Synthesis and activity study of novel N,N-diphenylurea derivatives as IDO1 inhibitors.

Indoleamine 2,3-dioxygenase 1 (IDO1) has attracted much attention in the field of cancer immunotherapy as an immunomodulatory enzyme. To identify potential IDO1 inhibitors, a novel series of compounds with N,N-diphenylurea and triazole structures were synthesized. The designed compounds underwent organic synthesis, and subsequent enzymatic activity experiments targeting IDO1 confirmed their activity at the molecular level. These experiments provided validation for the efficacy of the designed compounds in inhibiting IDO1, compound 3g exhibited an IC50 value of 1.73 ± 0.97 µM. Further molecular docking study further explained the binding mode and reaction potential of compound 3g with IDO1. Our research has resulted in a series of novel IDO1 inhibitors, which is beneficial to the development of drugs targeting IDO1 in numerous cancer diseases.

A Hump-like Neck Mass in a Child.

A 7-year-old boy with no medical history of trauma, infection, or surgery presented with a slowly growing, asymptomatic lump on his left lower neck since birth. What is your diagnosis?

AMPK Activation Alleviates Myocardial Ischemia-Reperfusion Injury by Regulating Drp1-Mediated Mitochondrial Dynamics.

Mitochondrial dysfunction is a salient feature of myocardial ischemia/reperfusion injury (MIRI), while the potential mechanism of mitochondrial dynamics disorder remains unclear. This study sought to explore whether activation of Adenosine monophosphate-activated protein kinase (AMPK) could alleviate MIRI by regulating GTPase dynamin-related protein 1 (Drp1)-mediated mitochondrial dynamics. Isolated mouse hearts in a Langendorff perfusion system were subjected to ischemia/reperfusion (I/R) treatment, and H9C2 cells were subjected to hypoxia /reoxygenation (H/R) treatment in vitro. The results showed that AICAR, the AMPK activator, could significantly improve the function of left ventricular, decrease arrhythmia incidence and myocardial infarction area of isolated hearts. Meanwhile, AICAR increased superoxide dismutase (SOD) activity and decreased malondialdehyde (MDA) content in myocardial homogenate. Mechanistically, AICAR inhibited the phosphorylation of Drp1 at Ser 616 while enhanced phosphorylation of Drp1 at Ser 637. In addition, AICAR reduced the expression of inflammatory cytokines including TNF-ɑ, IL-6, and IL-1ß, as well as mitochondrial fission genes Mff and Fis1, while improved the expression of mitochondrial fusion genes Mfn1 and Mfn2. Similar results were also observed in H9C2 cells. AICAR improved mitochondrial membrane potential (MMP), reduced reactive oxygen species (ROS) production, and inhibited mitochondrial damage. To further prove if Drp1 regulated mitochondrial dynamics mediated AMPK protection effect, the mitochondrial fission inhibitor Mdivi-1 was utilized. We found that Mdivi-1 significantly improved MMP, inhibited ROS production, reduced the expression of TNF-a, IL-6, IL-1ß, Fis1, and Mff, and improved the expression of Mfn1 and Mfn2. However, the protection effect of Mdivi-1 was not reversed by AMPK inhibitor Compound C. In conclusion, this study confirmed that activation of AMPK exerted the protective effects on MIRI, which were largely dependent on the inhibition of Drp1-mediated mitochondrial fission.