title: JNK1 as a molecular target to limit cellular mortality under hypoxia.
abstract: Many pathological conditions and environmental impacts lead to a decrease in tissue oxygen supply and severe cellular hypoxia. This secondary hypoxia can disturb cellular homeostasis, limiting the efficacy of the prescribed treatment for the primary lesion, eventually leading to cellular and organismal death. Jun N-terminal kinase 1 (JNK1) plays a major role in the hypoxic cellular damage. Therefore, we hypothesized that suppression of JNK1 activity will decrease cellular mortality under hypoxia and might increase the efficacy of traditional treatment of many pathological conditions. These investigations are aimed at studying the influence of the suppression of JNK1 activity on the development of cellular hypoxic damage. We used antisense oligonucleotides (ASO) and small interfering RNA (siRNA) targeted to JNK1 mRNA to inhibit the protein synthesis. Experiments were carried out on a cell culture under normoxia and hypoxic conditions that led to the death of approximately 50% of cells. ASO or siRNA was delivered by neutral or cationic liposomes. Intracellular localization of ASO and liposomes and mechanisms of apoptosis were studied. We found that the suppression of JNK1 activity by liposomal antisense oligonucleotides or siRNA limits the caspase-dependent apoptosis signaling pathway and decreases cellular mortality after severe hypoxia. JNK1 protein might be an attractive target for antihypoxic therapy in increasing resistance to many pathological conditions and diseases, leading to the oxygen deficit.
authors.affiliation: Department of Pharmaceutics, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854-8020, USA.
authors.forename: Seema
authors.initials: S
authors.lastname: Betigeri
authors.forename: Refika I
authors.initials: RI
authors.lastname: Pakunlu
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.forename: Jayant J
authors.initials: JJ
authors.lastname: Khandare
authors.forename: Tamara
authors.initials: T
authors.lastname: Minko
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D001483:Base Sequence; D015687:Cell Hypoxia / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008081:Liposomes; D048055:Mitogen-Activated Protein Kinase 8 / Q000037:antagonists & inhibitors* / Q000235:genetics*; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology
chemical_list: D008081:Liposomes; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D048055:Mitogen-Activated Protein Kinase 8