The inflammatory/cancer-related IL-6/STAT3/NF-B positive feedback loop includes AUF1 and maintains the active state of breast myofibroblasts

Streptococcus mutans are an oral pathogen that causes dental caries, endocarditis, and systemic dysfunctions, an alternative antibacterial solution from silver nanoparticles (AgNPs) are investigated. AgNPs were synthesized using the ethnobotanical product gum Arabic. It influenced the nanoparticles with medicinal value through their role as capping, stabilizing, or surface-attached components. The biophysical characteristics of the synthesized AgNPs were studied using UV-vis spectrum, XRD, EDAX, SEM, and TEM tools. The AgNPs were spherical with the average size less than 10 nm. By using the well diffusion and microdilution techniques, the impact of synthesized AgNPs was tested against S. mutans isolates. The smaller the size, the greater the antibacterial and antiviral potential the particles exhibit. The biophysical characteristics of AgNPs the presence of phenols, alcohols, amides, sulfoxide, flavanoids, terpenoids and steroids. The AgNPs exhibited a good antibacterial action against the oral pathogen S. mutans. The synthesized NPs at a dose level of 200 μg/mL exhibited an inhibition zone with 18.30 ± 0.5 nm diameter. The synthesised nanoparticles inhibited the genes responsible for biofilm formation of S. mutans over host tooth and gums (gtfB, gtfc, gtfD) and virulent protective factors (comDE, brpA and smu 360) and survival promoter genes (gyrA and spaP, gbpB). The potent antibiotic action over S. mutans seen with the synthesized NPs, paves the way for the development of novel dental care products. Also, the small-sized NPs promote its applicability in COVID-19 pandemic containment.

Cancer-associated fibroblasts (CAFs), the most abundant and probably the most active cellular component of breast cancer-associated stroma, promote carcinogenesis through paracrine effects; however, the molecular basis remains elusive. We have shown here that p16^INK4A expression is reduced in 83% CAFs as compared with their normal adjacent counterparts cancer-free tissues isolated from the same patients. This decrease is mainly due to AUF1-dependent higher turnover of the CDKN2A mRNA in CAFs. Importantly, p16^INK4A downregulation using specific siRNA activated breast fibroblasts and increased the expression/secretion levels of stromal cell-derived factor 1 (SDF-1) and matrix metalloproteinase (MMP)-2. Consequently, media conditioned with these cells stimulated the proliferation of epithelial cells. Furthermore, the migration/invasion of breast cancer cells was also enhanced in an SDF-1-dependent manner. This effect was mediated through inducing an epithelial–mesenchymal transition state. By contrast, increase in p16^INK4A level through ectopic expression or AUF1 downregulation, reduced the secreted levels of SDF-1 and MMP-2 and suppressed the pro-carcinogenic effects of CAFs. In addition, p16^INK4A-defective fibroblasts accelerated breast tumor xenograft formation and growth rate in mice. Importantly, tumors formed in the presence of p16^INK4A-defective fibroblasts exhibited higher levels of active Akt, Cox-2, MMP-2 and MMP-9, showing their greater aggressiveness as compared with xenografts formed in the presence of p16^INK4A-proficient fibroblasts. These results provide the first indication that p16^INK4A downregulation in breast stromal fibroblasts is an important step toward their activation.