RESUMO
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic liver condition that often progresses to more advanced stages, such as metabolic dysfunction-associated steatohepatitis (MASH). MASH is characterized by inflammation and hepatocellular ballooning, in addition to hepatic steatosis. Despite the relatively high incidence of MASH in the population and its potential detrimental effects on human health, this liver disease is still not fully understood from a pathophysiological perspective. Deregulation of polyamine levels has been detected in various pathological conditions, including neurodegenerative diseases, inflammation, and cancer. However, the role of the polyamine pathway in chronic liver disorders such as MASLD has not been explored. In this study, we measured the expression of liver ornithine decarboxylase (ODC1), the rate-limiting enzyme responsible for the production of putrescine, and the hepatic levels of putrescine, in a preclinical model of MASH as well as in liver biopsies of patients with obesity undergoing bariatric surgery. Our findings reveal that expression of ODC1 and the levels of putrescine, but not spermidine nor spermine, are elevated in hepatic tissue of both diet-induced MASH mice and patients with biopsy-proven MASH compared with control mice and patients without MASH, respectively. Furthermore, we found that the levels of putrescine were positively associated with higher aspartate aminotransferase concentrations in serum and an increased SAF score (steatosis, activity, fibrosis). Additionally, in in vitro assays using human HepG2 cells, we demonstrate that elevated levels of putrescine exacerbate the cellular response to palmitic acid, leading to decreased cell viability and increased release of CK-18. Our results support an association between the expression of ODC1 and the progression of MASLD, which could have translational relevance in understanding the onset of this disease. © 2024 The Pathological Society of Great Britain and Ireland.
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Progressão da Doença , Fígado , Ornitina Descarboxilase , Putrescina , Animais , Humanos , Putrescina/metabolismo , Ornitina Descarboxilase/metabolismo , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Camundongos , Modelos Animais de Doenças , Feminino , Pessoa de Meia-Idade , Obesidade/metabolismo , Obesidade/complicações , Células Hep G2 , AdultoRESUMO
Acute myeloid leukemia (AML) is a cancer of the myeloid blood cells mainly treated with chemotherapy for cancer remission, but this non-selective treatment also induces numerous side effects. Investigations with bioactive compounds from plant-derived foods against cancer have increased in the last years because there is an urgent need to search for new anti-leukemic agents possessing higher efficacy and selectivity for AML cells and fewer negative side effects. In this study, we analyzed the anti-leukemic activity of several phytochemicals that are representative of the major classes of compounds present in cruciferous foods (glucosinolates, isothiocyanates, hydroxycinnamic acids, flavonols, and anthocyanins) in the human acute myeloid leukemia cell line HL-60. Our results revealed that among the different Brassica-derived compounds assayed, sulforaphane (SFN) (an aliphatic isothiocyanate) showed the most potent anti-leukemic activity with an IC50 value of 6 µM in dose-response MTT assays after 48 h of treatment. On the other hand, chlorogenic acid (a hydroxycinnamic acid) and cyanidin-3-glucoside (an anthocyanin) also displayed anti-leukemic potential, with IC50 values of 7 µM and 17 µM after 48 h of incubation, respectively. Importantly, these compounds did not show significant cell toxicity in macrophages-like differentiated cells at 10 and 25 µM, indicating that their cytotoxic effects were specific to AML cancer cells. Finally, we found that these three compounds were able to induce the NRF2/KEAP1 signaling pathway in a dose-dependent manner, highlighting SFN as the most potent NRF2 activator. Overall, the present evidence shed light on the potential for using foods and ingredients rich in anticancer bioactive phytochemicals from Brassica spp.
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Brassica , Leucemia Mieloide Aguda , Humanos , Brassica/metabolismo , Antocianinas/farmacologia , Antocianinas/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Células HL-60 , Isotiocianatos/farmacologia , Isotiocianatos/metabolismo , Compostos Fitoquímicos/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológicoRESUMO
Obesity and colorectal cancer (CRC) are among the leading diseases causing deaths in the world, showing a complex multifactorial pathology. Obesity is considered a risk factor in CRC development through inflammation, metabolic, and signaling processes. Leptin is one of the most important adipokines related to obesity and an important proinflammatory marker, mainly expressed in adipose tissue, with many genetic variation profiles, many related influencing factors, and various functions that have been ascribed but not yet fully understood and elucidated, the most important ones being related to energy metabolism, as well as endocrine and immune systems. Aberrant signaling and genetic variations of leptin are correlated with obesity and CRC, with the genetic causality showing both inherited and acquired events, in addition to lifestyle and environmental risk factors; these might also be related to specific pathogenic pathways at different time points. Moreover, mutation gain is a crucial factor enabling the genetic process of CRC. Currently, the inconsistent and insufficient data related to leptin's relationship with obesity and CRC indicate the necessity of further related studies. This review summarizes the current knowledge on leptin genetics and its potential relationship with the main pathogenic pathways of obesity and CRC, in an attempt to understand the molecular mechanisms of these associations, in the context of inconsistent and contradictory data. The understanding of these mechanisms linking obesity and CRC could help to develop novel therapeutic targets and prevention strategies, resulting in a better prognosis and management of these diseases.
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Neoplasias Colorretais , Leptina , Adipocinas/metabolismo , Tecido Adiposo/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Humanos , Leptina/genética , Leptina/metabolismo , Obesidade/complicações , Obesidade/genética , Obesidade/metabolismo , Receptores para Leptina/metabolismoRESUMO
PURPOSE: Urolithins, metabolites produced by the gut microbiota from ellagic acid, have been acknowledged with cancer chemopreventive activity. Although urolithin A (Uro-A) has been reported to be the most active one, 10-50 % of humans can also produce the isomer isourolithin A (IsoUro-A). However, no biological activity for IsoUro-A has been reported so far. Herein, we describe for the first time the antiproliferative effect of IsoUro-A, compared to Uro-A, against both human colon cancer (Caco-2) and normal (CCD18-Co) cell lines. METHODS: Cell proliferation was evaluated by MTT and Trypan blue exclusion assays. Cell cycle was analyzed by flow cytometry and apoptosis measured by the Annexin V/PI method. Finally, urolithins metabolism was analyzed by HPLC-DAD-MS/MS. RESULTS: IsoUro-A inhibited the proliferation of Caco-2 cells in a time- and dose-dependent manner, though it was significantly lower than Uro-A (IC50 = 69.7 ± 4.5 and 49.2 ± 3.8 µM at 48 h, respectively). Both urolithins arrested Caco-2 cell cycle at S and G2/M phases and induced apoptosis at concentrations previously found in human colon tissues. Notably, Caco-2 cells glucuronidated more efficiently IsoUro-A than Uro-A (~50 vs. ~20 % of conversion after 48 h, respectively). Both Uro-A and IsoUro-A glucuronides did not exert antiproliferative effects. In addition, cell growth inhibition was higher in Caco-2 than in normal cells. CONCLUSIONS: IsoUro-A exerts strong antiproliferative activity, which is reduced by the extensive glucuronidation at 9-position in cancer cells. Further studies are needed to elucidate whether the in vitro structure-activity relationship found for Uro-A and IsoUro-A plays any role in humans.
Assuntos
Anticarcinógenos/metabolismo , Apoptose , Colo/metabolismo , Neoplasias do Colo/metabolismo , Cumarínicos/metabolismo , Mucosa Intestinal/metabolismo , Anticarcinógenos/efeitos adversos , Anticarcinógenos/química , Biomarcadores/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Colo/citologia , Colo/patologia , Neoplasias do Colo/patologia , Cumarínicos/efeitos adversos , Cumarínicos/química , Fase G2 , Glucuronídeos/química , Glucuronídeos/metabolismo , Humanos , Mucosa Intestinal/citologia , Mucosa Intestinal/patologia , Isomerismo , Cinética , Estrutura Molecular , Fase SRESUMO
PURPOSE: Urolithins, gut microbiota metabolites derived from ellagic acid and ellagitannins, reach micromolar concentrations in the colon lumen where can have anti-inflammatory and anticancer effects. The antiproliferative activity of urolithins (Uro-A, Uro-B, Uro-C and Uro-D) and their most relevant in vivo glucuronides were evaluated in three human colon cancer cell lines (Caco-2, SW480 and HT-29). METHODS: Cell proliferation was evaluated by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide and Trypan blue exclusion assays. Cell cycle was evaluated by flow cytometry and urolithins metabolism by HPLCMS/MS. RESULTS: Urolithins inhibited cell proliferation and cell cycle progression in a time- and dose-dependent manner and arrested the cells at S and G2/M phases, depending on the urolithin. Uro-A exerted the highest antiproliferative activity, followed by Uro-C, Uro-D and Uro-B. Unlike Caco-2 and SW480 cells, HT-29 cells partially overcame the effects after 48 h, which was related to the complete glucuronidation of urolithins. Uro-A or Uro-B glucuronides did not affect cell cycle and showed lower antiproliferative activity than their aglycone counterparts. Uro-A or Uro-B plus inhibitors of drug efflux ABC transporters partially prevented the glucuronidation of urolithins in HT-29 cells which became more sensitive. CONCLUSIONS: Uro-A, Uro-B, Uro-C and Uro-D exerted different antiproliferative effects depending on the colon cancer cell line. We also report here, for the first time, the role of ABC transporters and Phase-II metabolism in HT-29 cells as a mechanism of cancer resistance against urolithins due to their conversion to glucuronide conjugates that exerted lower antiproliferative activity.
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Antibióticos Antineoplásicos/farmacologia , Neoplasias do Colo/tratamento farmacológico , Cumarínicos/farmacologia , Taninos Hidrolisáveis/farmacologia , Desintoxicação Metabólica Fase II , Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Transportadores de Cassetes de Ligação de ATP/metabolismo , Anti-Inflamatórios não Esteroides/antagonistas & inibidores , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/metabolismo , Anti-Inflamatórios não Esteroides/farmacologia , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Colo/efeitos dos fármacos , Colo/metabolismo , Neoplasias do Colo/metabolismo , Cumarínicos/antagonistas & inibidores , Cumarínicos/química , Cumarínicos/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fase G2/efeitos dos fármacos , Glucuronídeos/química , Glucuronídeos/metabolismo , Humanos , Taninos Hidrolisáveis/antagonistas & inibidores , Taninos Hidrolisáveis/química , Taninos Hidrolisáveis/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Cinética , Moduladores de Transporte de Membrana/farmacologia , Fase S/efeitos dos fármacosRESUMO
Liver-targeted acetyl-coenzyme A (CoA) carboxylase (ACC) inhibitors in metabolic dysfunction-associated steatotic liver disease (MASLD) trials reveal notable secondary effects: hypertriglyceridemia and altered glucose metabolism, paradoxically with reduced hepatic steatosis. In their study, Deja et al. explored how hepatic ACC influences metabolism using different pharmacological and genetic methods, coupled with targeted metabolomics and stable isotope-based tracing techniques.
Assuntos
Acetil-CoA Carboxilase , Fígado , Animais , Humanos , Acetil-CoA Carboxilase/antagonistas & inibidores , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Fígado Gorduroso/metabolismo , Fígado/metabolismoRESUMO
Associations between dyslipidemia and metabolic dysfunction-associated steatotic liver disease (MASLD) have been reported. Previous studies have shown that the triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio may be a surrogate marker of MASLD, assessed by liver ultrasound. However, no studies have evaluated the utility of this ratio according to biopsy-proven MASLD and its stages. Therefore, our aim was to evaluate if the TG/HDL-C ratio allows for the identification of biopsy-proven MASLD in patients with obesity. We conducted a case-control study in 153 patients with obesity who underwent metabolic surgery and had a concomitant liver biopsy. Fifty-three patients were classified as no MASLD, 45 patients as metabolic dysfunction-associated steatotic liver-MASL, and 55 patients as metabolic dysfunction-associated steatohepatitis-MASH. A receiver operating characteristic (ROC) analysis was performed to assess the accuracy of the TG/HDL-C ratio to detect MASLD. We also compared the area under the curve (AUC) of the TG/HDL-C ratio, serum TG, and HDL-C. A higher TG/HDL-C ratio was observed among patients with MASLD, compared with patients without MASLD. No differences in the TG/HDL-C ratio were found between participants with MASL and MASH. The greatest AUC was observed for the TG/HDL-C ratio (AUC 0.747, p < 0.001) with a cut-off point of 3.7 for detecting MASLD (sensitivity = 70%; specificity = 74.5%). However, no statistically significant differences between the AUC of the TG/HDL-C ratio and TG or HDL-C were observed to detect MASLD. In conclusion, although an elevated TG/HDL-C ratio can be found in patients with MASLD, this marker did not improve the detection of MASLD in our study population, compared with either serum TG or HDL-C.
Assuntos
HDL-Colesterol , Fígado Gorduroso , Doenças Metabólicas , Obesidade , Triglicerídeos , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Biópsia , Estudos de Casos e Controles , HDL-Colesterol/sangue , Fígado Gorduroso/sangue , Fígado Gorduroso/complicações , Fígado Gorduroso/diagnóstico , Fígado Gorduroso/patologia , Doenças Metabólicas/sangue , Doenças Metabólicas/complicações , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/patologia , Obesidade/sangue , Obesidade/complicações , Obesidade/patologia , Curva ROC , Triglicerídeos/sangue , Biomarcadores/sangueRESUMO
BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely tied to obesity. The degree ranges from steatosis (MASL) and steatohepatitis (MASH) to liver cirrhosis. PCSK9 controls cholesterol and lipid particle transport to the liver. PCSK9 might interfere with the pathophysiology of MASLD and bariatric surgery (BS) outcomes of patients with MASLD. OBJECTIVES: Evaluate the relationship between serum and hepatic PCSK9 levels with the degree of MASLD and the metabolic outcome of BS. SETTING: University Hospital, Spain. METHODS: A total of 110 patients with obesity undergoing BS were classified according to liver histology as controls, MAS, and MASH. PCSK9 levels in serum were measured before and 6 months after BS using enzyme-linked immunosorbent assay. PCSK9 protein and mRNA levels in liver tissue were analyzed by immunohistochemistry and reverse transcriptase-polymerase chain reaction, respectively. RESULTS: Hepatic PCSK9 protein levels were diminished in MASL and MASH compared with patients without MASLD and showed a strong negative association with MASLD severity scores. Liver PCSK9 mRNA was higher in MASH compared with controls and MASL and showed positive associations with MASLD severity scores. There were no differences in serum PCSK9 pre or postBS between the groups. Pre- and postsurgery serum PCSK9 positively correlated with cholesterol fold-changes and body mass index (BMI), cholesterol, and low-density lipoprotein -cholesterol fold-changes, respectively. PCSK9 fold-change positively correlated with BMI changes and was the sole variable explaining BMI fold changes in a regression model. CONCLUSIONS: PCSK9 mRNA and protein in the liver might be associated with the degree of MASLD. Serum PCSK9 may be associated with cholesterol and/or BMI fold changes. Serum changes of PCSK9 after BS could explain BMI loss outcome.
Assuntos
Cirurgia Bariátrica , Fígado Gorduroso , Pró-Proteína Convertase 9 , Humanos , Pró-Proteína Convertase 9/sangue , Pró-Proteína Convertase 9/metabolismo , Masculino , Feminino , Pessoa de Meia-Idade , Fígado Gorduroso/metabolismo , Adulto , Obesidade Mórbida/cirurgia , Obesidade Mórbida/complicações , Resultado do Tratamento , Fígado/metabolismo , Fígado/patologiaRESUMO
CONTEXT: Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by the intracellular lipid accumulation in hepatocytes. Excess caloric intake and high-fat diets are considered to significantly contribute to MASLD development. OBJECTIVE: To evaluate the hepatic and serum fatty acid (FA) composition in patients with different stages of MASLD, and their relationship with FA dietary intake and MASLD-related risk factors. METHODS: This was a case-control study in patients with obesity undergoing bariatric surgery at a university hospital between January 2020 and December 2021. Participants were distributed in 3 groups: no MASLD (n = 26), steatotic liver disease (n = 33), and metabolic dysfunction-associated steatohepatitis (n = 32). Hepatic and serum FA levels were determined by gas chromatography-mass spectrometry. Nutritional status was evaluated using validated food frequency questionnaires. The hepatic expression of genes involved in FA metabolism was analyzed by reverse transcription quantitative polymerase chain reaction. RESULTS: The hepatic, but not serum, FA profiles were significantly altered in patients with MASLD compared with those without MASLD. No differences were observed in FA intake between the groups. Levels of C16:0, C18:1, and the C18:1/C18:0 ratio were higher, while C18:0 levels and C18:0/C16:0 ratio were lower in patients with MASLD, being significantly different between the 3 groups. Hepatic FA levels and ratios correlated with histopathological diagnosis and other MASLD-related parameters. The expression of genes involved in the FA metabolism was upregulated in patients with MASLD. CONCLUSION: Alterations in hepatic FA levels in MASLD patients were due to enhancement of de novo lipogenesis in the liver.
Assuntos
Ácidos Graxos , Fígado Gorduroso , Lipidômica , Fígado , Obesidade , Humanos , Masculino , Feminino , Estudos de Casos e Controles , Adulto , Pessoa de Meia-Idade , Fígado/metabolismo , Fígado/patologia , Obesidade/metabolismo , Obesidade/complicações , Ácidos Graxos/metabolismo , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Metabolismo dos Lipídeos , Cirurgia BariátricaRESUMO
Silk fibroin nanoparticles (SFN) have become a promising tool in drug delivery systems due to their physicochemical characteristics. SFN have shown their outstanding properties as an active vehicle for polyphenols, enhancing their antioxidant and anti-inflammatory effects on macrophages; therefore, it becomes necessary to have an easy, reproducible and scalable production method. In order to improve the production of nanoparticles, we performed direct precipitation of non-dialyzed silk fibroin solutions and evaluated the reproducibility of the method using dynamic light scattering. We also studied the loading efficiency of three different natural polyphenols using propylene glycol as a solvent. The loaded nanoparticles were fully characterized and used to treat human macrophage cells to assess the anti-inflammatory activity of these nanoparticles. The measured hydrodynamic characteristics of the SFN and the overall yield of the process showed that the new preparation method is highly reproducible and repeatable. Thus, we not only present a new scalable method to prepare silk nanoparticles but also how to improve the loading of natural polyphenolic compounds to the SFN, as well as the important anti-inflammatory effects of these loaded nanoparticles in a cell model of human macrophage cells.
RESUMO
OBJECTIVE: Alterations in the hepatic lipidome are a crucial factor involved in the pathophysiology of nonalcoholic fatty liver disease (NAFLD). The aim of this study was to evaluate the serum and hepatic profile of branched-chain fatty acids (BCFAs) in patients with different stages of NAFLD. METHODS: This was a case-control study performed in 27 patients without NAFLD, 49 patients with nonalcoholic fatty liver, and 17 patients with nonalcoholic steatohepatitis, defined by liver biopsies. Serum and hepatic levels of BCFAs were analyzed by gas chromatography-mass spectrometry. The hepatic expression of genes involved in the endogenous synthesis of BCFAs was analyzed by real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: A significant increase in hepatic BCFAs was found in subjects with NAFLD compared with those without NAFLD; no differences were observed in serum BCFAs between study groups. Trimethyl BCFAs, iso-BCFAs, and anteiso-BCFAs were increased in subjects with NAFLD (either nonalcoholic fatty liver or nonalcoholic steatohepatitis) compared with those without NAFLD. Correlation analysis showed a relationship between hepatic BCFAs and the histopathological diagnosis of NAFLD, as well as other histological and biochemical parameters related to this disease. Gene expression analysis in liver showed that the mRNA levels of BCAT1, BCAT2, and BCKDHA were upregulated in patients with NAFLD. CONCLUSIONS: These results suggest that the increased production of liver BCFAs might be related to NAFLD development and progression.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Estudos de Casos e Controles , Fígado/metabolismo , Ácidos Graxos/metabolismo , Transaminases/metabolismoRESUMO
BACKGROUND: Alterations in the neural polyamine system are known to be associated with different brain pathological conditions. In addition, the regulation of enzymes involved in polyamine metabolism such as ornithine decarboxylase (ODC), antizymes (AZs), and antizyme inhibitors (AZINs) is critical during brain development. However, while most studies focus on ODC and AZs, less is known about AZIN expression and function in the brain. Thus, our aim was to analyze the expression pattern of AZIN2 during postnatal development, its brain distribution, and its possible implication in phenotypical alterations. METHODS: The expression pattern of Azin2 and other genes related to polyamine metabolism was analyzed by RT-qPCR. ß-D-galactosidase staining was used to determine the anatomical distribution of AZIN2 in a Azin2 knockout model containing the ßGeo marker. Brain polyamine content was determined by HPLC. The Rota-Rod and Pole functional tests were used to evaluate motor skills in Azin2-lacking mice. RESULTS: Our results showed that expression of genes codifying for AZs and AZINs showed a similar increasing pattern over time that coincided with a decrease in ODC activity and putrescine levels. The analysis of AZIN2 distribution demonstrated that it is strongly expressed in the cerebellum and distributed along the neuron body and dendrites. The ablation of Azin2 showed a decrease in putrescine levels and is related to reduced motor skills. CONCLUSIONS: Our study revealed that AZIN2 expression in the brain is particularly limited to the cerebellum. In addition, the ablation of Azin2 leads to a reduction in putrescine that relates to alterations in motor function, suggesting the role of AZIN2 in the functioning of dopaminergic neurons.
Assuntos
Proteínas de Transporte , Poliaminas , Camundongos , Animais , Proteínas de Transporte/metabolismo , Poliaminas/metabolismo , Putrescina , Ornitina Descarboxilase/metabolismo , Encéfalo/metabolismo , LocomoçãoRESUMO
Colorectal cancer (CRC) is the third most common cancer and the second cause of cancer death worldwide. Several factors have been postulated to be involved in CRC pathophysiology, including heritable and environmental factors, which are the latest to be closely associated with nutritional habits, physical activity, obesity, and the gut microbiota. The latter may also play a key role in CRC prognosis and derived complications in patients undergoing surgery. This is a single-center, open, controlled, randomized clinical trial, in patients with scheduled surgical intervention for CRC. The primary objective is to assess whether a pre-surgical nutritional intervention, based on a high-fiber diet rich in polyunsaturated fatty acids (PUFAs), can reduce disturbances of the gut microbiota composition and, consequently, the rate of post-surgical complications in patients with CRC. Patients will be randomized in a 1:1 ratio after receiving a diagnosis of CRC. In the control arm, patients will receive standard nutritional recommendations, while patients in the intervention arm will be advised to follow a high-fiber diet rich in PUFAs before surgery. Participants will be followed up for one year to evaluate the overall rate of postsurgical complications, recurrences of CRC, response to adjuvant therapy, and overall/disease-free survival.
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Oxidative stress is involved in cell death in neurodegenerative diseases. Dietary polyphenols can exert health benefits, but their direct effects on neuronal cells are debatable because most phenolics are metabolized and do not reach the brain as they occur in the dietary sources. Herein, we evaluate the effects of a panel of bioavailable polyphenols and derived metabolites at physiologically relevant conditions against H2O2-induced apoptosis in human neuroblastoma SH-SY5Y cells. Among the 19 metabolites tested, 3,4-dihydroxyphenylpropionic acid, 3,4-dihydroxyphenylacetic acid, gallic acid, ellagic acid, and urolithins prevented neuronal apoptosis via attenuation of ROS levels, increased REDOX activity, and decreased oxidative stress-induced apoptosis by preventing the caspase-3 activation via the mitochondrial apoptotic pathway in SH-SY5Y cells. This suggests that dietary sources containing the polyphenol precursors of these molecules such as cocoa, berries, walnuts, and tea could be potential functional foods to reduce oxidative stress associated with the onset and progress of neurodegenerative diseases.
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Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Polifenóis/farmacologia , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Linhagem Celular Tumoral , Humanos , Estrutura Molecular , Neurônios/citologia , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , Polifenóis/química , Polifenóis/metabolismoRESUMO
Colon cancer stem cells (CSCs) offer a novel paradigm for colorectal cancer (CRC) treatment and dietary polyphenols may contribute to battle these cells. Specifically, polyphenol-derived colon metabolites have the potential to interact with and affect colon CSCs. We herein report the effects against colon CSCs of two mixtures of ellagitannin (ET) metabolites, ellagic acid (EA) and the gut microbiota-derived urolithins (Uro) at concentrations detected in the human colon tissues following the intake of ET-containing products (pomegranate, walnuts). These mixtures reduce phenotypic and molecular features in two models of colon CSCs: Caco-2 cells and primary tumour cells from a patient with CRC. The mixture containing mostly Uro-A (85% Uro-A, 10% Uro-C, 5% EA) was most effective at inhibiting the number and size of colonospheres and aldehyde dehydrogenase activity (ALDH, a marker of chemoresistance) whereas the mixture containing less Uro-A but IsoUro-A and Uro-B (30% Uro-A, 50% IsoUro-A, 10% Uro-B, 5% Uro-C, 5% EA) had some effects on the number and size of colonospheres but not on ALDH. These data support a role for polyphenols metabolites in the control of colon cancer chemoresistance and relapse and encourage the research on the effects of polyphenols against CSCs.
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Neoplasias do Colo/tratamento farmacológico , Cumarínicos/farmacologia , Ácido Elágico/farmacologia , Taninos Hidrolisáveis/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Biomarcadores Tumorais/metabolismo , Neoplasias do Colo/patologia , Quimioterapia Combinada , Humanos , Células-Tronco Neoplásicas/patologia , Células Tumorais CultivadasRESUMO
SCOPE: Ellagitannins, ellagic acid, and the colonic metabolites urolithins (Uros) exhibit anticancer effects against colon cells, but a comprehensive molecular analysis has not been done. Herein, we used a panel of cell lines to first time evaluate the antiproliferative properties and accompanying molecular responses of two ellagitannin metabolites mixtures mimicking the situation in vivo and of each individual metabolite. METHODS AND RESULTS: We examined cell growth, cell cycle, apoptosis, and the expression of related genes and microRNAs (miRs) in a panel of nonmalignant and malignant colon cell lines. Regardless of the composition, the mixed metabolites similarly inhibited proliferation, induced cycle arrest, and apoptosis. All the metabolites contributed to these effects, but Uro-A, isourolithin A, Uro-C, and Uro-D were more potent than Uro-B and ellagic acid. Despite molecular differences between the cell lines, we discerned relevant changes in key cancer markers and corroborated the induction of CDKN1A (cyclin-dependent kinase inhibitor 1A gene (p21, Cip1); encoding p21) as a common step underlying the anticancer properties of Uros. Interestingly, cell-unique downregulation of miR-224 or upregulation of miR-215 was found associated with CDKN1A induction. CONCLUSION: Physiologically relevant mixtures of Uros exert anticancer effects against colon cancer cells via a common CDKN1A upregulatory mechanism. Other associated molecular responses are however heterogeneous and mostly cell-specific.
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Neoplasias Colorretais/dietoterapia , Inibidor de Quinase Dependente de Ciclina p21/genética , Ácido Elágico/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Anticarcinógenos/metabolismo , Anticarcinógenos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Colo/citologia , Colo/efeitos dos fármacos , Colo/metabolismo , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/prevenção & controle , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Cumarínicos/farmacologia , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Ácido Elágico/metabolismo , Células HT29/efeitos dos fármacos , Humanos , Taninos Hidrolisáveis/farmacologia , MicroRNAs/genéticaRESUMO
Diabetes education has proved to be an essential tool in the care of patients with type 1 diabetes mellitus. To perform this educational task, the VII Area Murcia East Diabetes Unit, incorporated nurses in advanced diabetes education in the Hospital General Universitario Reina Sofía of Murcia. We carried out a retrospective study, which assessed the performance of these nurses by evaluating the type 1 diabetic patients attending inquiries between 2007 and 2011. We analyzed a total of 179 medical records, of patients with type 1 diabetes mellitus over 11 years, with 103 (52.3%) males and 94 (47.7%) women. Patients had a mean age 38.25 ± 14.02 years and a mean duration of diabetes of 16.22 ± 11.73 years. The initial mean value of HbA1c was 8.49 ± 2.04%. Only 37 (16.2%) of the 197 patients were under 25 at the start of the study. The results showed that the decrease in HbA1c (-0.57 ± 1.80%) was significant after 6 months (p = 0.002) from the first query, reaching values of 7.86 ± 1.39% and remained from that time. Insulin doses were stable throughout the study.
La educación diabetológica ha demostrado ser esencial en la atención del paciente diabético. Para realizar esta tarea educacional, la Unidad de Diabetes del Área VII Murcia Este, que incorporó a enfermeras especializadas en educación diabetológica avanzada en el Hospital General Universitario Reina Sofía de Murcia. Se realizó un estudio retrospectivo, donde se valoró la actuación de dichas enfermeras mediante la evaluación de los pacientes diabéticos tipo 1 que acudieron a sus consultas entre los años 2007 y 2011. Se analizaron un total de 179 historias clínicas de pacientes con diabetes mellitus tipo 1 (DM1) mayores de 11 años, siendo 103 (52.3 %) varones y 94 (47.7 %) mujeres. Los pacientes presentaban una edad media de 38.25 ± 14.02 años y un tiempo de duración de la diabetes medio de 16.22 ± 11.73 años. El valor de HbA1c inicial medio fue de 8.49 ± 2.04 %. De los 197 pacientes, solo 37 (16.2 %) eran menores de 25 años en el momento de acudir a consulta. Los resultados obtenidos demostraron que la disminución de la HbA1c (-0,57 ± 1,80 %) era significativa a los 6 meses (p: 0,002) de la primera consulta alcanzando valores de 7.86 ± 1.39 y manteniéndose a partir de ese momento. Las dosis de insulina fueron estables a lo largo del estudio.