This study aimed to unravel the regulatory role of noncoding RNAs (ncRNA) on the nitric oxide (NO) machinery system in triple‐negative breast cancer (TNBC) patients and to further assess the influence of NO‐modulating ncRNAs on TNBC progression, immunogenic profile, and the tumor microenvironment (TME). The results revealed miR‐939‐5p and lncRNA HEIH as novel ncRNAs modulating NO machinery in TNBC. MiR‐939‐5p, an underexpressed microRNA (miRNA) in BC patients, showed an inhibitory effect on NOS2 and NOS3 transcript levels on TNBC cells. In contrast, HEIH was found to be markedly upregulated in TNBC patients and showed a modulatory role on miR‐939‐5p/NOS2/NO axis. Functionally, miR‐939‐5p was characterized as a tumor suppressor miRNA while HEIH was categorized as a novel oncogenic lncRNA in TNBC. Finally, knocking down of HEIH resulted in improvement of immunogenic profile of TNBC cells through inducing MICA/B and suppressing the immune checkpoint inhibitor PDL1. In the same context, knockdown of HEIH resulted in the alleviation of the immune‐suppressive TME by repressing interleukin‐10 and tumor necrosis factor‐α levels. In conclusion, this study identifies miR‐939‐5p as a tumor suppressor miRNA while HEIH as an oncogenic lncRNA exhibiting its effect through miR‐939‐5p/NOS2/NO axis. Therefore, repressing BC hallmarks, improving TNBC immunogenic profile, and trimming TME.

Background: Over the last few years, the number of people suffering from sleeping disorders has increased significantly despite negative effects on cognition and an association with brain inflammation. Objectives: We assessed memory deficits caused by sleep deprivation (SD) to determine the therapeutic effect of phosphodiesterase 4 (PDE4) inhibitors on SD-induced memory deficits and to investigate whether the modulation of memory deficits by PDE4 inhibitors is mediated by a protein kinase A (PKA)-independent pathway in conjunction with a PKA-dependent pathway. Methods: Adult male mice were divided into four groups. Three SD groups were deprived of Rapid eye movement (REM) sleep for 12 h a day for six consecutive days. They were tested daily in the Morris water maze to evaluate learning and memory. One of the SD groups was injected with a PDE4 inhibitor, rolipram (1 mg/kg ip), whereas another had rolipram co-administered with chlorogenic acid (CHA, 20 mg/kg ip), an inhibitor of PKA. After 6 days, the mice were sacrificed, and the hippocampi were evaluated for cyclic AMP (cAMP) and nuclear factor Nrf-2 levels. The hippocampal expression of PKA, phosphorylated cAMP response element-binding protein (CREB), and phosphorylated glycogen synthase 3β (Ser389) were also evaluated. Results: SD caused a significant decrease in cAMP levels in the brain and had a detrimental effect on learning and memory. The administration of rolipram or rolipram+CHA resulted in an improvement in cognitive function. Conclusion: The present study provides evidence that restoration of memory with PDE4 inhibitors occurs through a dual mechanism involving the PKA and Epac pathways.

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