RESUMEN
Chemotherapeutic regimens containing camptothecin (CPT), 5-fluorouracil, and oxaliplatin are used to treat advanced colorectal cancer. We previously reported that an indole derivative, 3-(2-bromoethyl)indole (BEI-9), inhibited the proliferation of colon cancer cells and suppressed NF-κB activation. Here, we show that a combination of BEI-9 with either CPT or tumor necrosis factor alpha (TNFα) enhances cell death. Using colorectal cancer cells, we examined the activation of NF-κB by drugs, the potential of BEI-9 for inhibiting drug-induced NF-κB activation, and the enhancement of cell death by combination treatments. Cells were treated with the chemotherapeutic drugs alone or in combination with BEI-9. NF-κB activation, cell cycle profiles, DNA-damage response, markers of cell death signaling and targets of NF-κB were evaluated to determine the effects of single and co-treatments. The combination of BEI-9 with CPT or TNFα inhibited NF-κB activation and reduced the expression of NF-κB-responsive genes, Bcl-xL and COX2. Compared to CPT or BEI-9 alone, sequential treatment of the cells with CPT and BEI-9 significantly enhanced caspase activation and cell death. Co-treatment with TNFα and BEI-9 also caused more cytotoxicity than TNFα or BEI-9 alone. Combined BEI-9 and TNFα enhanced cell death through caspase activation and cleavage of the switch-protein, RIP1 kinase. BEI-9 reduced the expression of COX2 both alone and in combination with CPT or TNF. We postulate that BEI-9 enhances the effects of these drugs on cancer cells by turning off or redirecting NF-κB signaling. Therefore, the combination of BEI-9 with drugs that activate NF-κB needs to be evaluated for clinical applications.
Asunto(s)
Camptotecina/farmacología , Muerte Celular/efectos de los fármacos , Neoplasias del Colon/metabolismo , Indoles/farmacología , FN-kappa B/metabolismo , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/farmacología , Apoptosis/efectos de los fármacos , Camptotecina/administración & dosificación , Caspasas/metabolismo , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Neoplasias del Colon/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Humanos , Indoles/administración & dosificación , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Factores de Tiempo , Proteína bcl-X/genéticaRESUMEN
Psoriasis is a chronic relapsing/remitting autoimmune disease affecting skin and fingernails. It is associated with many other autoimmune diseases such as rheumatoid arthritis, celiac disease, Crohn's disease, and thyroid diseases. Two important autoimmune thyroid diseases - Hashimoto's thyroiditis (hypothyroidism) and Grave's disease (hyperthyroidism) - affect the body's significant organs such as the brain, muscles, digestive function, and the skin. Although some studies have established the connection between psoriasis and thyroid diseases with autoimmunity, our article provides an in-depth analysis of the connection between these two diseases and other common etiological factors associated with them, along with autoimmunity. We reviewed articles from PubMed using regular keywords and Medical Subject Headings (MeSH) keywords and finalized 45 articles to find an association between these two diseases. These articles showed that this association is more prevalent in obese patients and late-onset psoriasis. Most of the articles showed a positive association, but few articles showed no connection between them. However, there is no concrete explanation to prove the association due to limited research; additional studies are necessary. It requires the attention of both clinicians and researchers to develop a universal drug that will work on both diseases, and also thyroid evaluation could be included in psoriatic patient care so that there is a possibility to decrease cost and efforts while treating these diseases.
RESUMEN
Shwachman-Diamond syndrome (SDS) is an autosomal recessive inherited disease of the SBDS gene. It has multi-organ involvement but primarily affects the bone marrow and the pancreas. This disease is more commonly found in males than females, and its earliest manifestation in infancy is pancytopenia, most especially neutropenia. Our article attempts an in-depth analysis of the hepatic and cardiac association in this disease and the severity of this association. For the purpose of this study, we engaged in an in-depth research of critically appraised literature and published articles. We searched for such articles on PubMed and Google Scholar using regular and Medical Subject Headings (MeSH) keywords. We eventually selected 32 articles from the search results and carefully read through and analyzed them. These articles showed the usual age of diagnosis of SDS to be at infancy (before age one), with a predominantly median survival age of 35 years. All the published articles we reviewed showed some hepatic and cardiac associations with SDS, but the extent of the associations varied. Even though most hepatic involvements were found to be benign, some severe cases led to fibrosis and hepatic failure. Although there is no particular consensus as to the exact outcome of cardiac involvement, the few cases we reviewed showed that cardiac association could be a severe complication and could even be fatal. Most of the cases reported in the literature had been diagnosed at autopsy.
RESUMEN
Dietary consumption of polyphenol-rich fruits, such as grapes, may reduce inflammation and potentially prevent diseases linked to inflammation. Here, we used a genetically engineered murine model to measure Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) activity and pro-inflammatory cytokine secretion to test the hypothesis that oral consumption of whole grape formulation reduces inflammatory signaling in the body. NF-κB luciferase reporter mice were divided into two groups, one which was fed an experimental diet formulated with 4% (w/w) whole grape powder (WGP) or another which was fed a control diet formulated with 3.6% glucose/fructose (w/w) combination. Simulated inflammation was induced in the mice by intraperitoneal injection of lipopolysaccharide (LPS). In vivo imaging was used to determine the effect of each diet on NF-κB activity. We found that there were no significant differences in weight gain between the WGP and control diet groups. However, there was a statistically significant (p<0.0001) difference in the progression of basal levels of NF-κB signaling between mice fed on control or WGP diet. There were no significant differences in NF-κB reporter indices between WGP- and control-diet groups after either acute or repeated inflammatory challenge. However, terminal blood collection revealed significantly (p<0.01) lower serum concentrations of the inflammatory cytokines Interleukin-6 (IL-6) and Tumor Necrosis Factor alpha (TNFα) only among WGP diet mice subjected to acute inflammatory challenge. Overall, these data suggest that while diets supplemented with WGP may suppress steady-state low levels of inflammatory signaling, such a supplementation may not alleviate exogenously induced massive NF-κB activation.
RESUMEN
PURPOSE: African-American (AA) women living in four Black Belt Counties (BBC) of Alabama; consisting of Barbour, Macon, Green and Wilcox are known to have lower mammogram utilization and breast self-exam rates when compared to their white female counterparts. The influence of socioeconomic and demographic factors on these disparities has not been clearly defined so far. Our study was designed to determine whether these observed disparities can be predicted with the socioeconomic and other demographic attributes. METHODS: Health Disparity Questionnaires data (n = 516) for BBC of Alabama was analyzed using a logistic regression model to examine the association of breast cancer screening rates and breast self-exam with income, the level of education, family doctor, type of health insurance, obesity, and age. RESULTS: Income, education, family doctor, age and health insurance were independent predictors for the low utilization rate of mammography and breast self-exam (BSE). CONCLUSION: Improving socioeconomic conditions such as level of education and availability of health care are essential to increase the rates of breast cancer screening test and breast self-exam in the BBC of Alabama.
RESUMEN
To study the ameliorating effects of curcumin in lipopolysaccharide (LPS) induced cardiac hypertrophy, mice were assigned to 4 groups (3 males and 3 females in each group): (A) control, (B) curcumin: 100 µ g/kg of body weight by intraperitoneal route (IP), (C) LPS: 60 mg/kg (IP), and (D) LPS + curcumin: both at previously stated concentrations by IP route. All mice were sacrificed as 12 hr and 24 hrs groups accordingly after LPS injection. The hearts were collected, photographed for cardiomegaly, and weighed to compare heart weight/brain weight (HW/BW) in mg/mg. For immunohistochemistry, the tissue sections were exposed to histone H3, H4 and acetylated histone H3, H4 antibody. LPS induced a significant increase in histone acetylation as shown by intense staining. In curcumin + LPS treated mice nuclear staining was similar to the control group indicating that curcumin traversed the histone acetylation activity of the LPS. To further check the mechanism of action of curcumin, p300 protein acetylation levels were analyzed. This study suggests that the probable mechanism of action of curcumin is via the reduction of p300 HAT activity.