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Janus kinases (JAKs) are a family of proinflammatory enzymes able to mediate the immune responses and the inflammatory cascade by modulating multiple cytokine expressions as well as various growth factors. In the present study, the inhibition of the JAK–signal transducer and activator of transcription (STAT) signaling pathway is explored as a potential strategy for treating autoimmune and inflammatory disorders. A computationally driven approach aimed at identifying novel JAK inhibitors based on molecular topology, docking, and molecular dynamics simulations was carried out. For the best candidates selected, the inhibitory activity against JAK2 was evaluated in vitro. Two hit compounds with a novel chemical scaffold, 4(IC50= 0.81 μM) and 7(IC50= 0.64 μM), showed promising results when compared with the reference drug Tofacitinib (IC50= 0.031 μM).

Introduction: Similarly to the μ opioid receptor, kappa opioid receptor (KOR), is present either in the central nervous system or in peripheral tissues. In the last years, several molecules, able to interact with KOR, have been the focus of basic research for their therapeutic potential in the field of chronic pain, as well as in depression, autoimmune disorders and neurological diseases. Discussion: The role of KOR system and the consequent clinical effects derived by its activation or inhibition are discussed. Their potential therapeutic utilization in conditions of stress and drug relapse, besides chronic pain, is presented here, including the possible use of KORagonists in drug addiction. Moreover, the potential role of KOR-antagonists, KOR agonistantagonists and peripheral KOR agonists is proposed. Conclusion: Other than pain, KORs have a role in regulating reward and mood. Due to its location, KORs seem to mediate interactions between psychiatric disorders, addiction and depression. Experimental studies in animal models have identified brain mechanisms that may contribute to clarify specific pathophysiological processes.

WE studied pronociceptin gene expression following limbic seizures. Northern blot analysis revealed increased pronociceptin mRNA levels in the thalamus (but not in the hippocampus) 3–24 h after kainate administration, with maximal effect (2-fold increase over basal levels) reached at 6 h. No variation in pronociceptin mRNA levels was observed 1–6 h after a stimulus-evoked kindled seizure. Carrageenan failed to affect pronociceptin gene expression in the thalamus, indicating that pain and/or acute stress do not account for kainate effects. In situhybridization revealed that kainate evokes a dramatic (4-fold) increase in pronociceptin mRNA levels over the thalamic reticular nucleus. Kindled seizures evoked only a small, nonsignificant increase in pronociceptin gene expression over the dentate gyrus of the hippocampus.

The effects of κ-opioid agonist treatment on prodynorphin mRNA expression in the rat brain were studied. Rats were treated with the selective κ-opioid agonist U-69593 or vehicle for 5 days and prodynorphin mRNA was measured on day 8 (3 days after the last injection) or 22 (17 days after the last injection). On day 8 prodynorphin mRNA was increased in the hypothalamus and decreased in the striatum, frontal cortex, and hippocampus of rats treated with U-69593. On day 22, prodynorphin mRNA was increased in the hypothalamus, frontal cortex and striatum of U-69593 treated rats. These findings suggests that κ-opioid receptor agonist treatment has long-term, continually changing effects on prodynorphin mRNA expression.

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