Translational research : the journal of laboratory and clinical medicine
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Oxidative stress has been implicated in the unfavorable changes in cardiac function and remodeling that occur after ovarian estrogen loss. Using ovariectomized rat models, we previously reported that the cardioprotective actions of estrogen are mediated by the G protein-coupled estrogen receptor (GPER). Here, in 9-month-old, female cardiomyocyte-specific GPER knockout (KO) mice vs sex- and age-matched wild-type (WT) mice, we found increased cardiac oxidative stress and oxidant damage, measured as a decreased ratio of reduced glutathione to oxidized glutathione, increased 4-hydroxynonenal and 8-hydroxy-2'-deoxyguanosine (8-oxo-DG) staining, and increased expression of oxidative stress-related genes. ⋯ Treatment of GPER KO mice for 8 weeks with phosphonium [10-(4,5-dimethoxy-2-methyl 3,6-dioxo-1,4-cyclohexadien-1-yl)decyl] triphenyl-,mesylate (MitoQ), a mitochondria-targeted antioxidant, significantly attenuated these measures of cardiac dysfunction, and MitoQ decreased 8-oxo-DG intensity compared with treatment with an inactive comparator compound, (1-decyl)triphenylphosphonium bromide (P <0.05). A real-time polymerase chain reaction array analysis of 84 oxidative stress and antioxidant defense genes revealed that MitoQ attenuates the increase in NADPH oxidase 4 and prostaglandin-endoperoxide synthase 2 and the decrease in uncoupling protein 3 and glutathione S-transferase kappa 1 seen in GPER KO mice. Our findings suggest that the cardioprotective effects of GPER include an antioxidant role and that targeted strategies to limit oxidative stress after early noncancerous surgical extirpation of ovaries or menopause may help limit alterations in cardiac structure and function related to estrogen loss.
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Cell homeostasis requires precise coordination of cellular proteins function. Ubiquitination is a post-translational modification that modulates protein half-life and function and is tightly regulated by ubiquitin E3 ligases and deubiquitinating enzymes. ⋯ Ubiquitination plays an important role in the pathobiology of acute lung injury as it regulates the proteins modulating the alveolocapillary barrier and the inflammatory response. Better understanding of the signaling pathways regulated by ubiquitination may lead to novel therapeutic approaches by targeting specific elements of the ubiquitination pathways.
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The present review aims to summarize available knowledge on the role of the ubiquitin-proteasome system (UPS) in the pathogenesis of scleroderma and scleroderma-related disease mechanisms. This will provide the reader with a more mechanistic understanding of disease pathogenesis and help to identify putative novel targets within the UPS for potential therapeutic intervention. Because of the heterogenous manifestations of scleroderma, we will primarily focus on conserved mechanisms that are involved in the development of lung scleroderma phenotypes.
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Nuclear factor-κB (NF-κB) has been widely implicated in the development and progression of cancer. In colorectal cancer (CRC), NF-κB has a key role in cancer-related processes such as cell proliferation, apoptosis, angiogenesis, and metastasis. ⋯ Although there is sufficient evidence gained from cell lines and animal models that NF-κB is involved in cancer-related processes, because of a lack of studies in human tissue, the clinical evidence of its importance is limited in patients with CRC. This review summarizes evidence relating to how NF-κB is involved in the development and progression of CRC and comments on future work to be carried out.
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Homozygosity for the hemoglobin (Hb) S mutation (HbSS, sickle cell anemia) results in hemoglobin polymerization under hypoxic conditions leading to vaso-occlusion and hemolysis. Sickle cell anemia affects 1:500 African Americans and is a strong risk factor for kidney disease, although the mechanisms are not well understood. Heterozygous inheritance (HbAS; sickle cell trait) affects 1:10 African Americans and is associated with an increased risk for kidney disease in some reports. ⋯ Gene expression studies highlighted the differential expression of several genes involved in prostaglandin metabolism (AKR1C18), heme and iron metabolism (HbA-A2, HMOX1, SCL25A37), electrolyte balance (SLC4A1, AQP6), immunity (RSAD2, C3, UBE2O), fatty acid metabolism (FASN), hypoxia hall-mark genes (GCK, SDC3, VEGFA, ETS1, CP, BCL2), as well as genes implicated in other forms of kidney disease (PODXL, ELMO1, FRMD3, MYH9, APOA1). Pathway analysis highlighted increased gene enrichment in focal adhesion, extracellular matrix-receptor interaction, and axon guidance pathways. In summary, using transgenic sickle mice, we observed that inheritance of the HbS mutation is associated with glomerular and tubular damage and identified several candidate genes and pathways for future investigation in sickle cell trait and sickle cell anemia-related kidney disease.