Myc Dysregulation in Activated Macrophages Initiates Iron-Mediated Lipid Peroxidation that Fuels Type I Interferon and Compromises TB Resistance.

A quarter of human population is infected with Mycobacterium tuberculosis, but less than 10% of those infected develop clinical, mostly pulmonary, TB. To dissect mechanisms of susceptibility in immunocompetent individuals, we developed a genetically defined sst1-susceptible mouse model that uniquely reproduces a defining feature of human TB: development of necrotic lung lesions after infection with virulent Mtb. In this study, we explored the connectivity of the sst1-regulated pathways during prolonged macrophage activation with TNF. We determined that the aberrant response of the sst1-susceptible macrophages to TNF was primarily driven by conflicting Myc and antioxidant response pathways that resulted in a coordinated failure to properly sequester intracellular iron and activate ferroptosis inhibitor enzymes. Consequently, iron-mediated lipid peroxidation fueled IFNß superinduction and sustained the Type I Interferon (IFN-I) pathway hyperactivity that locked the sst1-susceptible macrophages in a state of unresolving stress and compromised their resistance to Mtb. The accumulation of the aberrantly activated, stressed, macrophages within granuloma microenvironment led to the local failure of anti-tuberculosis immunity and tissue necrosis. Our findings suggest a novel link between metabolic dysregulation in macrophages and susceptibility to TB, offering insights into potential therapeutic targets aimed at modulating macrophage function and improving TB control.

Luminescent diagnostics of skin defects in the near-infrared range.

Photodynamic therapy becomes a widely spread method due to cancer growth in the world. However, to detect tumors at early stages, it is necessary to carry out diagnostic measures in a timely manner. Our aim was to test the developed pharmaceutical composition, which can be used for external application in early fluorescent diagnostics even in the absence of visual changes, as well as for therapy effectiveness control. Pharmacokinetic studies on laboratory animals and volunteers were carried out. The results have shown that the dipotassium salt of Yb3+-dimethoxyhematoporphyrin IX, which is highly soluble in water and stable in storage, is a promising marker for earlier diagnostics of tumors and can be used in dermatology, dentistry, gynecology, cosmetology, ear, nose, and throat diseases, veterinary, and in other areas of medicine.