A comparative study of pathogen inactivation technologies in human platelet lysate and its optimal efficiency in human placenta-derived stem cells culture.

BACKGROUND: Pathogen inactivation (PI) is necessary for the pooled components derived from a biological source. Recently, the use of human platelet lysate (hPL) has increased in the cell manufacturing process as a xeno-free substitute for Fetal Bovine Serum (FBS). Therefore, an effective PI process to produce a pathogen-free hPL with the optimal efficiency in the manufacturing of cell therapy products is a vital requirement. STUDY DESIGN AND METHODS: To evaluate the efficacy of gamma irradiation and riboflavin/ultraviolet light (RB/UV) as PI methods for hPL, the reduction factor (RF) of titer of model viruses and bacteria were examined. Furthermore, the effect of different PI methods on the hPL performance was evaluated by the in vitro expansion of human placenta-derived mesenchymal stem cells (PLMSCs). To compare different study groups, the growth kinetic, immunophenotype, colony formation, and differentiation capacity (osteogenic and adipogenic) of PLMSCs were examined. In addition, the concentration of growth factors was assayed in each study group. RESULTS: Achievement to the RF more than 5 log10 for all pathogens, showed the effectiveness of two PI methods. In comparison with the other study groups, the dose of 45 kGy gamma irradiation considerably decreased the growth factor level of the hPL. It also showed a significant adverse effect on PLMSCs growth kinetics. The dose of 30 KGy gamma irradiation and RB/UV demonstrated a favorable effect on different assays of the in vitro expanded PLMSCs. CONCLUSION: The 30 KGy gamma irradiation and RB/UV were effective in the RF of the viral and bacterial models of the contaminated hPL. The efficacy of these PI-hPLs for PLMSCs expansion was preserved. To increase the safety of cell therapy products, PI methods should be considered for the hPL preparations.

The PI3K/Akt signaling axis in Alzheimer's disease: a valuable target to stimulate or suppress?

Among the long list of age-related complications, Alzheimer's disease (AD) has the most dreadful impact on the quality of life due to its devastating effects on memory and cognitive abilities. Although a plausible correlation between the phosphatidylinositol 3-kinase (PI3K) signaling and different processes involved in neurodegeneration has been evidenced, few articles reviewed the task. The current review aims to unravel the mechanisms by which the PI3K pathway plays pro-survival roles in normal conditions, and also to discuss the original data obtained from international research laboratories on this topic. Responses to questions on how alterations of the PI3K/Akt signaling pathway affect Tau phosphorylation and the amyloid cascade are given. In addition, we provide a general overview of the association between oxidative stress, neuroinflammation, alterations of insulin signaling, and altered autophagy with aberrant activation of this axis in the AD brain. The last section provides a special focus on the therapeutic possibility of the PI3K/Akt/mTOR modulators, either categorized as chemicals or herbals, in AD. In conclusion, determining the correct timing for the administration of the drugs seems to be one of the most important factors in the success of these agents. Also, the role of the PI3K/Akt signaling axis in the progression or repression of AD widely depends on the context of the cells; generally speaking, while PI3K/Akt activation in neurons and neural stem cells is favorable, its activation in microglia cells may be harmful.

Neurokinin-1 receptor (NK1R) inhibition sensitizes APL cells to anti-tumor effect of arsenic trioxide via restriction of NF-κB axis: Shedding new light on resistance to Aprepitant.

While a batch of efforts are fastened on synthesizing the novel targeted anti-cancer agents, recent investigations have achieved a breakthrough in identifying a favorable anti-tumor activity for some supportive drugs, which their safety have been confirmed thus far. The results of the present study highlighted the efficacy of Aprepitant, an oral antagonist of the neurokinin-1 receptor (NK1R), against both APL (NB4) and pre-B ALL (Nalm-6) cell lines; however, a differential sensitivity pattern was found in these cells. To the best of our knowledge, this is the first time that the molecular mechanisms of resistance to Aprepitant have been investigated and, herein, we proposed that the effectiveness of Aprepitant could be overshadowed, at least partially, through over-activated nuclear factor-κB in Nalm-6 pre-B ALL cells. In contrast to Nalm-6, the cytotoxic property of Aprepitant in NB4 was divulged at the lower concentrations. Of particular interest, we found that the cytotoxicity of the inhibitor became even more evident in the synergistic experiments, where an enhanced reduction in viability was noted after treatment of NB4 cells with ATO-plus-Aprepitant. The stimulatory effect of NK1R inhibition on ATO cytotoxicity is probably mediated through up-regulation of p73, which can subsequently engage p21 and NF-κB pathway via transcriptional suppression of c-Myc. Taken together, the present study suggests that inhibition of NK1R using Aprepitant, either alone or in combination with chemotherapeutic drugs, could be a novel therapeutic strategy for the treatment of acute leukemia, especially APL, that may be clinically accessible in the near future.

Antileukemic effects of neurokinin-1 receptor inhibition on hematologic malignant cells: a novel therapeutic potential for aprepitant.

Genetic and laboratory studies have remodeled the conventional understanding of cancer pathogenesis by identifying different molecular alterations. Intrigued by the contribution of neurokinin-1 receptor (NK1R) network in cancer pathogenesis, we investigated the antileukemic effects of aprepitant, a nonpeptide antagonist of NK1R, in a panel of hematological cell lines. In this study, we found that aprepitant decreased the survival of all the tested cells; however, as compared with NB4, viability of the other cell lines was inhibited at higher concentrations. By increasing both p21 and p73 along with suppressing c-Myc and hTERT, aprepitant probably disordered cell distribution in the cell cycle, decreased DNA replication rate, and, thereby, impeded the proliferative capability of NB4 cells. Moreover, exposing cells to this agent led to activation of the caspase-3-dependent apoptotic pathway through altering the expression of apoptosis-related genes. Noteworthy, aprepitant also sensitized NB4 cells to the cytotoxic effects of arsenic trioxide and vincristine. Overall, it seems that pharmaceutical targeting of NK1R using aprepitant, either as a single agent or in combination, possesses novel promising potential for leukemia treatment strategies.