PARP7 negatively regulates the type I interferon response in cancer cells and its inhibition triggers antitumor immunity

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Dysregulation in nucleic acid‐sensing pathway genes is associated with cancer patients’ prognosis

The innate immune system, the first line of defense against pathogens, is activated by nucleic acids from microbial invaders that are recognized by nucleic acid‐sensing receptors. Recent evidence affirms the ability of these receptors to respond to nucleic acids released by damaged cancer cells. The innate immune system is also involved in cancer immunosurveillance, and could be modulated for devising effective antitumor therapies by targeting nucleic acid‐sensing pathways. A systematic, comprehensive analysis of dysregulation in nucleic acid‐sensing pathways in cancer is required to fully understand its role. Based on multidimensional data of The Cancer Genome Atlas pan‐cancer cohort, we revealed that upregulation of cytosolic DNA‐sensing genes like AIM2 and CGAS was common in tumor tissues. We used 15 genes in the nucleic acid‐sensing pathway to cluster all tumor patients into 2 subgroups and found that the subgroup with higher expression of nucleic acid‐sensing pathway genes was associated with poorer prognosis across cancer types. However, in homologous recombination deficient patients, the nucleic acid recognition activated subgroup was associated with better prognosis, which confirms the therapeutic effect of nucleic acid recognition. This study contributes to a better understanding of the functions and mechanisms of nucleic acid recognition in cancer, lays the foundation for new therapeutic strategies, and enlarges the scope of development of new drugs.     

Screening strategies for quorum sensing inhibitors in combating bacterial infections

Interference with quorum sensing (QS) represents an antivirulence strategy with a significant promise for the treatment of bacterial infections and a new approach to restoring antibiotic tolerance. Over the past two decades, a novel series of studies have reported that quorum quenching approaches and the discovery of quorum sensing inhibitors (QSIs) have a strong impact on the discovery of anti-infective drugs against various types of bacteria. The discovery of QSI was demonstrated to be an appropriate strategy to expand the anti-infective therapeutic approaches to complement classical antibiotics and antimicrobial agents. For the discovery of QSIs, diverse approaches exist and develop in-step with the scale of screening as well as specific QS systems. This review highlights the latest findings in strategies and methodologies for QSI screening, involving activity-based screening with bioassays, chemical methods to seek bacterial QS pathways for QSI discovery, virtual screening for QSI screening, and other potential tools for interpreting QS signaling, which are innovative routes for future efforts to discover additional QSIs to combat bacterial infections.     

Essential oils of Origanum compactum increase membrane permeability,disturb cell membrane integrity,and suppress quorum-sensing phenotype in bacteria

The aim of this study was to investigate antibacterial activity of Origanum compactum essential oils collected at three phenological stages on Escherichia coli and Bacillus subtilis. The antibacterial activity was evaluated using the agar-well diffusion assay. The MIC and MBC values were determined using the micro-dilution assay. The investigation of the antibacterial action was carried out by the evaluation of the effect of O. compactum essential oils on the antibacterial kinetic growth, the integrity of cell membrane and permeability of the cell membrane. The anti-quorum sensing activity was tested by the inhibition of the biofilm formation. The findings of this study showed that O. compactum essential oil has potent antibacterial activities against E. coli and B. subtilis. The lowest inhibition value against B. subtilis was obtained with O. compactum essential oil at the post-flowering stage (MIC = MBC = 0.0312% (v/v)). The antibacterial mechanisms of O. compactum essential oils are related to the disturbing of the cell membrane integrity and the increasing of the membrane permeability, which leads to the leakage of genetic materials (DNA and RNA). Moreover, O. compactum essential oils inhibited the formation of the biofilms, a phenotype that has been known to be quorum sensing regulated.     

Ventromedial hypothalamus glucose‐inhibited neurones: A role in glucose and energy homeostasis?

The ventromedial hypothalamus (VMH) plays a complex role in glucose and energy homeostasis. The VMH is necessary for the counter‐regulatory response to hypoglycaemia (CRR) that increases hepatic gluconeogenesis to restore euglycaemia. On the other hand, the VMH also restrains hepatic glucose production during euglycaemia and stimulates peripheral glucose uptake. The VMH is also important for the ability of oestrogen to increase energy expenditure. This latter function is mediated by VMH modulation of the lateral/perifornical hypothalamic area (lateral/perifornical hypothalamus) orexin neurones. Activation of VMH AMP‐activated protein kinase (AMPK) is necessary for the CRR. By contrast, VMH AMPK inhibition favours decreased basal glucose levels and is required for oestrogen to increase energy expenditure. Specialised VMH glucose‐sensing neurones confer the ability to sense and respond to changes in blood glucose levels. Glucose‐excited (GE) neurones increase and glucose‐inhibited (GI) neurones decrease their activity as glucose levels rise. VMH GI neurones, in particular, appear to be important in the CRR, although a role for GE neurones cannot be discounted. AMPK mediates glucose sensing in VMH GI neurones suggesting that, although activation of these neurones is important for the CRR, it is necessary to silence them to lower basal glucose levels and enable oestrogen to increase energy expenditure. In support of this, we found that oestrogen reduces activation of VMH GI neurones in low glucose by inhibiting AMPK. In this review, we present the evidence underlying the role of the VMH in glucose and energy homeostasis. We then discuss the role of VMH glucose‐sensing neurones in mediating these effects, with a strong emphasis on oestrogenic regulation of glucose sensing and how this may affect glucose and energy homeostasis.     

Role of 5-HT1A and 5-HT3 receptors in serotonergic activation of sensory neurons in relation to itch and pain behavior in the rat

Serotonin (5-hydroxytryptamine, 5-HT) released by platelets, mast cells, and immunocytes is a potent inflammatory mediator which modulates pain and itch sensing in the peripheral nervous system. The serotonergic receptors expressed by primary afferent neurons involved in these sensory functions are not fully identified and appear to be to a large extent species dependent. Moreover, the mechanisms through which 5-HT receptor activation is coupled to changes in neuronal excitability have not been completely revealed. Using a combination of in vitro (calcium and voltage imaging and patch-clamp) and in vivo behavioral methods, we used both male and female Wistar rats to provide evidence for the involvement of two 5-HT receptor subtypes, 5-HT1A and 5-HT3, in mediating the sustained and transient effects, respectively, of 5-HT on rat primary afferent neurons involved in pain and itch processing. In addition, our results are consistent with a model in which sustained serotonergic responses triggered via the 5-HT1A receptor are due to closure of background potassium channels, followed by membrane depolarization and action potentials, during which the activation of voltage-gated calcium channels leads to calcium entry. Our results may provide a better understanding of mammalian serotonergic itch signaling.     

Compressed sensing with signal averaging for improved sensitivity and motion artifact reduction in fluorine‐19 MRI

Fluorine‐19 (¹⁹F) MRI of injected perfluorocarbon emulsions (PFCs) allows for the non‐invasive quantification of inflammation and cell tracking, but suffers from a low signal‐to‐noise ratio and extended scan time. To address this limitation, we tested the hypotheses that a ¹⁹F MRI pulse sequence that combines a specific undersampling regime with signal averaging has both increased sensitivity and robustness against motion artifacts compared with a non‐averaged fully sampled pulse sequence, when both datasets are reconstructed with compressed sensing. As a proof of principle, numerical simulations and phantom experiments were performed on selected variable ranges to characterize the point spread function of undersampling patterns, as well as the vulnerability to noise of undersampling and reconstruction parameters with paired numbers of x signal averages and acceleration factor x (NAx ‐AFx ). The numerical simulations demonstrated that a probability density function that uses 25% of the samples to fully sample the k‐space central area allowed for an optimal balance between limited blurring and artifact incoherence. At all investigated noise levels, the Dice similarity coefficient (DSC) strongly depended on the regularization parameters and acceleration factor. In phantoms, the motion robustness of an NA8‐AF8 undersampling pattern versus NA1‐AF1 was evaluated with simulated and real motion patterns. Differences were assessed with the DSC, which was consistently higher for the NA8‐AF8 compared with the NA1‐AF1 strategy, for both simulated and real cyclic motion patterns (P < 0.001). Both strategies were validated in vivo in mice (n = 2) injected with perfluoropolyether. Here, the images displayed a sharper delineation of the liver with the NA8‐AF8 strategy than with the NA1‐AF1 strategy. In conclusion, we validated the hypotheses that in ¹⁹F MRI the combination of undersampling and averaging improves both the sensitivity and the robustness against motion artifacts.