Boswellsmall3644

Malignant melanoma is the cause of 80% of deaths in skin cancer patients. Treatment of melanoma in the 4th stage of clinical advancement, in which inoperable metastasis occur, does not provide sufficient effects. Ketoprofen has phototoxic properties and it can be used as a new treatment option for skin cancers as a part of photochemotherapy. The present study was designed to investigate whether ketoprofen in combination with UVA induces cytotoxic, anti-proliferative and pro-apoptotic effects on melanoma cells. It was stated that co-treatment with 1.0 mM ketoprofen and UVA irradiation disturbed homeostasis of C32 melanoma cells by lowering its vitality (decrease of GSH level). Contrary to C32 cells, melanocytes showed low sensitivity to ketoprofen and UVA radiation, pointing selectivity in the mode of action towards melanoma cells. Co-treatment with ketoprofen and UVA irradiation has cytotoxic and anti-proliferative and pro-apoptotic effect on C32. The co-treatment triggered the DNA fragmentation and changed the cell cycle in C32 cells. In conclusion, it could be stated that local application of ketoprofen in combination with UVA irradiation may be used to support the treatment of melanoma and creates the possibility of reducing the risk of cancer recurrence and metastasis.Acrylamide is known as a neurotoxicant found in commonly consumed food as well as in human body. However, the underlying mechanisms involved in neurotoxicity by acrylamide and its metabolite, glycidamide remain largely unknown. In this study, we have examined the interplay between CYP2E1, AMPK, ERK and PKC in acrylamide-induced neurotoxicity associated with autophagy in PC12 cells. Acrylamide-induced cell death was mediated by CYP2E1 expression and the activation of ERK, PKC-ɑ and PKC-δ, whereas AMPK knockdown exacerbated the acrylamide-induced neurotoxic effects. PKC-ɑ, but not PKC-δ, plays an upstream regulator of ERK and AMPK. Moreover, AMPK activation suppressed ERK, and CYP2E1 and AMPK bilaterally inhibit each other. Furthermore, acrylamide increased autophagy with impaired autophagic flux, evidenced by the increased beclin-1, LC3-II and p62 protein. Acrylamide-induced neuronal death was ameliorated by 3-methyladenine, an autophagy inhibitor, whereas neuronal death was exacerbated by chloroquine, a lysosomal inhibitor. Interestingly, PKC-δ siRNA, but not PKC-ɑ siRNA, dramatically reduced acrylamide-induced beclin-1 and LC3-II levels, whereas AMPK siRNA further increased beclin-1, LC3-II and p62 protein levels. Glycidamide, a major metabolite, mimicked acrylamide only with a higher potency. Taken together, acrylamide- and glycidamide-induced neurotoxicity may involve cytotoxic autophagy, which is mediated by interplay between PKCs and AMPK pathways.Various adaptive cellular stress response pathways are critical in the pathophysiology of liver disease and drug-induced liver injury. Protein Tyrosine Kinase inhibitor Human-induced pluripotent stem cell (hiPSC)-derived hepatocyte-like cells (HLCs) provide a promising tool to study cellular stress response pathways, but in this context there is limited insight on how HLCs compare to other in vitro liver models. Here, we systematically compared the transcriptomic profiles upon chemical activation in HLCs, hiPSC, primary human hepatocytes (PHH) and HepG2 liver cancer cells. We used targeted RNA-sequencing to map concentration transcriptional response using benchmark concentration modeling for the various stress responses in the different test systems. We found that HLCs are very sensitive towards oxidative stress and inflammation conditions as corresponding genes were activated at over 3 fold lower concentrations of the corresponding pathway inducing compounds as compared to PHH. PHH were the most sensitive model when studying UPR related effects. Due to the non-proliferative nature of PHH and HLCs, these do not pose a good/sensitive model to pick up DNA damage responses, while hiPSC and HepG2 were more sensitive in these conditions. We envision that this study contributes to a better understanding on how HLCs can contribute to the assessment of cell physiological stress response activation to predict hepatotoxic events.Conrad Waddington's theory of epigenetic landscape epitomize the process of cell fate and cellular decision-making during development. Wherein the epigenetic code maintains patterns of gene expression in pluripotent and differentiated cellular states during embryonic development and differentiation. Over the years disruption or reprogramming of the epigenetic landscape has been extensively studied in the course of cancer progression. Cellular dedifferentiation being a key hallmark of cancer allow us to take cues from the biological processes involved during development. Here, we discuss the role of epigenetic landscape and its modifiers in cell-fate determination, differentiation and prostate cancer progression. Lately, the emergence of RNA-modifications has also furthered our understanding of epigenetics in cancer. The overview of the epigenetic code regulating androgen signalling, and progression to aggressive neuroendocrine stage of PCa reinforces its gene regulatory functions during the development of prostate gland as well as cancer progression. Additionally, we also highlight the clinical implications of cancer cell epigenome, and discuss the recent advancements in the therapeutic strategies targeting the advanced stage disease.Extracellular vesicles (EVs) are increasingly recognised as a pivotal player in cell-cell communication, an attribute of EVs that derives from their ability to transport bioactive cargoes between cells, resulting in complex intercellular signalling mediated by EVs, which occurs under both physiological and pathological conditions. In the context of cancer, recent studies have demonstrated the versatile and crucial roles of EVs in the tumour microenvironment (TME). Here, we revisit EV biology, and focus on EV-mediated interactions between cancer cells and stromal cells, including fibroblasts, immune cells, endothelial cells and neurons. In addition, we focus on recent reports indicating interactions between EVs and non-cell constituents within the TME, including the extracellular matrix. We also review and summarise the intricate cancer-associated network modulated by EVs, which promotes metabolic reprogramming, horizontal transfer of neoplastic traits, and therapeutic resistance in the TME. We aim to provide a comprehensive and updated landscape of EVs in the TME, focusing on oncogenesis, cancer progression and therapeutic resistance, together with our future perspectives on the field.