Annals of medicine
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Altered epigenetic map is frequently observed in cancer and recent investigations have demonstrated a pertinent role of epigenetic modifications in the response to many anticancer drugs including the DNA damaging agents. Topoisomerase I (Top I) is a well-known nuclear enzyme that is critical for DNA function and cell survival and its inhibition causes DNA strand breaks and cell cycle arrest. Inhibitors of human Top I have proven to be a prosperous chemotherapeutic treatment for a vast number of cancer patients. While the treatment is efficacious in many cases, resistance and altered cellular response remain major therapeutic issues. ⋯ The field of epigenetic research is steadily growing. With its assistance, we could gain better understanding on how drug response and resistance work. Epigenetics can evolve as possible biomarkers and predictors of response to many medications including Top I inhibitors, and could have significant clinical implications that necessitate deeper attention.HIGHLIGHTSEpigenetic alterations, including DNA methylation and histone modifications, play a pertinent role in the response to several anticancer treatments, including DNA damaging agents like Top I inhibitors.Although camptothecin derivatives are used clinically as Top I inhibitors for management of cancer, certain types of cancer have inherent and or acquired resistance that limit the curative potential of them.Epigenetic modifications like DNA hypomethylation can either increase or decrease sensitivity to Top I inhibitors by different mechanisms.The combination of Top I inhibitors with the inhibitors of histone modifying enzymes can result in enhanced cytotoxic effects and sensitization of resistant cells to Top I inhibitors.MicroRNAs were found to directly influence the expression of Top I and other proteins in cancer cells resulting in positive or negative alteration of the response to Top I inhibitors.lncRNAs and their genetic polymorphisms have been found to be associated with Top I function and the response to its inhibitors.Clinical trials of epigenetic drugs in combination with Top I inhibitors are plentiful and some of them showed potentially promising outcomes.
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Disturbed circadian rhythms have been a risk factor for type 2 diabetes mellitus (T2DM). Melatonin is the major chronobiotic hormone regulating both circadian rhythm and glucose homeostasis. The rs10830963 (G allele) of the melatonin receptor 1B (MTNR1B) gene has the strongest genetic associations with T2DM according to several genome-wide association studies. ⋯ The rs10830963 G risk allele is associated with delayed melatonin secretion onset in dim-light and prolonged duration of peak melatonin. This delayed melatonin secretion may help human ancestors adapt to famine or food shortages during long nights and early mornings and avoid nocturnal hypoglycemia but confers susceptibility to T2DM due to adequate energy intake in modern society. We provide new insight into the role of MTNR1B variants in T2DM via disturbed circadian rhythms from the perspective of the "thrifty gene" hypothesis; these data indicate a novel target for the prevention and treatment of susceptible populations with the thrifty genotype.
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The chemokine CCL5 plays a potential role in the occurrence and development of colorectal cancer (CRC). Previous studies have shown that CCL5 directly acts on tumor cells to change tumor metastatic rates. In addition, CCL5 recruits immune cells and immunosuppressive cells into the tumor microenvironment (TME) and reshapes the TME to adapt to tumor growth or increase antitumor immune efficacy, depending on the type of secretory cells releasing CCL5, the cellular function of CCL5 recruitment, and the underlying mechanisms. ⋯ Key MessagesCCL5 plays dual roles in colorectal cancer progression. CCL5 remodels the tumor microenvironment to adapt to colorectal cancer tumor growth by recruiting immunosuppressive cells or by direct action. CCL5 inhibits colorectal cancer tumor growth by recruiting immune cells or by direct action.
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N-myristoyltransferase 1 (NMT1) is an indispensable eukaryotic enzyme that catalyses the transfer of myristoyl groups to the amino acid terminal residues of numerous proteins. This catalytic process is required for the growth and development of many eukaryotes and viruses. Elevated expression and activity of NMT1 is observed to varying degrees in a variety of tumour types (e.g. colon, lung and breast tumours). ⋯ Key MessagesElevated expression and activity of NMT1 is observed to varying degrees in a variety of tumour types which creates the possibility of targeting NMT1 in tumours. NMT1-mediated myristoylation plays a pivotal role in cancer cell metabolism and may be particularly relevant to cancer metastasis and drug resistance. These insights can be used to direct potential therapeutic avenues for NMT1 inhibitors.
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Review
Targeting interleukin 4 and interleukin 13: a novel therapeutic approach in bullous pemphigoid.
Aim: Bullous pemphigoid (BP) is an organ-specific autoimmune bullous disease characterized by autoantibodies that target the cellular adhesion molecules BP180 and BP230. Both immunoglobulin (Ig)G and IgE are involved in the induction of subepidermal blisters. Specifically, IgE autoantibodies are presumed to be responsible for the pruritic and erythematous features of BP. ⋯ KEY MESSAGESBP is an autoimmune skin disease with Th2-mediated autoimmune response involvement. As typical Th2 cytokines, IL-4 and IL-13 may contribute to the pathogenesis of BP in multiple ways, such as promoting Th2 cell polarization, driving the immunoglobulin class switching, recruiting eosinophils and basophils, and inducing pruritus. As a promising therapeutic approach for BP, IL-4/13 antagonists have shown satisfactory outcomes in preliminary clinical studies.