Experiencing some early life adversity can have an “inoculating” effect that promotes resilience in adulthood. However, the mechanisms underlying stress inoculation are unknown, and animal models are lacking. Here we used the limited bedding and nesting (LBN) model of adversity to evaluate stress inoculation of addiction-related phenotypes. In LBN, pups from postnatal days 2 to 9 and their dams were exposed to a low-resource environment. In adulthood, they were tested for addiction-like phenotypes and compared to rats raised in standard housing conditions. High levels of impulsivity are associated with substance abuse, but in males, LBN reduced impulsive choice compared to controls. LBN males also self-administered less morphine and had a lower breakpoint on a progressive ratio reinforcement schedule than controls. These effects of LBN on addiction-related behaviors were not found in females. Because the nucleus accumbens (NAc) mediates these behaviors, we tested whether LBN altered NAc physiology in drug-naïve and morphine-exposed rats. LBN reduced the frequency of spontaneous excitatory postsynaptic currents in males, but a similar effect was not observed in females. Only in males did LBN prevent a morphine-induced increase in the AMPA/NMDA ratio. RNA sequencing was performed to delineate the molecular signature in the NAc associated with LBN-derived phenotypes. LBN produced sex-specific changes in transcription, including in genes related to glutamate transmission. Collectively, these studies reveal that LBN causes a male-specific stress inoculation effect against addiction-related phenotypes. Identifying factors that promote resilience to addiction may reveal novel treatment options for patients.

Background Expression patterns between males and females vary in every adult tissue, even in organs with no conspicuous dimorphisms such as the heart. While studies of male and female differences have traditionally focused on the influence of sex hormones, these do not account for all the differences at the molecular and epigenetic levels. We previously reported that a substantial number of genes were differentially expressed in male and female mouse embryonic stem (ES) cells and revealed dose-dependent enhancer activity in response to Prdm14 , a key pluripotency factor expressed more highly in female ES cells. In this work, we investigated the role of Prdm14 in establishing sex-specific gene expression networks. We surveyed the sex-specific landscape in early embryogenesis with special reference to cardiac development. We generated sex-specific co-expression networks from mouse ES cells, examined the presence of sex-specific chromatin domains, and analyzed previously published datasets from different developmental time points to characterize how sex-biased gene expression waxes and wanes to evaluate whether sex-biased networks are detectable throughout heart development. Results We performed ChIP-seq on male and female mouse ES cells to determine differences in chromatin status. Our study reveals sex-biased histone modifications, underscoring the potential for the sex chromosome complement to prime the genome differently in early development with consequences for later expression biases. Upon differentiation of ES cells to cardiac precursors, we found sex-biased expression of key transcription and epigenetic factors, some of which persisted from the undifferentiated state. Using network analyses, we also found that Prdm14 plays a prominent role in regulating a subset of dimorphic expression patterns. To determine whether sex-biased expression is present throughout cardiogenesis, we re-analyzed data from two published studies that sampled the transcriptomes of mouse hearts from 8.5 days post-coitum embryos to neonates and adults. We found sex-biased expression at every stage in heart development, and interestingly, identified a subset of genes that exhibit the same bias across multiple cardiogenic stages. Conclusions Overall, our results support the existence of sexually dimorphic gene expression profiles and regulatory networks at every stage of cardiac development, some of which may be established in early embryogenesis and epigenetically perpetuated. Electronic supplementary material The online version of this article (10.1186/s13293-019-0259-1) contains supplementary material, which is available to authorized users.

Celecoxib or Celebrex, an NSAID (non-steroidal anti-inflammatory drug), is one of the most common medicines for treating inflammatory diseases. Recently, it has been shown that celecoxib is associated with implications in complex diseases such as Alzheimer's disease and cancer, as well as with cardiovascular risk assessment and toxicity, suggesting that celecoxib may affect multiple unknown targets. In this project, we detected targets of celecoxib within the nervous system using a label-free TPP (Thermal Proteome Profiling) method. First, proteins of the rat hippocampus were treated with multiple drug concentrations and temperatures. Next, we separated the soluble proteins from the denatured and sedimented total protein load by ultracentrifugation. Subsequently, the soluble proteins were analyzed by nano-liquid chromatography-mass spectrometry to determine the identity of the celecoxib targeted proteins based on structural changes by thermal stability variation of targeted proteins towards higher solubility in the higher temperatures. In the analysis of the soluble protein extract at 67 centigrade, 44 proteins were uniquely detected in drug-treated samples out of all 478 identified proteins at this temperature. Rab4a, one out of these 44 proteins, has previously been reported as one of the celecoxib off-targets in the rat CNS. Furthermore, we provide more molecular details through biomedical enrichment analysis to explore the potential role of all detected proteins in the biological systems. We show that the determined proteins play a role in the signaling pathways related to neurodegenerative disease-and cancer pathways. Finally, we fill out molecular supporting evidence for using celecoxib towards the drug repurposing approach by exploring drug targets.

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Background. Iranian traditional medicine (ITM) is a holistic medical system that uses a wide range of medicinal substances to treat disease. Reorganization and standardization of the data on ITM concepts is a necessity for optimal use of this rich source. In an initial step towards this goal, we created a database of ITM materia medica. Main Body. Primarily based on Makhzan al-Advieh, which is the most recent encyclopedia of materia medica in ITM with the largest number of monographs, a database of natural medicinal substances was created using both text mining methods and manual editing. UNaProd, a Universal Natural Product database for materia medica of ITM, is currently host to 2696 monographs, from herbal to animal to mineral compounds in 16 diverse attributes such as origin and scientific name. Currently, systems biology, and more precisely systems medicine and pharmacology, can be an aid in providing rationalizations for many traditional medicines and elucidating a great deal of knowledge they can offer to guide future research in medicine. Conclusions. A database of materia medica is a stepping stone in creating a systems pharmacology platform of ITM that encompasses the relationships between the drugs, their targets, and diseases. UNaProd is hyperlinked to IrGO and CMAUP databases for Mizaj and molecular features, respectively, and it is freely available at http://jafarilab.com/unaprod/.

Studying relationships among gene-products by gene expression profile analysis is a common approach in systems biology. Many studies have generalized the outcomes to the different levels of central dogma information flow and assumed correlation of transcript and protein expression levels. All these efforts partook in the current understanding of signaling network models and expanded the signaling databases. In fact, due to the unavailability or high-cost of the experiments, most of the studies do not usually look for direct interactions, and some parts of these networks are contradictory. Besides, it is now a standard step to accomplish enrichment analysis on biological annotations, to make claims about the potentially implicated biological pathways in any perturbation. Explicitly, upon identifying differentially expressed genes, they are spontaneously presumed the corresponding dysregulated pathways. Then, molecular mechanistic insights are proposed for disease etiology and drug discovery based on statistically enriched biological processes. In this study, using four common and comprehensive databases, we extracted all relevant gene expression data and all relationships among directly linked gene pairs. We aimed to evaluate the ratio of coherency or sign consistency between the expression level and the causal relationships among the gene pairs. We illustrated that the signaling network was not more consistent or coherent with the recorded expression profile compared to the random relationships. Finally, we provided the pieces of evidence and concluded that gene-product expression data, especially at the transcript level, are not reliable or at least insufficient to infer causal biological relationships among genes and in turn, describe cellular behavior.

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Parental history of opioid exposure is seldom considered when prescribing opioids for pain relief. To explore whether parental opioid exposure may affect sensitivity to morphine in offspring, we developed a “rat pain scale” with high-speed imaging, machine learning, and mathematical modeling in a multigenerational model of paternal morphine self-administration. We find that the most commonly used tool to measure mechanical sensitivity in rodents, the von Frey hair, is not painful in rats during baseline conditions. We also find that male progeny of morphine-treated sires had no baseline changes in mechanical pain sensitivity but were more sensitive to the pain-relieving effects of morphine. Using RNA sequencing across pain-relevant brain regions, we identify gene expression changes within the regulator of G protein signaling family of proteins that may underlie this multigenerational phenotype. Together, this rat pain scale revealed that paternal opioid exposure increases sensitivity to morphine’s pain-relieving effects in male offspring.