RESUMEN

The lung is exposed to various pollutants and is the primary site for the onset of various diseases, including infections, allergies, and cancers. One possible treatment approach for such pulmonary diseases involves direct administration of therapeutics to the lung so as to maintain the topical concentration of the drug. Particles with nanoscale diameters tend to reach the pulmonary region. Nanoparticles (NPs) have garnered significant interest for applications in biomedical and pharmaceutical industries because of their unique physicochemical properties and biological activities. In this article, we describe the biological and pharmacological activities of NPs as well as summarize their potential in the formulation of drugs employed to treat pulmonary diseases. Recent advances in the use of NPs in inhalation chemotherapy for the treatment of lung diseases have also been highlighted.

Asunto(s)

Enfermedades Pulmonares , Nanopartículas , Humanos , Enfermedades Pulmonares/tratamiento farmacológico , Pulmón , Administración por Inhalación , Terapia Respiratoria , Nanopartículas/química , Preparaciones Farmacéuticas , Sistemas de Liberación de Medicamentos

RESUMEN

Development of cerebral malaria (CM) is driven by parasitemia levels, harmful inflammatory response, oxidative stress and consequent breach of the blood brain barrier. Use of adjunct therapy that utilizes an antioxidant and anti-inflammatory agent alongside chloroquine (CQ), may improve treatment outcome and shorten recovery from post-infection sequelae. Though withdrawn in some countries, CQ is still in use for prophylaxis and treatment of malaria in many countries. Current study investigated whether oral co-administration of 50 mg/kg CQ and 200 mg/kg of coenzyme Q10 (CoQ10) would improve treatment outcome against experimental cerebral malaria (ECM) and assuage the deleterious effects of oxidative stress and inflammation upon infection by Plasmodium berghei ANKA (PbA) in a C57BL/6 J mouse model. Treatment with CQ + CoQ10 resulted in an improved parasite elimination; clearing the parasite one day early, when compared to mice on CQ alone. Remarkably, treatment with CQ and CoQ10 separately or in combination, assuaged PbA induced elevation of serum levels of TNF-α and IFN-γ an indication of protection from ECM progression. Furthermore, CQ and CoQ10-administration, blocked parasite-driven elevation of aspartate transaminase (AST), alanine transaminase (ALT) and bilirubin. In the presence of CQ and CoQ10, severe PbA-induced systemic induction of oxidative stress and resultant GSH depletion was reduced in the brain, liver, spleen, and kidney. Overall, these findings demonstrate that administration of CQ and CoQ10 ameliorates harmful parasite-driven oxidative stress and inflammation, while slowing the progression to full blown ECM and may improve treatment outcome in CM.

RESUMEN

Diabetes is a risk factor for breast cancer development and is associated with poor prognosis for breast cancer patients. However, the molecular and biochemical mechanisms underlying the association between diabetes and breast cancer have not been fully elucidated. Here, we investigated estradiol response in MCF-7 breast cancer cells with or without chronic exposure to insulin. We found that insulin priming is necessary and specific for estradiol-induced cancer cell growth, and induces anaplerotic shunting of glucose into macromolecule biosynthesis in the estradiol treated cells. Treatment with ERK or Akt specific inhibitors, U0126 or LY294002, respectively, suppressed estradiol-induced growth. Interestingly, molecular analysis revealed that estradiol treatment markedly increases expression of cyclin A and B, and decreases p21 and p27 in the insulin-primed cells. In addition, estradiol treatment activated metabolic genes in pentose phosphate (PPP) and serine biosynthesis pathways in the insulin-primed cells while insulin priming decreased metabolic gene expression associated with glucose catabolism in the breast cancer cells. Finally, we found that anti-diabetic drug metformin and AMPK ligand AICAR, but not thiazolidinediones (TZDs), specifically suppress the estradiol-induced cellular growth in the insulin-primed cells. These findings suggest that estrogen receptor (ER) activation under chronic hyperinsulinemic condition increases breast cancer growth through the modulation of cell cycle and apoptotic factors and nutrient metabolism, and further provide a mechanistic evidence for the clinical benefit of metformin use for ER-positive breast cancer patients with diabetes.

Asunto(s)

Neoplasias de la Mama/metabolismo , Complicaciones de la Diabetes/metabolismo , Diabetes Mellitus/tratamiento farmacológico , Estradiol/administración & dosificación , Receptor alfa de Estrógeno/biosíntesis , Neoplasias de la Mama/inducido químicamente , Neoplasias de la Mama/complicaciones , Neoplasias de la Mama/etiología , Butadienos/administración & dosificación , Proliferación Celular/efectos de los fármacos , Cromonas/administración & dosificación , Complicaciones de la Diabetes/inducido químicamente , Complicaciones de la Diabetes/etiología , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patología , Estradiol/efectos adversos , Receptor alfa de Estrógeno/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Glucosa/metabolismo , Humanos , Insulina/administración & dosificación , Insulina/metabolismo , Células MCF-7 , Proteína Quinasa 3 Activada por Mitógenos/antagonistas & inhibidores , Morfolinas/administración & dosificación , Nitrilos/administración & dosificación , Proteína Oncogénica v-akt/antagonistas & inhibidores , Factores de Riesgo

RESUMEN

Cancer heterogeneity is a big hurdle in achieving complete cancer treatment, which has led to the emergence of combinational therapy. In this study, we investigated the potential use of nuclear receptor (NR) ligands for combinational therapy with other anti-cancer drugs. We first profiled all 48 NRs and 48 biological anti-cancer targets in four pairs of lung cell lines, where each pair was obtained from the same patient. Two sets of cell lines were normal and the corresponding tumor cell lines while the other two sets consisted of primary versus metastatic tumor cell lines. Analysis of the expression profile revealed 11 NRs and 15 cancer targets from the two pairs of normal versus tumor cell lines, and 9 NRs and 9 cancer targets from the primary versus metastatic tumor cell lines had distinct expression patterns in each category. Finally, the evaluation of nuclear receptor ligand T0901317 for liver X receptor (LXR) demonstrated its combined therapeutic potential with tyrosine kinase inhibitors. The combined treatment of cMET inhibitor PHA665752 or EGFR inhibitor gefitinib with T0901317 showed additive growth inhibition in both H2073 and H1993 cells. Mechanistically, the combined treatment suppressed cell cycle progression by inhibiting cyclinD1 and cyclinB expression. Taken together, this study provides insight into the potential use of NR ligands in combined therapeutics with other biological anti-cancer drugs.

Asunto(s)

Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptores Citoplasmáticos y Nucleares/metabolismo , Línea Celular Tumoral , Ciclina B/antagonistas & inhibidores , Ciclina D1/antagonistas & inhibidores , Receptores ErbB/antagonistas & inhibidores , Gefitinib , Humanos , Hidrocarburos Fluorados/uso terapéutico , Indoles/uso terapéutico , Receptores X del Hígado , Receptores Nucleares Huérfanos/metabolismo , Quinazolinas/uso terapéutico , Sulfonamidas/uso terapéutico , Sulfonas/uso terapéutico

RESUMEN

AIM: Human induced pluripotent stem (hiPS) cells are an alternative cell source of regenerative medicine for liver disease. Because variations in hepatic differentiation efficacy among hiPS cells exist, it is important to select a hiPS cell line with hepatic differentiation propensity. In addition, nuclear receptors (NR) regulate essential biological processes including differentiation and development. In this study, we identified the hiPS cell line with hepatic differentiation propensity and examined expression levels of 48 NR during this process. METHODS: We screened 28 hiPS cell lines, which are established from various tissues of healthy persons with various reprogramming methods, using a three-step differentiation method, and examined expression levels of 48 NR by quantitative real-time polymerase chain reaction during the differentiation process in the selected cells. RESULTS: hiPS-RIKEN-2B and hiPS-RIKEN-2F cells have hepatic differentiation propensity. Differentiation propensity towards endoderm was affected by donor origin but not by reprogramming methods or cell type of origins. Expression levels of NR were closely associated with those of hepatic differentiation markers. Furthermore, expression patterns of NR were categorized as five patterns. In particular, seven NR such as chicken ovalbumin upstream promoter transcription factor 1, retinoic acid receptor α, peroxisome proliferator-activated receptor-γ, progesterone receptor, photoreceptor cell-specific nuclear receptor, tailless homolog orphan receptor and glucocorticoid receptor were identified as the genes of which expression gradually goes up with differentiation. CONCLUSION: These findings will be useful for not only elucidating mechanisms of hepatic differentiation of hiPS cells but also cell-based therapy for liver diseases.