Role of nanomedicine in reversing drug resistance mediated by ATP binding cassette transporters and P-glycoprotein in melanoma

Multidrug resistance (MDR) is one of the most common complex phenomenons exhibited by cancer cells. It is a very common property of melanoma postchemotherapy. MDR transporters, ATP binding cassette (ABC) transporters, play a critical role in conferring this property to melanoma cells. miRNA are post-transcriptional regulators that regulate the expression of these ABC transporters. Targeting these miRNA, in turn targeting ABC transporters with the help of nanodelivery systems to overcome drug resistance, is the primary focus for attaining successful treatment methods for drug-resistant melanoma. These delivery systems are endocytosed by the cancer cells and do not require ABC transporters for their delivery, being a promising therapeutic measure for melanoma.

Individual differences predict susceptibility to conditioned fear arising from psychosocial trauma

Background : Classical Pavlovian fear conditioning has been widely used in preclinical studies to gain insights into anxiety-related disorders. In this study we examined whether pre-existing behavioral differences, and/or behavioral differences displayed during fear induction, predict the severity of the conditioned fear response that can develop after an episode of psychosocial conflict.

Methods : Prior to conditioning, male rats (intruders) were behaviorally assessed using the novel environment exploration and defensive burying tests. These animals were subsequently placed in the territory of an older male (resident) that invariably attacked the intruder.

Results : Upon return to this territory 24 h later, intruders moved less than controls and produced more distress vocalizations, indicating conditioned fear to context. Additionally, analyses revealed that both pre-existing behavioral differences, and the animal’s response during social conflict, predicted the magnitude of the subsequent conditioned fear response. Specifically, animals that engaged in higher levels of novel environment exploration, that exhibited a greater number of defensive burying behaviors, and that demonstrated higher levels of fighting and guarding during social conflict, displayed less evidence of conditioned fear.

Conclusion : These findings show that the behavioral variability existent within a normal outbred population can predict the magnitude of the conditioned fear response.

Strain differences in coping behaviour, novelty seeking behaviour, and susceptibility to socially conditioned fear : a comparison between Wistar and Sprague Dawley rats

The aim of the current study was to generate socially conditioned fear in two different strains of rat (Wistar, W and Sprague Dawley, SD) using social conflict, in order to investigate whether the magnitude of the conditioned fear responses in each strain was related to behaviour exhibited prior to or during fear induction (i.e. social conflict). On day one of the study, all intruders were assessed for exploratory activity in a novel environment. Twenty four hours following the novel environment test the locomotor activity of the intruders was assessed, while they underwent a single familiarisation exposure to the arena in which the conflict was subsequently to occur in. Twenty-four hours following familiarisation, intruders underwent either a 10 min social conflict or sham conflict session. One day later we examined the response of the intruders when they were returned to the vacant resident's cage. Upon return to the conflict context, we examined the intruder's ultrasonic distress vocalisations and the extent to which locomotor activity was inhibited. We found that W rats displayed significantly more immobility (i.e. conditioned fear) upon return to context than did SD rats (p < 0.05). Importantly, we observed that the differences in the two strains behaviour upon return to context appeared to be related to their quite different patterns of coping behaviour. The results of the current study indicate that preclinical between-strain comparisons potentially have much to offer in regard to understanding the basis of resilience to social stress.

High glucose-induced impairment in insulin secretion is associated with reduction in islet glucokinase in a mouse model of susceptibility to islet dysfunction

Type 2 diabetes is characterized by islet dysfunction resulting in hyperglycemia, which can then lead to further deterioration in islet function. A possible mechanism for hyperglycemia-induced islet dysfunction is the accumulation of advanced glycation end products (AGE). The DBA/2 mouse develops pancreatic islet dysfunction when exposed to a high glucose environment and/or obesity-induced insulin resistance. To determine the biochemical cause of dysfunction, DBA/2 and C57BL/6 control islets were incubated in 11.1 mM or 40 mM glucose in the absence or presence of the AGE inhibitor aminoguanidine (AG) for 10 days. Basal (2.8 mM glucose) insulin release was increased in both DBA/2 and C57BL/6 islets incubated with 40 mM vs 11.1 mM glucose for 10 days. Chronic exposure to hyperglycemia decreased glucose (20 mM)-stimulated insulin secretion in DBA/2 but not in C57BL/6 islets. AG significantly increased fold-induced insulin release in high glucose cultured DBA/2 mouse islets, but did not affect C57BL/6 islet function. DBA/2 islet glucokinase was significantly reduced following 40 mM glucose culture, compared with 11.1 mM glucose cultured DBA/2 islets and 40 mM glucose cultured C57BL/6 islets. Incubation of islets with AG resulted in a normalization of DBA/2 islet glucokinase levels. In conclusion, chronic high glucose-induced increases in AGE can result in islet dysfunction and this is associated with reduced glucokinase levels in a mouse model with susceptibility to islet failure.

Blood pressure modifies retinal susceptibility to intraocular pressure elevation

Primary open angle glaucoma affects more than 67 million people. Elevated intraocular pressure (IOP) is a risk factor for glaucoma and may reduce nutrient availability by decreasing ocular perfusion pressure (OPP). An interaction between arterial blood pressure and IOP determines OPP; but the exact contribution that these factors have for retinal function is not fully understood. Here we sought to determine how acute modifications of arterial pressure will affect the susceptibility of neuronal function and blood flow to IOP challenge. Anaesthetized (ketamine:xylazine) Long-Evan rats with low (~60 mmHg, sodium nitroprusside infusion), moderate (~100 mmHg, saline), or high levels (~160 mmHg, angiotensin II) of mean arterial pressure (MAP, n = 5–10 per group) were subjected to IOP challenge (10–120 mmHg, 5 mmHg steps every 3 minutes). Electroretinograms were measured at each IOP step to assess bipolar cell (b-wave) and inner retinal function (scotopic threshold response or STR). Ocular blood flow was measured using laser-Doppler flowmetry in groups with similar MAP level and the same IOP challenge protocol. Both b-wave and STR amplitudes decreased with IOP elevation. Retinal function was less susceptible to IOP challenge when MAP was high, whereas the converse was true for low MAP. Consistent with the effects on retinal function, higher IOP was needed to attenuated ocular blood flow in animals with higher MAP. The susceptibility of retinal function to IOP challenge can be ameliorated by acute high BP, and exacerbated by low BP. This is partially mediated by modifications in ocular blood flow.

An ICT enabled conceptual framework for determining epidemic susceptibility and acute type response : an exemplar from India

In a developing nation such as India, the national government is pursuing the pathway of ICT supported decentralized programs, to combat endemics, in the social contexts of each State. The State of Kerala, which has been an exemplar for development, has become susceptible to endemics, brought in by urbanization and non-resident Indian population and compounded by environmental disasters. In this paper, the authors contend that the psyche of the community which has changed from social amity to self-interest need to be re-awakened with the power of ICTs and Internet, so as to efficiently combat endemics. The authors also propose a preliminary framework for emergency responses based on existing ICT systems, recommended by the national government, to fit the context.