Middle Ear Histopathology Following Magnetic Delivery to the Cochlea of Prednisolone-loaded Iron Oxide Nanoparticles in Rats.

Delivery of therapy to the cochlea is a challenge and limits the efficacy of therapies meant to treat hearing loss, reverse tinnitus, and protect hearing from chemotherapy regimens. Magnetic injection is a technique that uses magnetic fields to inject nanoparticles from the middle ear into the cochlea, where they can then elute therapy to treat hearing disorders. To evaluate the safety of this treatment in the middle ear, 30 rats were subdivided into 6 groups and treated by single or multiple intratympanic injections of saline, prednisolone, nanoparticles, or nanoparticles loaded with prednisolone. A specially designed magnet array was used to magnetically inject the particles from the middle ear to the cochlea. Treatment began at study day 0, and animals were euthanized on study day 2, 30, or 90. Temporal bones were collected and prepared for histopathological examination. Intratympanic administration of magnetic nanoparticles and/or prednisolone resulted in minimal to mild inflammatory changes in all treated groups. The incidence and severity of the inflammatory changes observed appeared slightly increased in animals administered nanoparticles, with or without prednisolone, when compared to animals administered prednisolone alone. At study day 90, there was partial reversibility of the findings noted at study day 2 and 30. Repeat administration did not appear to cause greater inflammatory changes.

Tolfenamic acid suppresses cytochrome P450 2E1 expression in mouse liver.

Non-steroidal anti-inflammatory drugs (NSAIDs) play a significant role in the chemoprevention of cancer. We recently showed the chemopreventive response of a NSAID, 2-[(3-chloro-2-methylphenyl)amino]benzoic acid) known as tolfenamic acid (TA) in N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumors in rats. Pre-clinical studies showed that TA inhibits Specificity protein (Sp) transcription factors and acts as an anti-cancer agent in several cancer models; however the pertinent mechanisms associated with its chemopreventive response in esophageal cancer are not known. Since the bioactivation of carcinogens through cytochrome P450 (CYP) is critical for the induction of cancer, we have studied the effect of TA on critical CYP isozymes in mouse liver samples. Athymic nude mice were treated with vehicle (corn oil) or TA (50 mg kg(-1), 3 times per week) for 4 weeks. Protein extracts (whole cell lysates and microsomal fractions) were prepared from liver tissue and the expression of various CYP isozymes was determined by Western blot analysis. Rat (Sprague-Dawley) livers were harvested and primary hepatocyte cultures were treated with vehicle (DMSO) or TA (50 µM) and cell viability was assessed at 2 and 5 days post-treatment. TA caused remarkable decrease in the expression of CYP2E1 in both liver lysates and sub-cellular fraction, while its response on other tested isozymes was marginal. TA did not affect the body weight of animals (mice) and viability of rat hepatocytes. These results demonstrate that TA modulates the expression of CYP2E1 which is associated with the bioactivation of carcinogens without causing apparent toxicity. These data suggest that TA-induced inhibition of CYP2E1 attenuates the bioactivation of carcinogens potentially leading to the chemoprevention of NMBA-induced esophageal tumorigenesis in rats.

Aptamer-nanoparticle assembly for logic-based detection.

In this work, gold nanoparticles perform Boolean logic operations in response to two proangiogenic targets important in cancer diagnosis and treatment: PDGF and VEGF. In the absence of protein target, gold nanoparticles are initially dispersed as a red solution; the addition of target proteins causes nanoparticle aggregation, turning the solution blue, as well as the release of dye-labeled aptamer probes, which causes an increase in fluorescence. These outputs constitute an AND or OR gate for simultaneous protein detection. We believe this logic-gate-based detection system will become the basis for novel rapid, cheap, and reliable sensors for diagnostic applications.

Environmental factors in causing human cancers: emphasis on tumorigenesis.

The environment and dietary factors play an essential role in the etiology of cancer. Environmental component is implicated in ~80 % of all cancers; however, the causes for certain cancers are still unknown. The potential players associated with various cancers include chemicals, heavy metals, diet, radiation, and smoking. Lifestyle habits such as smoking and alcohol consumption, exposure to certain chemicals (e.g., polycyclic aromatic hydrocarbons, organochlorines), metals and pesticides also pose risk in causing human cancers. Several studies indicated a strong association of lung cancer with the exposure to tobacco products and asbestos. The contribution of excessive sunlight, radiation, occupational exposure (e.g., painting, coal, and certain metals) is also well established in cancer. Smoking, excessive alcohol intake, consumption of an unhealthy diet, and lack of physical activity can act as risk factors for cancer and also impact the prognosis. Even though the environmental disposition is linked to cancer, the level and duration of carcinogen-exposure and associated cellular and biochemical aspects determine the actual risk. Modulations in metabolism and DNA adduct formation are considered central mechanisms in environmental carcinogenesis. This review describes the major environmental contributors in causing cancer with an emphasis on molecular aspects associated with environmental disposition in carcinogenesis.