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BACKGROUND: Cytogenotoxic damage caused by the consumption of legal and illegal drugs in drug abusers has been demonstrated, primarily due to alterations in their antioxidant capacity, cellular repair mechanisms, and increased production of free radicals. Folic acid shows antioxidant activity by acting as a reducing agent, neutralizing present free radicals, and reducing genomic damage. METHODS: The intervention involved administering 15 mg of folic acid, divided into three doses per day, to a group of 44 drug abusers. The frequency of nuclear abnormalities (NAs) was determined; micronuclei (MNs), nuclear buds (NBUDs), binucleated cells (BNs), abnormally condensed chromatin (CC), karyorrhexis (KX), pyknotic nuclei (PNs), and karyolysis (KL) were determined at different pre-treatment (baseline) and post-treatment time points at 15 and 30 days. Additionally, a group of 44 healthy individuals was used as the control group. RESULTS: We observed a statistically significant decrease in the frequency of NAs in the drug abuser group (28.45 ± 17.74 before supplementation vs. 11.18 ± 7.42 at 15 days and 9.11 ± 10.9 at 30 days of supplementation). Specifically, it decreased the frequency of NBUDs, BNs, CC, KX, and PNs (p < 0.05). CONCLUSION: Our study demonstrates a clear improvement in cytogenotoxic damage in drug abusers supplemented with folic acid.
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Drug abuse is considered a global health problem with serious social impact. In recent decades, changes in drug consumption patterns have shown a clear rising trend in the use of multiple drugs. Although the buccal micronucleus cytome (BMCyt) assay has evaluated cytotoxicity in drug abuse, there has not been an approach that takes into account this pattern of multiple drug use. Therefore, in this study, we evaluate for the first time the cytogenotoxic effects in multidrug users, and its correlation with the amount consumed and years of abuse. This study was conducted on 166 individuals by the BMCyt assay. A total of 83 individuals with a history of multiple licit (alcohol and tobacco) and at least one illicit drug abuse (marijuana, methamphetamines, cocaine, and/or inhalants), and 83 healthy individuals, non-drug abusers were analyzed. The results showed that drug abusers had higher frequencies of nuclear abnormalities nuclear buds, binucleated cells, pyknotic nuclei (PNs), karyorrhexis (KX), and abnormally condensed chromatin when compared with healthy controls. Moreover, results suggests that the use of licit and illicit drugs is related to cytogenotoxic damage, as was shown by an upward trend in the frequency of nuclear abnormalities identified in groups 1 (alcohol + tobacco + at least one illicit drug) and 2 (tobacco + at least one illicit drug). Furthermore, a positive correlation was found in the different groups, between the years and the amount of consumption of some drugs (alcohol, methamphetamine, and tobacco) with cytotoxicity markers such as KL, KX, and PNs.
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Drogas Ilícitas , Transtornos Relacionados ao Uso de Substâncias , Humanos , Testes para Micronúcleos/métodos , Núcleo Celular , Morte Celular , Nicotiana , Drogas Ilícitas/toxicidade , Mucosa BucalRESUMO
Energetic and nutritional requirements play a crucial role in shaping the immune cells that infiltrate tumor and parasite infection sites. The dynamic interaction between immune cells and the microenvironment, whether in the context of tumor or helminth infection, is essential for understanding the mechanisms of immunological polarization and developing strategies to manipulate them in order to promote a functional and efficient immune response that could aid in the treatment of these conditions. In this review, we present an overview of the immune response triggered during tumorigenesis and establishment of helminth infections, highlighting the transition to chronicity in both cases. We discuss the energetic demands of immune cells under normal conditions and in the presence of tumors and helminths. Additionally, we compare the metabolic changes that occur in the tumor microenvironment and the infection site, emphasizing the alterations that are induced to redirect the immune response, thereby promoting the survival of cancer cells or helminths. This emerging discipline provides valuable insights into disease pathogenesis. We also provide examples of novel strategies to enhance immune activity by targeting metabolic pathways that shape immune phenotypes, with the aim of achieving positive outcomes in cancer and helminth infections.
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Mycobacterium avium (M. avium) represents a species of concern, because of its ability to modulate the host's innate immune response, and therefore influence trajectory of adaptative immunity. Since eradicative response against mycobacteria, and M. tuberculosis/M. avium, relies on peptides actively presented on a Major Histocompatibility complex-II (MHC-II) context, we assessed paradoxical stimulation of Dendritic Cell resulting on immature immunophenotype characterized by membrane minor increase of MHC-II and CD40 despite of high expression of the pro-inflammatory tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) in supernatants. Identification of M. avium leucine rich peptides forming short α-helices shutting down Type 1T helper (Th1), contribute to the understanding of immune evasion of an increasingly prevalent pathogen, and may provide a basis for future immunotherapy to infectious and non-infectious disease.
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Mycobacterium avium , Mycobacterium tuberculosis , Interleucina-6 , Complexo Principal de Histocompatibilidade , Células DendríticasRESUMO
Introducción: Las fracturas por heridas de arma de fuego son un motivo de consulta habitual en nuestro país. Existe gran variabilidad de conductas respecto a su tratamiento. El objetivo principal de este trabajo es analizar los distintos tratamientos y sus indicaciones. Materiales: Se realizó una revisión sistematizada de la literatura en las bases de datos Pubmed y Scielo. Se incluyeron artículos con fracturas por herida de arma de fuego en miembros superiores e inferiores, excluyendo la mano. Se analizó: tratamiento (ortopédico o quirúrgico), debridamiento, antibioticoterapia y complicaciones. Resultados: Se obtuvieron 19 artículos que cumplían los criterios de inclusión y exclusión. Los artículos tuvieron un Nivel de Evidencia tipo 2b, 3 y 4. Conclusiones: Los artículos analizados tienen un bajo nivel de evidencia. La fijación quirúrgica es variable y depende de la topografía ósea, la lesión de partes blandas y las lesiones asociadas. El debridamiento profundo está relacionado con mayores índices de infección. Las fracturas estables de tratamiento ortopédico no deberían debridarse ya que aumenta los índices de infección. Debería realizarse antibioticoterapia intravenosa inicial en todos los pacientes, la terapia posterior es discutida.
Introduction: Fractures due to gunshot wounds are a common reason for consultation in our country. There is great variability of conduct regarding its treatment. The main objective of this work is to analyze the different treatments and their indications. Materials: A systematic review of the literature was carried out in the Pubmed and Scielo databases. Articles with fractures due to gunshot wounds in the upper and lower limbs (excluding the hand) were included. We analyzed: treatment (orthopedic or surgical), debridement, antibiotic therapy and complications. Results: 19 articles were obtained that met the inclusion and exclusion criteria. The articles had a Level of Evidence type 2b, 3 and 4. Conclusions: The articles analyzed have a low level of evidence. Surgical fixation is variable and depends on bone topography, soft tissue injury, and associated injuries. Deep debridement is associated with higher rates of infection. Stable orthopedically treated fractures should not be debrided as this increases infection rates. Initial intravenous antibiotic therapy should be performed in all patients, subsequent therapy is discussed.
Introdução: As fraturas por ferimentos por arma de fogo são motivo comum de consulta em nosso país. Há grande variabilidade de conduta quanto ao seu tratamento. O objetivo principal deste trabalho é analisar os diferentes tratamentos e suas indicações. Materiais: Foi realizada revisão sistemática da literatura nas bases de dados Pubmed e Scielo. Foram incluídos artigos com fraturas por arma de fogo em membros superiores e inferiores, excluindo a mão. Foram analisados: tratamento (ortopédico ou cirúrgico), desbridamento, antibioticoterapia e complicações. Resultados: foram obtidos 19 artigos que atenderam aos critérios de inclusão e exclusão. Os artigos tinham Nível de Evidência tipo 2b, 3 e 4. Conclusões: Os artigos analisados ââapresentam baixo nível de evidência. A fixação cirúrgica é variável e depende da topografia óssea, lesão de tecidos moles e lesões associadas. O desbridamento profundo está associado a maiores taxas de infecção. Fraturas estáveis ââtratadas ortopedicamente não devem ser desbridadas, pois isso aumenta as taxas de infecção. A antibioticoterapia intravenosa inicial deve ser realizada em todos os pacientes, a terapia subsequente é discutida.
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Humanos , Ferimentos por Arma de Fogo/terapia , Ossos do Braço/lesões , Fraturas Ósseas/terapia , Ossos da Perna/lesões , Ferimentos por Arma de Fogo/cirurgia , Fraturas Ósseas/cirurgiaRESUMO
Currently, the only available vaccine against tuberculosis is Mycobacterium bovis Bacille Calmette-Guérin (BCG). Pulmonary tuberculosis protection provided by the vaccine varies depending on the strain, the patient's age and the evaluated population. Although the adaptive immune responses induced by different BCG strains have been widely studied, little conclusive data is available regarding innate immune responses, especially in macrophages. Here, we aimed to characterize the innate immune responses of human THP-1-derived macrophages at the transcriptional level following a challenge with either the BCG Mexico (M.BCG) or Phipps (P.BCG) strains. After a brief in vitro characterization of the bacterial strains and the innate immune responses, including nitric oxide production and cytokine profiles, we analyzed the mRNA expression patterns and performed pathway enrichment analysis using RNA microarrays. Our results showed that multiple biological processes were enriched, especially those associated with innate inflammatory and antimicrobial responses, including tumor necrosis factor (TNF)-α, type I interferon (IFN-I) and IFN-γ. However, four DEGs were identified in macrophages infected with M.BCG compared to P. BCG. These findings indicated the proinflammatory stimulation of macrophages induced by both BCG strains, at the cytokine level and in terms of gene expression, suggesting a differential expression pattern of innate immune transcripts depending on the mycobacterial strain.
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Vacina BCG , Mycobacterium bovis , Citocinas/metabolismo , Humanos , Imunidade Inata , Macrófagos/metabolismo , Fenótipo , RNA/metabolismoRESUMO
BACKGROUND AND AIM: Circulating amino acids are modified by sex, body mass index (BMI) and insulin resistance (IR). However, whether the presence of genetic variants in branched-chain amino acid (BCAA) catabolic enzymes modifies circulating amino acids is still unknown. Thus, we determined the frequency of two genetic variants, one in the branched-chain aminotransferase 2 (BCAT2) gene (rs11548193), and one in the branched-chain ketoacid dehydrogenase (BCKDH) gene (rs45500792), and elucidated their impact on circulating amino acid levels together with clinical, anthropometric and biochemical parameters. METHODS AND RESULTS: We performed a cross-sectional comparative study in which we recruited 1612 young adults (749 women and 863 men) aged 19.7 ± 2.1 years and with a BMI of 24.9 ± 4.7 kg/m2. Participants underwent clinical evaluation and provided blood samples for DNA extraction and biochemical analysis. The single nucleotide polymorphisms (SNPs) were determined by allelic discrimination using real-time polymerase chain reaction (PCR). The frequencies of the less common alleles were 15.2 % for BCAT2 and 9.83 % for BCKDH. The subjects with either the BCAT2 or BCKDH SNPs displayed no differences in the evaluated parameters compared with subjects homozygotes for the most common allele at each SNP. However, subjects with both SNPs had higher body weight, BMI, blood pressure, glucose, and circulating levels of aspartate, isoleucine, methionine, and proline than the subjects homozygotes for the most common allele (P < 0.05, One-way ANOVA). CONCLUSION: Our findings suggest that the joint presence of both the BCAT2 rs11548193 and BCKDH rs45500792 SNPs induces metabolic alterations that are not observed in subjects without either SNP.
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3-Metil-2-Oxobutanoato Desidrogenase (Lipoamida)/genética , Aminoácidos/sangue , Antígenos de Histocompatibilidade Menor/genética , Polimorfismo de Nucleotídeo Único , Proteínas da Gravidez/genética , Transaminases/genética , 3-Metil-2-Oxobutanoato Desidrogenase (Lipoamida)/metabolismo , Adolescente , Fatores Etários , Biomarcadores/sangue , Glicemia/análise , Pressão Sanguínea , Índice de Massa Corporal , Estudos Transversais , Feminino , Frequência do Gene , Estudos de Associação Genética , Homozigoto , Humanos , Masculino , México , Antígenos de Histocompatibilidade Menor/metabolismo , Fenótipo , Proteínas da Gravidez/metabolismo , Transaminases/metabolismo , Adulto JovemRESUMO
The malignant energetic demands are satisfied through glycolysis, glutaminolysis and de novo synthesis of fatty acids, while the host curses with a state of catabolism and systemic inflammation. The concurrent inhibition of both, tumor anabolism and host catabolism, and their effect upon tumor growth and whole animal metabolism, have not been evaluated. We aimed to evaluate in colon cancer cells a combination of six agents directed to block the tumor anabolism (orlistat + lonidamine + DON) and the host catabolism (growth hormone + insulin + indomethacin). Treatment reduced cellular viability, clonogenic capacity and cell cycle progression. These effects were associated with decreased glycolysis and oxidative phosphorylation, leading to a quiescent energetic phenotype, and with an aberrant transcriptomic landscape showing dysregulation in multiple metabolic pathways. The in vivo evaluation revealed a significant tumor volume inhibition, without damage to normal tissues. The six-drug combination preserved lean tissue and decreased fat loss, while the energy expenditure got decreased. Finally, a reduction in gene expression associated with thermogenesis was observed. Our findings demonstrate that the simultaneous use of this six-drug combination has anticancer effects by inducing a quiescent energetic phenotype of cultured cancer cells. Besides, the treatment is well-tolerated in mice and reduces whole animal energetic expenditure and fat loss.
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Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Metabolismo Energético/efeitos dos fármacos , Redes e Vias Metabólicas/efeitos dos fármacos , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Daunorrubicina/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Hormônio do Crescimento/farmacologia , Humanos , Indazóis/farmacologia , Indometacina/farmacologia , Insulina/farmacologia , Metabolismo/efeitos dos fármacos , Camundongos , Mitoxantrona/farmacologia , Orlistate/farmacologia , Fosforilação Oxidativa/efeitos dos fármacos , Vincristina/farmacologiaRESUMO
Colon cancer is a highly anabolic entity with upregulation of glycolysis, glutaminolysis, and de novo synthesis of fatty acids, which also induces a hypercatabolic state in the patient. The blockade of either cancer anabolism or host catabolism has been previously proven to be a successful anticancer experimental treatment. However, it is still unclear whether the simultaneous blockade of both metabolic counterparts can limit malignant survival and the energetic consequences of such an approach. In this chapter, by using the CT26.WT murine colon adenocarcinoma cell line as a model of study, we provide a method to simultaneously perform a pharmacological blockade of tumor anabolism and host catabolism, as a feasible therapeutic approach to treat cancer, and to limit its energetic supply.
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Adenocarcinoma/metabolismo , Antineoplásicos/farmacologia , Neoplasias do Colo/metabolismo , Ácidos Graxos/metabolismo , Glutamina/metabolismo , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Diazo-Oxo-Norleucina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Ácido Graxo Sintase Tipo I/antagonistas & inibidores , Ácido Graxo Sintase Tipo I/metabolismo , Feminino , Glutaminase/antagonistas & inibidores , Glutaminase/metabolismo , Glicólise/efeitos dos fármacos , Hexoquinase/antagonistas & inibidores , Hexoquinase/metabolismo , Indazóis/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Terapia de Alvo Molecular/métodos , Orlistate/administração & dosagem , SmegmamorphaRESUMO
Cancer upregulates glycolysis, glutaminolysis and lipogenesis, and induces a catabolic state in patients. The concurrent inhibition of both tumor anabolism and host catabolism, and the energetic consequences of such an approach, have not previously been fully investigated. In the present study, CT26.WT murine colon cancer cells were treated with the combination of anti-anabolic drugs orlistat, lonidamine and 6-diazo-5-oxo-L-norleucine (DON; OLD scheme), which are inhibitors of the de novo synthesis of fatty acids, glycolysis and glutaminolysis, respectively. In addition, the effects of OLD scheme sumplemented with the combination of anti-catabolic compounds, namely growth hormone, insulin and indomethacin (GII scheme), were also evaluated. The effects of the compounds used in combination on CT26.WT cell viability, clonogenicity and energetic metabolism were assessed in vitro. The results demonstrated that the anti-anabolic approach reduced cell viability, clonogenicity and cell cycle progression, and increased apoptosis. These effects were associated with decreased oxidative phosphorylation, glycolysis and fuel flexibility. Furthermore, the anti-catabolic scheme, alone or supplemented with anti-anabolic compounds, did not favor tumor growth. These findings indicated that the simultaneous pharmacological inhibition of tumor anabolism and host catabolism exhibits antitumor effects that should be further evaluated.
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PURPOSE: Ivermectin is an antiparasitic drug that exhibits antitumor effects in preclinical studies, and as such is currently being repositioned for cancer treatment. However, divergences exist regarding its employed doses in preclinical works. Therefore, the aim of this study was to determine whether the antitumor effects of ivermectin are observable at clinically feasible drug concentrations. METHODS: Twenty-eight malignant cell lines were treated with 5 µM ivermectin. Cell viability, clonogenicity, cell cycle, cell death and pharmacological interaction with common cytotoxic drugs were assessed, as well as the consequences of its use on stem cell-enriched populations. The antitumor in vivo effects of ivermectin were also evaluated. RESULTS: The breast MDA-MB-231, MDA-MB-468, and MCF-7, and the ovarian SKOV-3, were the most sensitive cancer cell lines to ivermectin. Conversely, the prostate cancer cell line DU145 was the most resistant to its use. In the most sensitive cells, ivermectin induced cell cycle arrest at G0-G1 phase, with modulation of proteins associated with cell cycle control. Furthermore, ivermectin was synergistic with docetaxel, cyclophosphamide and tamoxifen. Ivermectin reduced both cell viability and colony formation capacity in the stem cell-enriched population as compared with the parental one. Finally, in tumor-bearing mice ivermectin successfully reduced both tumor size and weight. CONCLUSION: Our results on the antitumor effects of ivermectin support its clinical testing.
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Antineoplásicos/farmacologia , Antiparasitários/farmacologia , Neoplasias da Mama/tratamento farmacológico , Reposicionamento de Medicamentos/métodos , Ivermectina/farmacologia , Animais , Apoptose , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Ciclo Celular , Movimento Celular , Proliferação de Células , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE: Obesity is associated with metabolic abnormalities, including insulin resistance and dyslipidemias. Previous studies demonstrated that genistein intake modifies the gut microbiota in mice by selectively increasing Akkermansia muciniphila, leading to reduction of metabolic endotoxemia and insulin sensitivity. However, it is not known whether the consumption of genistein in humans with obesity could modify the gut microbiota reducing the metabolic endotoxemia and insulin sensitivity. RESEARCH DESIGN AND METHODS: 45 participants with a Homeostatic Model Assessment (HOMA) index greater than 2.5 and body mass indices of ≥30 and≤40 kg/m2 were studied. Patients were randomly distributed to consume (1) placebo treatment or (2) genistein capsules (50 mg/day) for 2 months. Blood samples were taken to evaluate glucose concentration, lipid profile and serum insulin. Insulin resistance was determined by means of the HOMA for insulin resistance (HOMA-IR) index and by an oral glucose tolerance test. After 2 months, the same variables were assessed including a serum metabolomic analysis, gut microbiota, and a skeletal muscle biopsy was obtained to study the gene expression of fatty acid oxidation. RESULTS: In the present study, we show that the consumption of genistein for 2 months reduced insulin resistance in subjects with obesity, accompanied by a modification of the gut microbiota taxonomy, particularly by an increase in the Verrucomicrobia phylum. In addition, subjects showed a reduction in metabolic endotoxemia and an increase in 5'-adenosine monophosphate-activated protein kinase phosphorylation and expression of genes involved in fatty acid oxidation in skeletal muscle. As a result, there was an increase in circulating metabolites of ß-oxidation and ω-oxidation, acyl-carnitines and ketone bodies. CONCLUSIONS: Change in the gut microbiota was accompanied by an improvement in insulin resistance and an increase in skeletal muscle fatty acid oxidation. Therefore, genistein could be used as a part of dietary strategies to control the abnormalities associated with obesity, particularly insulin resistance; however, long-term studies are needed.
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Proteínas Quinases Ativadas por AMP/metabolismo , Fármacos Antiobesidade/administração & dosagem , Microbioma Gastrointestinal/efeitos dos fármacos , Genisteína/administração & dosagem , Resistência à Insulina , Músculo Esquelético/efeitos dos fármacos , Obesidade/metabolismo , Obesidade/microbiologia , Método Duplo-Cego , Ácidos Graxos/metabolismo , Humanos , Músculo Esquelético/metabolismoRESUMO
BACKGROUND AND AIMS: Calreticulin is a chaperone and master regulator of intracellular calcium homeostasis. Several additional functions have been discovered. Human and parasite calreticulin have been shown to suppress mammary tumor growth in vivo. Here, we explored the capacity of recombinant Taenia solium calreticulin (rTsCRT) to modulate cancer cell growth in vitro. METHODS: We used different concentrations of rTsCRT to treat cancer cell lines and analyzed viability and colony formation capacity. We also tested the combination of the IC20 or IC50 doses of rTsCRT and of the chemotherapeutic drug 5-fluorouracil on MCF7 and SKOV3 cell lines. As a control, the non-tumorigenic cell line MCF10-A was employed. The effect of the drug combinations was also assessed in cancer stem-like cells. Additionally, scavenger receptor ligands were employed to identify the role of this receptor in the rTsCRT anti-tumoral effect. RESULTS: rTsCRT has a dose-dependent in vitro anti-tumoral effect, being SKOV3 the most sensitive cell line followed by MCF7. When rTsCRT/5-fluorouracil were used, MCF7 and SKOV3 showed a 60% reduction in cell viability; colony formation capacity was also diminished. Treatment of cancer stem-like cells from MCF7 showed a higher reduction in cell viability, while those from SKOV3 were more sensitive to colony disaggregation. Finally, pharmacological inhibition of the scavenger receptor, abrogated the reduction in viability induced by rTsCRT in both the parental and stem-like cells. CONCLUSION: Our data suggest that rTsCRT alone or in combination with 5-fluorouracil inhibits the growth of breast and ovarian cancer cell lines through its interaction with scavenger receptors.
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Neoplasias da Mama/tratamento farmacológico , Calreticulina/uso terapêutico , Células-Tronco Neoplásicas/efeitos dos fármacos , Neoplasias Ovarianas/tratamento farmacológico , Proteínas Recombinantes/uso terapêutico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Calreticulina/genética , Calreticulina/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Sinergismo Farmacológico , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/farmacologia , Células HeLa , Humanos , Células MCF-7 , Células-Tronco Neoplásicas/metabolismo , Neoplasias Ovarianas/patologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacologia , Taenia solium/genéticaRESUMO
OBJECTIVE: Angiotensin-(1-7) [Ang-(1-7)], a component of the renin angiotensin system, is a vasodilator that exerts its effects primarily through the Mas receptor. The discovery of the Mas receptor in white adipose tissue (WAT) suggests an additional role for this peptide. The aim of the present study was to assess whether Ang-(1-7) can induce the expression of thermogenic genes in white adipose tissue and increase mitochondrial respiration in adipocytes. MATERIALS/METHODS: Stromal Vascular fraction (SVF)-derived from mice adipose tissue was stimulated for one week with Ang-(1-7), then expression of beige markers and mitochondrial respiration were assessed. Mas+/+ and Mas-/- mice fed a control diet or a high fat-sucrose diet (HFSD) were exposed to a short or long term infusion of Ang-(1-7) and body weight, body fat, energy expenditure, cold resistance and expression of beige markers were assessed. Also, transgenic rats overexpressing Ang-(1-7) were fed with a control diet or a high fat-sucrose diet and the same parameters were assessed. Ang-(1-7) circulating levels from human subjects with different body mass index (BMI) or age were measured. RESULTS: Incubation of adipocytes derived from SVF with Ang-(1-7) increased the expression of beige markers. Infusion of Ang-(1-7) into lean and obese Mas+/+mice also induced the expression of Ucp1 and some beige markers, an effect not observed in Mas-/- mice. Mas-/- mice had increased body weight gain and decreased cold resistance, whereas rats overexpressing Ang-(1-7) showed the opposite effects. Overexpressing rats exposed to cold developed new thermogenic WAT in the anterior interscapular area. Finally, in human subjects the higher the BMI, low circulating concentration of Ang-(1-7) levels were detected. Similarly, the circulating levels of Ang-(1-7) peptide were reduced with age. CONCLUSION: These data indicate that Ang-(1-7) stimulates beige markers and thermogenesis via the Mas receptor, and this evidence suggests a potential therapeutic use to induce thermogenesis of WAT, particularly in obese subjects that have reduced circulating concentration of Ang-(1-7).
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Tecido Adiposo Bege/efeitos dos fármacos , Angiotensina I/farmacologia , Fragmentos de Peptídeos/farmacologia , Proteínas Proto-Oncogênicas/fisiologia , Receptores Acoplados a Proteínas G/fisiologia , Termogênese/efeitos dos fármacos , Tecido Adiposo Bege/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Adulto , Animais , Respiração Celular/efeitos dos fármacos , Respiração Celular/genética , Células Cultivadas , Metabolismo Energético/genética , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas/genética , Ratos , Ratos Transgênicos , Receptores Acoplados a Proteínas G/genética , Termogênese/genética , Adulto JovemRESUMO
Lonidamine, 6-Diazo-5-oxo-L-norleucine (DON) and orlistat are well known inhibitors of glycolysis, glutaminolysis and of de novo fatty acid synthesis, respectively. Although their antitumor effects have been explored in detail, the potential inhibition of the malignant metabolic phenotype and its influence on the expression of chemokines and growth factors involved in colon cancer, have not been previously reported to the best of our knowledge. In the present study, dose-response curves with orlistat, lonidamine or DON were generated from cell viability assays conducted in SW480 colon cancer cells. In addition, the synergistic effect of these compounds was evaluated in SW480 human colon cancer cells. The determination of the doses used for maximum synergistic efficacy led to the exploration of the mRNA levels of the target genes hexokinase-2 (HK2), glutaminase-1 (GLS-1) and fatty acid synthase (FASN) in human SW480 and murine CT26.WT colon cancer cells. The cell viability was evaluated following transfection with small interfering (si)RNA targeting these genes and was assessed with trypan blue. The expression levels of chemokines and growth factors were quantified in the supernatant of SW480 cells with LEGENDplex™. The combination of lonidamine, DON and orlistat resulted in a synergistic cytotoxic effect and induced the transcription of the corresponding gene targets but their corresponding proteins were actually downregulated. The downregulation of the expression levels of HK2, GLS-1 and FASN following transfection of the cells with the corresponding siRNA sequences decreased their viability. The treatment significantly reduced the expression levels of 9 chemokines [interleukin-9, C-X-C motif chemokine ligand (CXCL) 10, eotaxin, chemokine ligand (CCL) 9, CXCL5, CCL20, CXCL1, CXCL11 and CCCL4] and one growth factor (stem cell factor). These changes were associated with decreased phosphorylated-nuclear factor κB-p65. The data demonstrate that lonidamine, DON and orlistat in combination reduce the expression levels of chemokines and growth factors in colon cancer cells. Additional research is required to investigate the exact way by which both tumor and stromal cells regulate the expression levels of chemokines and growth factors.
RESUMO
Objetivo: Determinar la calidad de vida en mujeres con cáncer de mama que acuden al Departamento de Oncología en el Hospital Nacional Daniel Alcides Carrión (Callao). Materiales y métodos: El estudio fue de tipo básico, diseño observacional, nivel descriptivo, prospectivo y de corte transversal. Las unidades muestrales fueron 100 pacientes con cáncer de mama, en el periodo correspondiente a mayo y julio del 2018. El instrumento de recolección de datos es un cuestionario con 34 ítems. Resultados: La mayoría de mujeres con esta enfermedad se ubican en el nivel regular (93 %), en la dimensión física la mayoría de casos están en el nivel regular (98 %), la dimensión psicológica también se ubica en el nivel regular (87 %), y en la dimensión social en el nivel malo (77 %). Conclusiones: Las características de las mujeres con esta enfermedad son dificultades en diferentes partes del cuerpo; en la dimensión psicológica presentan una calidad de vida poco saludable con intranquilidad y ansiedad; en la dimensión social, la calidad de vida es de nivel malo, lo que describe que muchas mujeres que padecen el mal participan muy poco de las reuniones sociales, visitas de recreación y manifiestan un alejamiento de sus amistades y familiares.
Objective: To determine the quality of life in women with breast cancer who visit the Oncology Department of the Hospital Nacional Daniel Alcides Carrión (Callao). Materials and methods: This study had a basic, observational, descriptive, prospective and cross-sectional design. The sample consisted of 100 patients with breast cancer who visited the hospital between May and July 2018. The data collection instrument was a 34-item questionnaire. Results: Most women with this disease had a fair quality of life (93 %). In the physical and psychological dimensions, most of them also presented a fair quality of life (98 % and 87 %, respectively) and, in the social dimension, they showed a poor quality of life (77 %). Conclusions: These women experienced problems in different parts of their body. In the psychological dimension, they presented an unhealthy quality of life generating a sense of uneasiness and anxiety. In the social dimension, they also presented a poor quality of life resulting in little participation in social gatherings and recreational visits, and a rift from friends and family.
Assuntos
Feminino , Qualidade de Vida , Neoplasias da Mama , Saúde PúblicaRESUMO
Resumen Comunicamos seis casos de mujeres quienes, tras la aplicación mediante mesoterapia con plasma rico en plaquetas, así como de un material de relleno intradérmico de origen desconocido, desarrollaron una infección en los sitios de inyección asociada a Mycobacterium massiliense, así como granulomas con reacción a cuerpo extraño. Aunque los cultivos fueron negativos, se logró la identificación del microorganismo por extracción de ADN de tejidos blandos obtenido por biopsia y posterior secuenciación del producto obtenido. Debido a la gran similitud en los cultivos de M. massiliense con la especie relacionada Mycobacterium abscessus, y a que tienen diferente respuesta terapéutica, las técnicas moleculares de diagnóstico son una opción real a considerar para administrar en forma precoz el tratamiento específico contra el patógeno y evitar la progresión de la infección.
We report six cases of female patients who, after the application by mesotherapy with platelet-rich plasma, as well as of an intradermal filler material of unknown origin, developed infection at the injection sites associated to Mycobacterium massiliense, as well as granuloma with reaction to foreign body. Although the cultures were negative, the identification of the microorganism was achieved by extraction of soft tissue DNA obtained by biopsy and sequencing the obtained product, with which the therapy was redirected against the particular species. Due to the great similarity in the culture between M. massiliense with the related species M. abscessus, to the required time for its growth, and to the different therapeutic response of each strain, molecular diagnostic techniques are a real option to consider to administer in an early way the appropriate treatment against the pathogen and prevent infection progression.
Assuntos
Humanos , Beleza , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Injeções Intradérmicas , Técnicas de Diagnóstico MolecularRESUMO
Ribavirin exhibits inhibitory effects on the epigenetic enzyme enhancer of zeste homolog 2 (EZH2), which participates in lymphomagenesis. Additionally, preclinical and clinical studies have demonstrated the antilymphoma activity of this drug. To further investigate the potential of ribavirin as an anticancer treatment for lymphoma, the tumorsuppressive effects of ribavirin were analyzed in lymphoma cell lines. The effects of ribavirin on the viability and clonogenicity of the Bcell lymphoma cell line Pfeiffer (EZH2mutant), Toledo (EZH2 wildtype) and cutaneous Tcell lymphoma Hut78 cell line were assessed. Expression of EZH2 and trimethylation status of histone 3, lysine 27 trimethylated (H3K27m3) was also determined in response to ribavirin. The transcriptional effects of ribavirin on Hut78 cells were analyzed by microarray expression and the results were validated by reverse transcriptionquantitative polymerase chain reaction, western blotting and knockout of signal transducer and activator of transcription 1 (STAT1). The results of the present study demonstrated that ribavirin suppressed the growth and clonogenicity of cells in a dosedependent manner. Ribavirin did not affect the expression of EZH2 nor altered its activity as evaluated by H3K27 trimethylation status. Furthermore, the results of transcriptome analysis indicated that the majority of the canonical pathways affected by ribavirin were associated with the immune system, including 'antigen presentation', 'communication between innate and adaptive immune cells' and 'crosstalk between dendritic and natural killer cells'. The results of gene expression analysis were confirmed, by demonstrating at the RNA and protein levels, downregulation of stearoylCoA desaturase and upregulation of STAT1. Depletion of STAT1, which was proposed as a key regulator of the aforementioned pathways, exerted growth inhibitory effects almost to the same extent as ribavirin. In conclusion, ribavirin was proposed to exert growth inhibitory effects on lymphoma cell lines, particularly Hut78 cells, a cutaneous Tcell lymphoma cell line. Of note, these effects may depend on, at least in part, the activation of canonical immune pathways regulated by the key factors STAT1 and interferonγ. Our results provide insight into the antilymphoma potential of ribavirin; however, further investigations in preclinical and clinical studies are required to determine the effectiveness of ribavirin as a therapeutic agent for treating lymphoma.