-induced gastrointestinal toxicity and inflammation. METHODS: Transgenic (Tg) mice overexpressing FIBCD1 in the intestinal epithelium (Fibcd1Tg) and wild-type (WT) littermates (C57BL/6N) were randomized to receive an intraperitoneal injection of doxorubicin 20 mg/kg or saline and were terminated 2 or 7 days after the injection. Gastrointestinal toxicity was evaluated by weight change, intestinal length, villus height/crypt depth, and histological mucositis score. Expression of inflammatory markers (IL-6, IL-1ß, and Tnfα) was measured by quantitative real-time PCR in intestinal tissue samples. RESULTS: Following doxorubicin treatment, WT mice exhibited an increased weight loss compared with Tg littermates (p < 0.001). No differences between genotypes were seen in mucositis score, intestinal length, villus height/crypt depth, or IL-6, IL-1ß, and Tnfα expression. CONCLUSION: Our findings suggest that FIBCD1 could ameliorate chemotherapy-induced gastrointestinal toxicity by reducing weight loss; however, the mechanism of this possible protective effect remains to be defined warranting additional investigations.


Assuntos
Antineoplásicos/uso terapêutico , Mucosite/induzido quimicamente , Mucosite/tratamento farmacológico , Receptores de Superfície Celular/uso terapêutico , Perda de Peso/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Genótipo , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos C57BL
15.
Cancer Chemother Pharmacol ; 87(3): 327-336, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33130913

RESUMO

PURPOSE: Intestinal mucositis is an important adverse effect of antineoplastic therapy, which remains without adequate treatment. The present study aimed to carry out a complete evaluation of the histopathological changes during irinotecan-induced intestinal mucositis, using the protocol most found in the pharmacological reports nowadays to better understand irinotecan toxicity and support future studies on drug discovery. METHODS: Intestinal mucositis was induced by treating swiss mice for 4 days with irinotecan (75 mg/kg, i.p.). After 72 h post irinotecan, the mice were sacrificed and the small intestine and colon were excised to performed histological analysis by stained tissue with hematoxylin/eosin (H&E). RESULTS: Histoarchitecture loss, villus/crypt ratio reduction, atrophy of the muscular layer, hypertrophy in the submucosal and mucous layers, ruptures in the epithelium, as well as extent cellular infiltrate and presence of micro abscesses and the fusion of the crypts were observed in the histological analysis. Moreover, duodenum and colon had increased intraepithelial lymphocytes and mitotic figures. However, submucosal ganglia were decreased in the duodenum and increased in the colon. CONCLUSIONS: The data obtained in the present study provides new evidence that irinotecan-induced intestinal mucositis highly affects small intestine and colon, further contributing to establish criteria in light of the histopathological changes induced by irinotecan during intestinal mucositis and facilitating inter-study comparisons.


Assuntos
Mucosa Intestinal/efeitos dos fármacos , Irinotecano/toxicidade , Mucosite/induzido quimicamente , Inibidores da Topoisomerase I/toxicidade , Animais , Colo/efeitos dos fármacos , Colo/patologia , Feminino , Mucosa Intestinal/patologia , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/patologia , Irinotecano/administração & dosagem , Camundongos , Mucosite/patologia , Inibidores da Topoisomerase I/administração & dosagem
16.
Biomed Pharmacother ; 133: 111012, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33254017

RESUMO

The beneficial effects of prebiotic, such as fructo-oligosaccharides (FOS), in intestinal inflammation have been demonstrated in several studies. Herein, we evaluate whether joint treatment with FOS, both before and during mucositis, had additional beneficial effects and investigated the mechanisms underlying in the action of FOS on the intestinal barrier. BALB/c mice were randomly divided into five groups: CTR (without mucositis + saline solution), FOS (without mucositis + 6 % FOS), MUC (mucositis + saline solution), PT (mucositis + 6 % FOS supplementation before disease induction), and TT (mucositis + 6 % FOS supplementation before and during disease induction). Mucositis was induced by intraperitoneal injection (300 mg/kg) of 5-fluorouracil (5-FU). After 72 h, the animals were euthanized and intestinal permeability (IP), tight junction, bacterial translocation (BT), histology and morphometry, and immunoglobulin A secretory (sIgA), inflammatory infiltrate, and production of short-chain fatty acids (acetate, butyrate and propionate) were evaluated. The MUC group showed an increase in the IP, BT, and inflammatory infiltrate but a decrease in the tight junction expression and butyrate and propionate levels (P < 0.05). In the PT and TT groups, FOS supplementation maintained the IP, tight junction expression, and propionate concentration within physiologic levels, increased butyrate levels, and reduced BT and inflammatory infiltrate (P < 0.05). Total treatment with FOS (TT group) was more effective in maintaining histological score, morphometric parameters, and sIgA production. Thus, total treatment (prophylactic and therapeutic supplementation) with FOS was more effective than pretreatment alone, in reducing 5-FU-induced damage to the intestinal barrier.


Assuntos
Bactérias/efeitos dos fármacos , Ácidos Graxos Voláteis/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Íleo/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosite/induzido quimicamente , Oligossacarídeos/farmacologia , Prebióticos , Junções Íntimas/efeitos dos fármacos , Acetatos/metabolismo , Animais , Bactérias/metabolismo , Translocação Bacteriana/efeitos dos fármacos , Butiratos/metabolismo , Modelos Animais de Doenças , Fluoruracila , Íleo/metabolismo , Íleo/microbiologia , Íleo/patologia , Imunoglobulina A Secretora/metabolismo , Mediadores da Inflamação/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Masculino , Camundongos Endogâmicos BALB C , Mucosite/metabolismo , Mucosite/microbiologia , Mucosite/patologia , Permeabilidade , Propionatos/metabolismo , Junções Íntimas/metabolismo , Junções Íntimas/microbiologia , Junções Íntimas/patologia
17.
J Integr Med ; 19(2): 144-157, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33353843

RESUMO

OBJECTIVE: The present study investigated how mild moxibustion treatment affects the intestinal microbiome and expression of NLRP3-related immune factors in a rat model of intestinal mucositis (IM) induced with 5-fluorouracil (5-Fu). METHODS: Forty male Sprague-Dawley rats were randomly divided into control, chemotherapy, moxibustion and probiotics groups. The IM rat model was established by intraperitoneal injection of 5-Fu. Mild moxibustion treatment and intragastric probiotic administration were provided once daily for 15 days. Tissue morphology, serum levels of inflammatory factors and the expression levels of tight junction proteins, caspase-1, gasdermin D and NLRP3 were evaluated in colon tissue, through hematoxylin and eosin staining, electron microscopy, enzyme-linked immunosorbent assay, Western blotting, quantitative real-time reverse transcription polymerase chain reaction and immunofluorescence. Gut microbiome profiling was conducted through 16S rRNA amplicon sequencing. RESULTS: Moxibustion and probiotic treatments significantly increased the expression levels of tight junction proteins, reduced cell apoptosis and the expression levels of caspase-1, gasdermin D and NLRP3; they also decreased the serum levels of tumor necrosis factor-α, interleukin (IL)-6, IL-1ß and IL-18, while increasing serum levels of IL-10. Moxibustion and probiotic treatments also corrected the reduction in α-diversity and ß-diversity in IM rats, greatly increased the proportion of the dominant bacterial genus Lactobacillus and reduced the abundance of the genera Roseburia and Escherichia in chemotherapy-treated rats to levels observed in healthy animals. We also found that these dominant genera were firmly correlated with the regulation of pyroptosis-associated proteins and inflammatory factors. Finally, moxibustion and probiotic treatments elicited similar effects in regulating intestinal host-microbial homeostasis and the expression of NLRP3 inflammasome-related factors. CONCLUSION: Moxibustion exerts its therapeutic effect on IM by ameliorating mucosal damage and reducing inflammation. Moreover, moxibustion modulates the gut microbiota, likely via decreasing the expression levels of the NLRP3 inflammasome.


Assuntos
Microbioma Gastrointestinal , Moxibustão , Mucosite , Animais , Fluoruracila , Inflamassomos , Mucosa Intestinal , Masculino , Mucosite/induzido quimicamente , Mucosite/terapia , Proteína 3 que Contém Domínio de Pirina da Família NLR , RNA Ribossômico 16S , Ratos , Ratos Sprague-Dawley
18.
J Oral Maxillofac Surg ; 79(6): 1262-1269, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33358706

RESUMO

The indications for use of programed cell death receptor (PD-1) inhibitors to treat cancer continues to expand rapidly. Treatment with PD-1 inhibitors has been associated with numerous immune-mediated mucocutaneous side effects. Here, we report 2 cases of severe mucositis caused by the PD-1 inhibitor pembrolizumab and review the defining features of similar cases. Recognition of mucocutaneous toxicities of PD-1 inhibitors is increasingly important as their use continues to expand. A stepwise approach to diagnosis and management is also reviewed.


Assuntos
Mucosite , Algoritmos , Anticorpos Monoclonais , Anticorpos Monoclonais Humanizados , Humanos , Mucosite/induzido quimicamente , Receptor de Morte Celular Programada 1
19.
Trials ; 21(1): 948, 2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33225965

RESUMO

BACKGROUND: Since decades, fever and infections have been the most important complications of intensive chemotherapy and hematopoietic stem cell transplantation (HSCT) in the treatment of hematologic malignancies. Neutropenia has long been considered to be the most important risk factor for these complications. However, recent studies have shown that not neutropenia, but the development of mucositis is the most important cause of these complications. Currently, limited options for the prevention and treatment of mucositis are available, of which most are only supportive. The pro-inflammatory cytokine interleukin-1 (IL-1) plays a crucial role in the pathogenesis of mucositis. Pre-clinical studies of chemotherapy-induced mucositis have shown that recombinant human IL-1 receptor antagonist anakinra significantly ameliorated intestinal mucositis. In our pilot study AFFECT-1, we examined the safety and maximal tolerated dose of anakinra in patients with multiple myeloma, treated with high-dose melphalan (HDM) and autologous HSCT, selecting a dose of 300 mg daily for the phase IIb trial. The aim of the AFFECT-2 study is to determine the efficacy of anakinra in preventing fever during neutropenia (FN) and mucositis in this study population. METHODS/DESIGN: A multicenter, randomized, placebo-controlled, double-blind phase IIb trial will be conducted. Ninety patients with multiple myeloma scheduled for treatment with HDM and autologous HSCT will be included. Patients will be randomized between intravenous treatment with anakinra (300 mg) or placebo. Each group will be treated from day - 2 (day of HDM; day 0 is HSCT) up until day + 12. Outcome measures will be assessed at baseline, during admission, at discharge or day + 30, at day + 90, and + 1 year. The primary outcome will be reduction of FN. Secondary outcome measures include mucositis scores, bloodstream infections, citrulline levels, quality of life, and fatigue severity. DISCUSSION: The AFFECT-2 trial will examine the efficacy of anakinra in the management of fever during neutropenia and mucositis in patients with multiple myeloma treated with HDM and autologous HSCT. The results of this study may provide a new treatment option for these important complications. Also, this study will give us more insight in the pathophysiology of mucositis, including the role of IL-1 and the role of the microbiota in mucositis. TRIAL REGISTRATION: Clinicaltrials.gov NCT04099901 . Registered on September 23, 2019. EudraCT: 2018-005046-10.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Mucosite , Neutropenia , Método Duplo-Cego , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Proteína Antagonista do Receptor de Interleucina 1/efeitos adversos , Mucosite/induzido quimicamente , Mucosite/diagnóstico , Estudos Multicêntricos como Assunto , Neutropenia/induzido quimicamente , Neutropenia/diagnóstico , Projetos Piloto , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Transplante Autólogo
20.
Eur Rev Med Pharmacol Sci ; 24(21): 11365-11373, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33215457

RESUMO

OBJECTIVE: This experimental study explored the potential of oral zinc sulfate to protect the gut mucosa from 5-fluorouracil (5-FU)-induced degenerative lesions in Wistar rats. MATERIALS AND METHODS: Female Wistar rats were used and divided into 2 interventional groups (Z with 6 animals and F with 5 animals) and one control group (M with 5 rats). After 2 hours of fasting, group Z received via oral gavage 1.5 ml of solution, corresponding to 15 mg zinc sulfate for 9 consecutive days. Groups F and M received only the vehicles. On day 3, 400 mg/kg of 5-FU was administered intraperitoneally to groups Z and F. Tissue samples were collected from the duodenum, jejunum, colon and liver. Histological assessment for each gastrointestinal tract segment was determined semi-quantitatively by rating 11 histological features from normal (0) to severe (3). The independent groups were analyzed using the Kruskal-Wallis test and the Mann-Whitney U-test, with a Bonferroni correction for alpha (p ≤ 0.016). RESULTS: In group F the jejunum was the most affected area with a mean histological score of  27 (25-32). In the Z group, significantly lower histological scores were obtained compared with group F (duodenum Z vs. F: U = 0, p = 0.004; jejunum Z vs. F: U = 0, p = 0.006 and colon: Z vs. F: U = 0, p = 0.005). Graded liver necro-inflammatory lesions were significantly lower in group Z compared with group F (U = 0, p = 0.004), suggesting fewer bacterial intestinal translocation processes. CONCLUSIONS: Zinc sulfate has a beneficial role, decreasing the severity of gut mucosal injuries induced by 5-FU in Wistar rats.


Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Fluoruracila/efeitos adversos , Trato Gastrointestinal/efeitos dos fármacos , Mucosite/tratamento farmacológico , Sulfato de Zinco/farmacologia , Administração Oral , Animais , Antimetabólitos Antineoplásicos/administração & dosagem , Modelos Animais de Doenças , Feminino , Fluoruracila/administração & dosagem , Trato Gastrointestinal/patologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/patologia , Mucosite/induzido quimicamente , Mucosite/patologia , Ratos , Ratos Wistar , Sulfato de Zinco/administração & dosagem
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