Dynamics of p53 and Cancer

Cancer is a multifactorial disease in which cell types lost their capability to regulate growth, proliferation, and cell death pathways, causing the uncontrolled proliferation of tumor cells. Cell death pathway is supported by the operation of the p53–Mdm2-negative feedback loop that has a central role to prevent the development of tumor cells. Under severe DNA damage, this loop takes the control of the apoptotic pathway and activates Bax, which, in turn, activates the caspase cascade to produce the death of the injured cell. However, events like Mdm2 overexpression or the suppression of caspase-9 gene can block the transmission of the death signal to the caspase cascade allowing the survival of the mutated cell. In this chapter, a mathematical model that explores the effect of Mdm2 overexpression and the suppression of caspase-9 on the control of death by the p53–Mdm2 loop is presented. From the model, two strategies for tumor cell survival are indentified, showing how mutations that affect the death pathway allow the survival of transformed cells. The model suggests that the combination of different simultaneous treatments against these mutations can be a suitable strategy against cancer

Hybrid lineages of CD4+ T cells: a handbook update

CD4+ T lymphocytes have been classified into several lineages, according to their gene expression profiles and their effector responses. Interestingly, recent evidence is showing that many lineages could yield hybrid phenotypes with unique properties and functions. It has been reported that such hybrid lineages might underlie pathologies or may function as effector cells with protection capacities against molecular threats. In this work, we reviewed the characteristics of the hybrid lineages reported in the literature, in order to identify the expression profiles that characterize them and the markers that could be used to identify them. We also review the differentiation cues that elicit their hybrid origin and what is known about their physiological roles

Dynamics of the Gene Regulatory Network of HIV-1 and the Role of Viral Non-coding RNAs on Latency Reversion

The use of latency reversing agents (LRAs) is currently a promising approach to eliminate latent reservoirs of HIV-1. However, this strategy has not been successful in vivo. It has been proposed that cellular post-transcriptional mechanisms are implicated in the underperformance of LRAs, but it is not clear whether proviral regulatory elements like viral non-coding RNAs (vncRNAs) are also implicated. In order to visualize the complexity of the HIV-1 gene expression, we used experimental data to construct a gene regulatory network (GRN) of latent proviruses in resting CD4+ T cells. We then analyzed the dynamics of this GRN using Boolean and continuous mathematical models. Our simulations predict that vncRNAs are able to counteract the activity of LRAs, which may explain the failure of these compounds to reactivate latent reservoirs of HIV-1. Moreover, our results also predict that using inhibitors of histone methyltransferases, such as chaetocin, together with releasers of the positive transcription elongation factor (P-TEFb), like JQ1, may increase proviral reactivation despite self-repressive effects of vncRNAs

DataSheet_3_Molecular tracking of insulin resistance and inflammation development on visceral adipose tissue.docx

BackgroundVisceral adipose tissue (VAT) is one of the most important sources of proinflammatory molecules in obese people and it conditions the appearance of insulin resistance and diabetes. Thus, understanding the synergies between adipocytes and VAT-resident immune cells is essential for the treatment of insulin resistance and diabetes.MethodsWe collected information available on databases and specialized literature to construct regulatory networks of VAT resident cells, such as adipocytes, CD4+ T lymphocytes and macrophages. These networks were used to build stochastic models based on Markov chains to visualize phenotypic changes on VAT resident cells under several physiological contexts, including obesity and diabetes mellitus.ResultsStochastic models showed that in lean people, insulin produces inflammation in adipocytes as a homeostatic mechanism to downregulate glucose intake. However, when the VAT tolerance to inflammation is exceeded, adipocytes lose insulin sensitivity according to severity of the inflammatory condition. Molecularly, insulin resistance is initiated by inflammatory pathways and sustained by intracellular ceramide signaling. Furthermore, our data show that insulin resistance potentiates the effector response of immune cells, which suggests its role in the mechanism of nutrient redirection. Finally, our models show that insulin resistance cannot be inhibited by anti-inflammatory therapies alone.ConclusionInsulin resistance controls adipocyte glucose intake under homeostatic conditions. However, metabolic alterations such as obesity, enhances insulin resistance in adipocytes, redirecting nutrients to immune cells, permanently sustaining local inflammation in the VAT.</p

DataSheet_2_Molecular tracking of insulin resistance and inflammation development on visceral adipose tissue.xlsx

BackgroundVisceral adipose tissue (VAT) is one of the most important sources of proinflammatory molecules in obese people and it conditions the appearance of insulin resistance and diabetes. Thus, understanding the synergies between adipocytes and VAT-resident immune cells is essential for the treatment of insulin resistance and diabetes.MethodsWe collected information available on databases and specialized literature to construct regulatory networks of VAT resident cells, such as adipocytes, CD4+ T lymphocytes and macrophages. These networks were used to build stochastic models based on Markov chains to visualize phenotypic changes on VAT resident cells under several physiological contexts, including obesity and diabetes mellitus.ResultsStochastic models showed that in lean people, insulin produces inflammation in adipocytes as a homeostatic mechanism to downregulate glucose intake. However, when the VAT tolerance to inflammation is exceeded, adipocytes lose insulin sensitivity according to severity of the inflammatory condition. Molecularly, insulin resistance is initiated by inflammatory pathways and sustained by intracellular ceramide signaling. Furthermore, our data show that insulin resistance potentiates the effector response of immune cells, which suggests its role in the mechanism of nutrient redirection. Finally, our models show that insulin resistance cannot be inhibited by anti-inflammatory therapies alone.ConclusionInsulin resistance controls adipocyte glucose intake under homeostatic conditions. However, metabolic alterations such as obesity, enhances insulin resistance in adipocytes, redirecting nutrients to immune cells, permanently sustaining local inflammation in the VAT.</p

DataSheet_1_Molecular tracking of insulin resistance and inflammation development on visceral adipose tissue.xlsx

BackgroundVisceral adipose tissue (VAT) is one of the most important sources of proinflammatory molecules in obese people and it conditions the appearance of insulin resistance and diabetes. Thus, understanding the synergies between adipocytes and VAT-resident immune cells is essential for the treatment of insulin resistance and diabetes.MethodsWe collected information available on databases and specialized literature to construct regulatory networks of VAT resident cells, such as adipocytes, CD4+ T lymphocytes and macrophages. These networks were used to build stochastic models based on Markov chains to visualize phenotypic changes on VAT resident cells under several physiological contexts, including obesity and diabetes mellitus.ResultsStochastic models showed that in lean people, insulin produces inflammation in adipocytes as a homeostatic mechanism to downregulate glucose intake. However, when the VAT tolerance to inflammation is exceeded, adipocytes lose insulin sensitivity according to severity of the inflammatory condition. Molecularly, insulin resistance is initiated by inflammatory pathways and sustained by intracellular ceramide signaling. Furthermore, our data show that insulin resistance potentiates the effector response of immune cells, which suggests its role in the mechanism of nutrient redirection. Finally, our models show that insulin resistance cannot be inhibited by anti-inflammatory therapies alone.ConclusionInsulin resistance controls adipocyte glucose intake under homeostatic conditions. However, metabolic alterations such as obesity, enhances insulin resistance in adipocytes, redirecting nutrients to immune cells, permanently sustaining local inflammation in the VAT.</p