Cytotoxicity, Oxidative Stress, Cell Cycle Arrest, and Mitochondrial Apoptosis after Combined Treatment of Hepatocarcinoma Cells with Maleic Anhydride Derivatives and Quercetin

The inflammatory condition of malignant tumors continually exposes cancer cells to reactive oxygen species, an oxidizing condition that leads to the activation of the antioxidant defense system. A similar activation occurs with glutathione production. This oxidant condition enables tumor cells to maintain the energy required for growth, proliferation, and evasion of cell death. The objective of the present study was to determine the effect on hepatocellular carcinoma cells of a combination treatment with maleic anhydride derivatives (prooxidants) and quercetin (an antioxidant). The results show that the combination of a prooxidant/antioxidant had a cytotoxic effect on HuH7 and HepG2 liver cancer cells, but not on either of two normal human epithelial cell lines or on primary hepatocytes. The combination treatment triggered apoptosis in hepatocellular carcinoma cells by activating the intrinsic pathway and causing S phase arrest during cell cycle progression. There is also clear evidence of a modification in cytoskeletal actin and nucleus morphology at 24 and 48 h posttreatment. Thus, the current data suggest that the combination of two anticarcinogenic drugs, a prooxidant followed by an antioxidant, can be further explored for antitumor potential as a new treatment strategy

[Epidemiological profile of rheumatoid arthritis]

Abstract Background: Rheumatoid arthritis affects approximately between 0.3 and 1.2% of the world population. In Latin America, different studies have estimated a prevalence between 0.2 and 0.5% in the population over 16 years of age. Objective: To identify the epidemiological profile of rheumatoid arthritis. Material and methods: Descriptive cross-sectional design carried out in an urban population of a social security institution in Mexico. The information of the clinical file of 373 patients was studied. The epidemiological profile included the sociodemographic dimension, family history, health, clinical, therapeutic, biochemical, extra-articular manifestations and complications. Statistical analysis percentages, means, confidence intervals for percentages and confidence intervals for averages were calculated. Results: The wrists were the most affected joints with 44.6% (95% CI: 39.5-49.6%). The extra-articular manifestation with the highest prevalence was asthenia with 9.9% (95% CI: 6.9-12.9%); predominant diagnosis according to ICD-10 was seropositive rheumatoid arthritis with 59.8% (95% CI: 54.8-64.8%), and the rheumatoid factor was highly positive in 78.3% (95% CI: 74.1-82.5%); predominant treatment was with combined therapy at diagnosis in 97.6% (95% CI: 96.0-99.1%). The duration of treatment was > 10 years in 34.1% (95% CI: 29.2-38.8%). Conclusion: This work has described the epidemiological profile of the patient with rheumatoid arthritis in different dimensions. Resumen Introducción: la artritis reumatoide afecta aproximadamente entre 0.3 y 1.2% de la población mundial. En Latinoamérica diferentes estudios han estimado una prevalencia entre 0.2 y 0.5% en población mayor de 16 años de edad. Objetivo: identificar el perfil epidemiológico de la artritis reumatoide. Material y métodos: diseño transversal descriptivo llevado a cabo en población urbana de una institución de seguridad social en México. Se estudió la información del expediente clínico de 373 pacientes. El perfil epidemiológico incluyó la dimensión sociodemográfica, antecedentes heredofamiliares, de salud, clínicos, terapéuticos, bioquímicos, de manifestaciones extraarticulares y de complicaciones. Se calcularon porcentajes, promedios, e intervalos de confianza para porcentajes y promedios. Resultados: las muñecas fueron las articulaciones más afectadas con 44.6% (IC 95%: 39.5-49.6%). La manifestación extraarticular con más alta prevalencia fue la astenia con 9.9% (IC 95%: 6.9-12.9%); el diagnóstico predominante de acuerdo con el CIE-10 fue la artritis reumatoide seropositiva con 59.8% (IC 95%: 54.8-64.8%) y se encontró el factor reumatoide positivo alto en un 78.3% (IC 95%: 74.1%-82.5%); el tratamiento predominante fue con terapia combinada al diagnóstico en un 97.6%, (IC 95%: 96.0-99.1%). La duración del tratamiento fue > 10 años en el 34.1% (IC 95%: 29.2-38.8%). Conclusión: este trabajo ha descrito el perfil epidemiológico del paciente con artritis reumatoide en diferentes dimensiones

Evaluation of renal damage in a bleomycin-induced murine model of systemic sclerosis

Objective(s): Systemic sclerosis (SSc) is an autoimmune disease of unknown etiology with a high mortality rate. Renal crisis has been reported as one of the predictors of early mortality in these patients. The present study was performed to evaluate bleomycin-induced SSc using an osmotic minipump as a possible model for the analysis of renal damage in SSc.Materials and Methods: Male CD1 mice were implanted with osmotic minipumps loaded with saline or bleomycin and sacrificed at 6 and 14 days. Histopathological analysis was performed through hematoxylin and eosin (H&E) and Masson’s trichrome staining. The expression of endothelin 1 (ET-1), inducible nitric oxide synthase (iNOS), transforming growth factor β (TGF-β), and 8-hydroxy-2-deoxyguanosine (8-OHdG) was also evaluated by immunohistochemistry.Results: The administration of bleomycin induced a decrease in the length of Bowman’s space (3.6 μm, P<0.001); an increase in collagen deposition (14.6%, P<0.0001); and an increase in the expression of ET-1 (7.5%, P<0.0001), iNOS (10.8%, P<0.0001), 8-OHdG (161 nuclei, P<0.0001), and TGF-β (2.4% µm, P<0.0001) on Day 6. On Day 14, a decrease in the length of Bowman’s space (2.6 μm, P<0.0001); increased collagen deposition (13.4%, P<0.0001); and increased expression of ET-1 (2.7%, P<0.001), iNOS (10.1%, P<0.0001), 8-OHdG (133 nuclei, P<0.001), and TGF-β (0.6%, P<0.0001) were also observed.Conclusion: Systemic administration of bleomycin via an osmotic minipump produces histopathological changes in the kidneys, similar to kidney damage in SSc. Therefore, this model would allow the study of molecular alterations associated with SSc-related renal damage

Quercetin Reverses Rat Liver Preneoplastic Lesions Induced by Chemical Carcinogenesis

Quercetin is a flavonoid widely studied as a chemopreventive agent in different types of cancer. Previously, we reported that quercetin has a chemopreventive effect on the liver-induced preneoplastic lesions in rats. Here, we evaluated if quercetin was able not only to prevent but also to reverse rat liver preneoplastic lesions. We used the modified resistant hepatocyte model (MRHM) to evaluate this possibility. Treatment with quercetin was used 15 days after the induction of preneoplastic lesions. We found that quercetin reverses the number of preneoplastic lesions and their areas. Our results showed that quercetin downregulates the expression of EGFR and modulates this signaling pathway in spite of the activated status of EGFR as detected by the upregulation of this receptor, with respect to that observed in control rats. Besides, quercetin affects the phosphorylation status of Src-1, STAT5, and Sp-1. The better status of the liver after the treatment with quercetin could also be confirmed by the recovery in the expression of IGF-1. In conclusion, we suggest that quercetin reversed preneoplastic lesions by EGFR modulation and the activation state of Src, STAT5, and Sp1, so as the basal IGF-1

Chemopreventive Effect of Cooked Chickpea on Colon Carcinogenesis Evolution in AOM/DSS-Induced Balb/c Mice

Chickpeas are one of the most widely consumed legumes worldwide and they might prevent diseases such as cancer. Therefore, this study evaluates the chemopreventive effect of chickpea (Cicer arietinum L.) on the evolution of colon carcinogenesis induced with azoxymethane (AOM) and dextran sodium sulfate (DSS) in a mice model at 1, 7, and 14 weeks after induction. Accordingly, the expression of biomarkers—such as argyrophilic nucleolar organizing regions (AgNOR), cell proliferation nuclear antigen (PCNA), β-catenin, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2)—was assessed in the colon of BALB/c mice fed diets supplemented with 10 and 20% cooked chickpea (CC). The results showed that a 20% CC diet significantly reduced tumors and biomarkers of proliferation and inflammation in AOM/DSS-induced colon cancer mice. Moreover, body weight loss decreased and the disease activity index (DAI) was lower than the positive control. Lastly, tumor reduction was more evident at week 7 in the groups fed a 20% CC diet. In conclusion, both diets (10% and 20% CC) exert a chemopreventive effect

Focal adhesion kinase is required for actin polymerization and remodeling of the cytoskeleton during sperm capacitation

Several focal adhesion proteins are known to cooperate with integrins to link the extracellular matrix to the actin cytoskeleton; as a result, many intracellular signaling pathways are activated and several focal adhesion complexes are formed. However, how these proteins function in mammalian spermatozoa remains unknown. We confirm the presence of focal adhesion proteins in guinea pig spermatozoa, and we explore their role during capacitation and the acrosome reaction, and their relationship with the actin cytoskeleton. Our results suggest the presence of a focal adhesion complex formed by β1-integrin, focal adhesion kinase (FAK), paxillin, vinculin, talin, and α-actinin in the acrosomal region. Inhibition of FAK during capacitation affected the protein tyrosine phosphorylation associated with capacitation that occurs within the first few minutes of capacitation, which caused the acrosome reaction to become increasingly Ca2+ dependent and inhibited the polymerization of actin. The integration of vinculin and talin into the complex, and the activation of FAK and paxillin during capacitation, suggests that the complex assembles at this time. We identify that vinculin and α-actinin increase their interaction with F-actin while it remodels during capacitation, and that during capacitation focal adhesion complexes are structured. FAK contributes to acrosome integrity, likely by regulating the polymerization and the remodeling of the actin cytoskeleton

Effect of Silk Fibroin on Cell Viability in Electrospun Scaffolds of Polyethylene Oxide

In this study, a coating from electrospun silk fibroin was performed with the aim to modify the surface of breast implants. We evaluated the effect of fibroin on polymeric matrices of poly (ethylene oxide) (PEO) to enhance cell viability, adhesion, and proliferation of HaCaT human keratinocytes to enhance the healing process on breast prosthesis implantation. We electrospun six blends of fibroin and PEO at different concentrations. These scaffolds were characterized by scanning electron microscopy, contact angle measurements, ATR-FTIR spectroscopy, and X-ray diffraction. We obtained diverse network conformations at different combinations to examine the regulation of cell adhesion and proliferation by modifying the microstructure of the matrix to be applied as a potential scaffold for coating breast implants. The key contribution of this work is the solution it provides to enhance the healing process on prosthesis implantation considering that the use of these PEO&ndash;fibroin scaffolds reduced (p &lt; 0.05) the amount of pyknotic nuclei. Therefore, viability of HaCaT human keratinocytes on PEO&ndash;fibroin matrices was significantly improved (p &lt; 0.001). These findings provide a rational strategy to coat breast implants improving biocompatibility

Is Nucleoredoxin a Master Regulator of Cellular Redox Homeostasis? Its Implication in Different Pathologies

Nucleoredoxin (NXN), an oxidoreductase enzyme, contributes to cellular redox homeostasis by regulating different signaling pathways in a redox-dependent manner. By interacting with seven proteins so far, namely disheveled (DVL), protein phosphatase 2A (PP2A), phosphofructokinase-1 (PFK1), translocation protein SEC63 homolog (SEC63), myeloid differentiation primary response gene-88 (MYD88), flightless-I (FLII), and calcium/calmodulin-dependent protein kinase II type alpha (CAMK2A), NXN is involved in the regulation of several key cellular processes, including proliferation, organogenesis, cell cycle progression, glycolysis, innate immunity and inflammation, motility, contraction, protein transport into the endoplasmic reticulum, neuronal plasticity, among others; as a result, NXN has been implicated in different pathologies, such as cancer, alcoholic and polycystic liver disease, liver fibrogenesis, obesity, Robinow syndrome, diabetes mellitus, Alzheimer&rsquo;s disease, and retinitis pigmentosa. Together, this evidence places NXN as a strong candidate to be a master redox regulator of cell physiology and as the hub of different redox-sensitive signaling pathways and associated pathologies. This review summarizes and discusses the current insights on NXN-dependent redox regulation and its implication in different pathologies

Is Nucleoredoxin a Master Regulator of Cellular Redox Homeostasis? Its Implication in Different Pathologies

Nucleoredoxin (NXN), an oxidoreductase enzyme, contributes to cellular redox homeostasis by regulating different signaling pathways in a redox-dependent manner. By interacting with seven proteins so far, namely disheveled (DVL), protein phosphatase 2A (PP2A), phosphofructokinase-1 (PFK1), translocation protein SEC63 homolog (SEC63), myeloid differentiation primary response gene-88 (MYD88), flightless-I (FLII), and calcium/calmodulin-dependent protein kinase II type alpha (CAMK2A), NXN is involved in the regulation of several key cellular processes, including proliferation, organogenesis, cell cycle progression, glycolysis, innate immunity and inflammation, motility, contraction, protein transport into the endoplasmic reticulum, neuronal plasticity, among others; as a result, NXN has been implicated in different pathologies, such as cancer, alcoholic and polycystic liver disease, liver fibrogenesis, obesity, Robinow syndrome, diabetes mellitus, Alzheimer’s disease, and retinitis pigmentosa. Together, this evidence places NXN as a strong candidate to be a master redox regulator of cell physiology and as the hub of different redox-sensitive signaling pathways and associated pathologies. This review summarizes and discusses the current insights on NXN-dependent redox regulation and its implication in different pathologies

Modification of In Vitro and In Vivo Antioxidant Activity by Consumption of Cooked Chickpea in a Colon Cancer Model

Chickpea has been classified as a nutraceutical food due to its phytochemical compounds, showing antioxidant, anti-inflammatory, and anticancer activity. To investigate this, we evaluated the effect of cooking on the nutritional and non-nutritional composition and the in vitro and in vivo antioxidant activity of chickpea seed. The latter was determined by the variation in the concentration of nitric oxide (NO), oxidized carbonyl groups (CO), malondialdehyde (MDA), and the expression of 4-hydroxy-2-nonenal (4-HNE) in the colon of male BALB/c mice fed with a standard diet with 10 and 20% cooked chickpea (CC). We induced colon cancer in mice by administering azoxymethane/dextran sulfate sodium (AOM/DSS); for the evaluation, these were sacrificed 1, 7, and 14 weeks after the induction. Results show that cooking does not significantly modify (p &lt; 0.05) nutritional compounds; however, it decreases the concentration of non-nutritional ones and, consequently, in vitro antioxidant activity. The in vivo evaluation showed that animals administered with AOM/DSS presented higher concentrations of NO, CO, MDA, and 4-HNE than those in animals without AOM/DSS administration. However, in the three evaluated times, these markers were significantly reduced (p &lt; 0.05) with CC consumption. The best effect on the oxidation markers was with the 20% CC diet, demonstrating the antioxidant potential of CC