Current Pharmaceutical Design - Volume 24, Issue 44, 2018

Consumption of dietary supplements by millions of people is increasing [1]. Between 64 to 81% of cancer patients and survivors use multivitamin supplements after the cancer diagnosis [2]. The use of antioxidants during cancer therapy has been a hot topic in medical science for the last 20 years without clear answers and recommendations. It seems that antioxidants are able to I) decrease the cancer formation risk by quenching ROS that are involved in cancer initiation and progression and II) assist in survival of cancer/precancer cells once the malignant transformation already occurred. Antioxidants were shown to assist cancer initiation, interfere with cancer treatment by reducing its efficacy and patient survival, and vice versa, there are reports of beneficial antioxidant effect during the cancer treatment.

Aging is one of the biggest risk factors for the major prevalent diseases such as cardiovascular diseases, neurodegeneration and cancer, but due to the complex and multifactorial nature of the aging process, the molecular mechanisms underlying age-related diseases are not yet fully understood. Research has been intensive in the last years aiming to characterize the pathophysiology of aging and develop therapies to fight age-related diseases. In this context advanced glycation end products (AGEs) have received attention. AGEs, when accumulated in tissues, significantly increase the level of inflammation in the body which has long been associated with the development of cancer. Here we discuss the classical settings promoting AGE formation, as well as reduction strategies, occurrence and relevance of AGEs in cancer tissues and the role of AGE-interaction with the receptor for advanced glycation end products (RAGE) in cancer initiation and progression.

Redox homeostasis is important for the maintenance of cell survival. Under physiological conditions, redox system works in a balance and involves activation of many signaling molecules. Regulation of redox balance via signaling molecules is achieved by different pathways and proteasomal system is a key pathway in this process. Importance of proteasomal system on signaling pathways has been investigated for many years. In this direction, many proteasome targeting molecules have been developed. Some of them are already in the clinic for cancer treatment and some are still under investigation to highlight underlying mechanisms. Although there are many studies done, molecular mechanisms of proteasome inhibitors and related signaling pathways need more detailed explanations. This review aims to discuss redox status and proteasomal system related signaling pathways. In addition, cancer therapies targeting proteasomal system and their effects on redox-related pathways have been summarized.

Background: Reactive oxygen species sustain tumorigenesis and cancer progression through deregulated redox signalling which also sensitizes cancer cells to therapy. Photodynamic therapy (PDT) is a promising anti-cancer therapy based on a provoked singlet oxygen burst, exhibiting a better toxicological profile than chemo- and radiotherapy. Important gaps in the knowledge on underlining molecular mechanisms impede on its translation towards clinical applications. Aims and Methods: The main objective of this review is to critically analyse the knowledge lately gained on therapeutic targets related to redox and inflammatory networks underlining PDT and its outcome in terms of cell death and resistance to therapy. Emerging therapeutic targets and pharmaceutical tools will be documented based on the identified molecular background of PDT. Results: Cellular responses and molecular networks in cancer cells exposed to the PDT-triggered singlet oxygen burst and the associated stresses are analysed using a systems medicine approach, addressing both cell death and repair mechanisms. In the context of immunogenic cell death, therapeutic tools for boosting anti-tumor immunity will be outlined. Finally, the transcription factor NRF2, which is a major coordinator of cytoprotective responses, is presented as a promising pharmacologic target for developing co-therapies designed to increase PDT efficacy. Conclusion: There is an urgent need to perform in-depth molecular investigations in the field of PDT and to correlate them with clinical data through a systems medicine approach for highlighting the complex biological signature of PDT. This will definitely guide translation of PDT to clinic and the development of new therapeutic strategies aimed at improving PDT.

Monocytes are leading component of the mononuclear phagocytic system that play a key role in phagocytosis and removal of several kinds of microbes from the body. Monocytes are bone marrow precursor cells that stay in the blood for a few days and migrate towards tissues where they differentiate into macrophages. Monocytes can be used as a carrier for delivery of active agents into tissues, where other carriers have no significant access. Targeting monocytes is possible both through passive and active targeting, the former one is simply achieved by enhanced permeation and retention effect while the later one by attachment of ligands on the surface of the lipid-based particulate system. Monocytes have many receptors e.g., mannose, scavenger, integrins, cluster of differentiation 14 (CD14) and cluster of differentiation 36 (CD36). The ligands used against these receptors are peptides, lectins, antibodies, glycolipids, and glycoproteins. This review encloses extensive introduction of monocytes as a suitable carrier system for drug delivery, the design of lipid-based carrier system, possible ways for delivery of therapeutics to monocytes, and the role of monocytes in the treatment of life compromising diseases such as cancer, inflammation, stroke, etc.

This study investigates the efficiency and predictive value of light-transmission aggregometry (LTA), vasodilator-stimulated phosphoprotein (VASP) and VerifyNow for ischemia in patients undergoing percutaneous coronary intervention (PCI). Studies that used LTA, VASP or VerifyNow to predict ischemia were included, and their quality and efficiency were analyzed using Review Manager 5.3. The sensitivity and specificity of subgroup studies based on the outcome, cut-off value, and follow-up days were calculated and the summary ROC (sROC) curves were compared after having been fitted. Thirty-one studies including a total of 17,314 participants were analyzed. LTA, VASP and VerifyNow presented a considerable efficiency in predicting ischemic clinical events. In the subgroup analysis, the sensitivities of LTA, VASP and VerifyNow in predicting cardiac death, all-cause death, myocardial infarction, stent thrombosis, stroke, and revascularization were 0.40/0.63/0.62, 0.47/0.56/0.39, 0.40/0.48/0.60, 0.44/0.58/0.70, 0.29/not applicable/0.60 and 0.44/0.57/0.37, respectively and the specificities of LTA, VASP, and VerifyNow were 0.85/0.48/0.63, 0.73/0.52/0.63, 0.74/0.55/0.64, 0.75/0.47/0.61, 0.72/not applicable/ 0.61, and 0.70/0.47/0.67, respectively. LTA showed a higher sensitivity in predicting the outcomes over six months than those within six months, while VerifyNow prediction sensitivity was found to be higher within six months. Meanwhile, VerifyNow showed no statistically significant higher AUC of sROC in comparison to LTA and VASP in predicting ischemic events in patients undergoing clopidogrel treatment. The cut-off values of LTA, VASP and VerifyNow were suggested to be 56%, 50% and 235 respectively according to our study.

Background: Human mesenchymal stem cell-derived exosomes (hMSC-Exo) have been shown to reduce ischemia/reperfusion injury (I/R) in multiple models. I/R-induced apoptosis or autophagy play important roles in cell death. However, little or no reports demonstrate any roles of hMSC-Exo in this regards. Objective: To test the hypothesis that the inhibition of I/R-induced apoptosis and autophagy play a pivotal role in the cardioprotection of hMSC-Exo. Methods: Myoblast H9c2 cells and isolated rat hearts underwent hypoxia/re-oxygenate (H/R) or ischemia/ reperfusion (I/R) respectively. H9c2 were treated with 1.0 μg/ml Exo, in comparison with 3-MA or rapamycin (Rapa), a known anti- or pro-autophagic agent respectively. Hearts were treated with 0.5, 1.0 and 2.0 μg/ml Exo for 20 min in the beginning of reperfusion. Cell viability, WST assay, LDH release, Annexin-V staining apoptosis assay and GFP-LC3 labeled autophagosomes formation, cardiac function and Western blot were measured. Results: Exo significantly reduced H/R injury as indicated by increased cell viability and reduced LDH and apoptosis. 3-MA, while Rapa, showed increased or decreased protective effects. Rapa-induced injury was partially blocked by Exo. Exo decreased LC3-II/I ratio and increased p62, inhibited autophagosome formation, an indication of autophagy inhibition. In isolated heart, Exo increased cardiac functional recovery and reduced LDH release in I/R. Bcl-2 was significantly upregulated by Exo but not 3-MA. Exo downregulated Traf6 and upregulated mTORC1/p-4eBP1. Conclusion: Exo reduce I/R-induced apoptosis and autophagy. Up-regulation of Bcl-2 is the cross-talk between these two processes. The down-regulation of Traf6 and activation of mTORC1 are additional mechanisms in the inhibition of apoptosis and autophagy.

Background: Ulinastatin (UTI) plays the beneficial roles in modifying cerebral ischemic injury evoked by cardiac arrest (CA). XueBiJing (XBJ), comprised of extracts from Chinese herbals, has been used for the treatment of sepsis and ischemic disorders linked to multiple organ dysfunction syndromes. The current study was to find interventions that can enhance effectiveness of these drugs and further to provide a fundamental for their rational application in clinical practice. Thus, we examined how apoptosis signal in the hippocampus is engaged in a facilitating role of UTI and XBJ in improving neural injury and neurological functions after transient cerebral ischemia. Methods: CA was induced by asphyxia followed by cardiopulmonary resuscitation in rats. Western Blot analysis and ELISA were employed to determine the protein expression of Caspase-3 and Caspase-9 in the hippocampus; and representative apoptosis pathways. The modified neurological severity score (mNSS) and spatial working memory performance were used to assess neurological deficiencies in CA rats. Results: CA increased Caspase-3 and Caspase-9 in the hippocampus CA1 region. A lower dose of UTI did not attenuate upregulation of apoptosis signal pathways evoked by CA. However, a systemic administration of XBJ significantly amplified the inhibitory effects of the lower dose of UTI on apoptosis signal of the hippocampus. In addition, a combination of UTI and XBJ improved mNSS and spatial working memory performance to a greater degree. Conclusions: Our data indicate that a combination of XBJ and UTI plays a facilitating role in improving neuronal injury and neurological deficits observed in transient cerebral ischemia; and an inhibition of apoptosis signal pathways is involved in neuroprotective effects of united XBJ and UTI.