Mollerup Mueller (expertfield84)

Ischemia reperfusion (IR) injury dampens renal function and usually confers a great risk of renal failure. Aberrant expression of G9a, a H3K9 methyltransferase of mammalian histone, has been implicated as a driving event in various kidney diseases. However, the role of G9a plays in renal IR injury is required to be clarified. Herein, our results showed that renal IR injury resulted in a rapid elevation of G9a, accompanying the down-regulation of Sirt1, a deacetylase that has been reported to afford renoprotection. Genetic overexpression or therapeutic activation of Sirt1 efficiently ameliorated renal IR injury by elevating anti-oxidative genes expression and reducing the accumulation of reactive oxygen species, including O2·- and ·OH. In addition, inhibition of G9a activity by BIX01294 (BIX) alleviated IR injury through abolishing O2·- and ·OH levels in a Sirt1-dependent manner. Mechanistically, we observed that demethylated H3K9 was accumulated on the Sirt1 promoter in renal IR injury. Silencing or suppression of G9a activity erased H3K9me2 from Sirt1 promoter and normalized Sirt1 expression. Further exploration revealed that G9a interacted with chromobox homolog 1 (CBX1) to catalyze H3K9 de-methylation and formed a transcription repressor complex on the Sirt1 promoter, ultimately repressing Sirt1 transcription. In this study, we provided strong evidence that G9a modulated renal IR injury through cooperation with CBX1 to form a transcription repressor complex on the Sirt1 promoter and regulate O2·- and ·OH generation, indicating that G9a-Sirt1 axis might be a promising therapeutic target in an epigenetic manner.Cyclooxygenase-2 (COX-2) is up-regulated by redox imbalance and is considered a target for cancer therapy. The rationale of the COX-2 inhibitor lies in suppressing COX-2 catalyzed peroxidation of omega-6 polyunsaturated fatty acids (PUFAs), which are essential and pervasive in our daily diet. However, COX-2 inhibitors fail to improve cancer patients' survival and may lead to severe side effects. Here, instead of directly inhibiting COX-2, we utilize a small molecule, iminodibenzyl, which could reprogram the COX-2 catalyzed omega-6 PUFAs peroxidation in lung cancer by inhibiting delta-5-desaturase (D5D) activity. Iminodibenzyl breaks the conversion from dihomo-γ-linolenic acid (DGLA) to arachidonic acid, resulting in the formation of a distinct byproduct, 8-hydroxyoctanoic acid, in lung cancer cells and solid tumors. By utilizing COX-2 overexpression in cancer, the combination of DGLA supplementation and iminodibenzyl suppressed YAP1/TAZ pathway, decreasing the tumor size and lung metastasis in nude mice and C57BL/6 mice. This D5D inhibition-based strategy selectively damaged lung cancer cells with a high COX-2 level, whereas it could avoid harassing normal lung epithelial cells. This finding challenged the COX-2 redox basis in cancer, providing a new direction for developing omega-6 (DGLA)-based diet/regimen in lung cancer therapy. Informed consent is an ethical and legal requirement that differs from informed decision-making-a collaborative process that fosters participation and provides information to help patients reach treatment decisions. The objective of this study was to measure informed consent and informed decision-making before major surgery. We audio-recorded 90 preoperative patient-surgeon conversations before major cardiothoracic, vascular, oncologic, and neurosurgical procedures at 3 centers in the US and Canada. Transcripts were scored for 11 elements of informed consent based on the American College of Surgeons' definition and 9 elements of informed decision-making using Braddock's validated scale. Uni- and bivariate analyses tested associations between decision outcomes as well as patient, consultation, and surgeon characteristics. Overall, surgeons discussed more elements of informed consent than informed decision-making. They most frequently described the nature of the