PTX3, a member of the long pentraxin subfamily, associated with innate immunity is indispensable for resistance to some cancer. Gemcitabine, an analog of cytosine arabinoside, has shown restrained benefits because of profound chemoresistance. The PTX3 expression on GEM in human lung cancer cells have not yet been clarified; the present study aimed to show reactive oxygen species (ROS) mediatory PTX3 expression through distinct mechanisms. Whereas ginsenoside Rg3 is a herbal medicine with strong antitumor activity. Furthermore, we tested the hypothesis; Rg3 abrogates GEM‐induced production of ROS‐mediated activation of Akt and extracellular signal‐regulated kinase (ERK) pathways and inhibits nuclear piling‐up of nuclear factor kappa B (NF‐κB) and HIF‐1α. On the basis of time and dose‐dependent manner, our data demonstrated that GEM‐induced PTX3 expression was dependent on ROS generation as it was abrogated by pretreatment of lung cancer cells with the free radical scavenger N‐acetyl‐l‐cysteine. Our data demonstrated that PTX3 upregulation by GEM correlated with the time‐dependent escalation of NF‐κB and HIF‐1α in the nucleus resulted from phosphorylation‐induced degradation of IκBα, whereas HIF‐1α upregulation was NF‐κB‐dependent. Increase in ROS expression in lung cancer cells on GEM treatment preceded the nuclear accumulation of NF‐κB and HIF‐1α and suppression of ROS diminished these effects. ERK1/2 and Akt activation mediated the effect of ROS on NF‐κB and HIF‐1α and their pharmacological inhibition suppressed GEM‐induced PTX3. Our study findings reinforced the role regarding PTX3 signaling in GEM‐induced resistance and pointed toward an unintended and undesired effect of chemotherapy and to get an active regimen; the synergy was associated with NF‐κB downregulation in lung cancer.

Hepatic transporters facilitate the uptake of xenobiotic compounds and confer immense potential as multimodality reporters, as they can uptake multitude of bioluminescent, fluorescence, near Infra-red (NIR), and magnetic resonance imaging (MRI) compounds. Here, it is aimed to identify the prospects of three human hepatocyte membrane proteins, organic anion transporters (OATP) 1B1, OATP1B3, and sodium-taurocholate cotransporting polypeptide in tracing the transplanted cells dynamics, by the uptake of clinically approved MRI compound, gadolinium ethoxybenzyl-diethylenetriaminepentaacetic acid (GD-EOB DTPA) or NIR fluorescent dye, Indocyanine Green (ICG). First, OATP1B1 is introduced as new MRI reporter which is the human orthologue of previously established rodent (Oatp1a1) reporter. Comparative sequential assays by assimilating MR image parameters reveal OATP1B3 as superior reporter on T1-weighted images and display highest contrast enhancement reported to-date when using a clinical 3T MR scanner (≈21-fold in vitro; ≈8-fold in vivo). Stably expressing these hepatic transporters have no effect on human adipose derived mesenchymal stem cells (hADSCs) characteristics. However, only OATP1B3 able to trace as few as 2 × 10 5 hADSCs intramuscular xenograft survival time on NIR and 3T MRI. These data suggest that OATP1B3 is relatively a robust Gd-EOB-DTPA/ICG-dependent multimodality reporter in visualizing dynamic processes for cell-based therapies.

Homozygous lamina/c p.R527C mutations result in severe mandibuloacral dysplasia (MAD) and progeroid syndrome, but the underlying molecular pathology remains unknown. Here, we report on three patients with MAD, all displaying severe systemic inflammaging and characterized the major molecular pathways involved in the manifestation of this disease. Analysis of induced pluripotent stem cell (IPSC)-derived mesenchymal stem cells (MAD-iMSCs) obtained from the patients revealed that increased mitochondrial Ca+2 loading was the root cause of lost mitochondrial membrane potential, abnormal fission/fusion and fragmentation, which then participated in inflammaging by inducing the inflammasome. These alterations in Ca+2 homeostasis were mediated by signal transducer and activator of transcription 3 (STAT3), which is located on the mitochondrial associated membrane (MAM). STAT3 function could be rescued by treatment with clinically-approved IL-6 blockers, or by correction of R527C mutations. In addition, extracellular vesicles (EVs) obtained from MAD-iMSCs displayed reduced immunomodulatory function, being unable to rescue bleomycin-induced lung fibrosis and triggering mitochondrial dysfunction, senescence, and fibrosis in healthy cells. Our results provide new insights into the pathology of complex lamin-associated MAD with systemic immunosenescence, and suggest that targeting defective mitochondrial Ca+2 homeostasis may represent a promising novel therapy for this condition.