Myocardial infarction is the most common form of acute coronary syndrome. Blockage of a coronary artery due to blood clotting leads to ischemia and subsequent cell death in the form of necrosis, ...apoptosis, necroptosis and ferroptosis. Revascularization by coronary artery bypass graft surgery or non-surgical percutaneous coronary intervention combined with pharmacotherapy is effective in relieving symptoms and decreasing mortality. However, reactive oxygen species (ROS) are generated from damaged mitochondria, NADPH oxidases, xanthine oxidase, and inflammation. Impairment of mitochondria is shown as decreased metabolic activity, increased ROS production, membrane permeability transition, and release of mitochondrial proteins into the cytoplasm. Oxidative stress activates Nrf2 transcription factor, which in turn mediates the expression of mitofusin 2 (Mfn 2) and proteasomal genes. Increased expression of Mfn2 and inhibition of mitochondrial fission due to decreased Drp1 protein by proteasomal degradation contribute to mitochondrial hyperfusion. Damaged mitochondria can be removed by mitophagy via Parkin or p62 mediated ubiquitination. Mitochondrial biogenesis compensates for the loss of mitochondria, but requires mitochondrial DNA replication and initiation of transcription or translation of mitochondrial genes. Experimental evidence supports a role of Nrf2 in mitophagy, via up-regulation of PINK1 or p62 gene expression; and in mitochondrial biogenesis, by influencing the expression of PGC-1α, NResF1, NResF2, TFAM and mitochondrial genes. Oxidative stress causes Nrf2 activation via Keap1 dissociation, de novo protein translation, and nuclear translocation related to inactivation of GSK3β. The mechanism of Keap 1 mediated Nrf2 activation has been hijacked for Nrf2 activation by small molecules derived from natural products, some of which have been shown capable of mitochondrial protection. Multiple lines of evidence support the importance of Nrf2 in protecting mitochondria and preserving or renewing energy metabolism following tissue injury.
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•Myocardial ischemia and reperfusion produce ROS via mitochondria and oxidases.•ROS activates Nrf2 transcript factor by protein translation or protein stabilization.•Nrf2 increases Mfn2, PINK1, p62, PGC-1α, NResF1 and mitochondrial gene expression.•Nrf2 aids in regulation of mitochondrial hyerfusion, mitophagy and biogenesis.•Nrf2 inducers show mitochondrial protection in animal models of cardiac injury.
Myocardial ischemia or reperfusion increases the generation of reactive oxygen species (ROS) from damaged mitochondria, NADPH oxidases, xanthine oxidase, and inflammation. ROS can be removed by eight ...endogenous antioxidant and redox systems, many components of which are expressed under the influence of the activated Nrf2 transcription factor. Transcriptomic profiling, sequencing of Nrf2-bound DNA, and Nrf2 gene knockout studies have revealed the power of Nrf2 beyond the antioxidant and detoxification response, from tissue recovery, repair, and remodeling, mitochondrial turnover, and metabolic reprogramming to the suppression of proinflammatory cytokines. Multifaceted regulatory mechanisms for Nrf2 protein levels or activity have been mapped to its functional domains, Nrf2-ECH homology (Neh)1–7. Oxidative stress activates Nrf2 via nuclear translocation, de novo protein translation, and increased protein stability due to removal of the Kelch-like ECH-associated protein 1 (Keap1) checkpoint, or the inactivation of β-transducin repeat-containing protein (β-TrCP), or Hmg-CoA reductase degradation protein 1 (Hrd1). The promise of small-molecule Nrf2 inducers from natural products or derivatives is discussed here. Experimental evidence is presented to support Nrf2 as a lead target for drug development to further improve the treatment outcome for myocardial infarction (MI).
Myocardial ischemic reperfusion leads to increased oxidative stress and cell death by necrosis, apoptosis, and necroptosis.During oxidative stress, the activity of Nrf2 as a transcription factor is regulated by protein stability, translation, nuclear localization, and protein–protein interactions.The Nrf2 transcription factor controls the expression of key components in eight antioxidant and redox systems for the removal of reactive oxygen species.The genes under the influence of Nrf2 status suggest its involvement in mitochondrial turnover, tissue recovery, repair, or remodeling, metabolic reprogramming, and the limitation of proinflammatory cytokines.Small-molecule Nrf2 inducers have shown promise in eliciting cardiac protection and inhibiting inflammation in experimental animals, suggesting a future direction for the development of nontoxic Nrf2 inducers using modern technologies.
The NFE2L2 gene encodes the transcription factor Nrf2 best known for regulating the expression of antioxidant and detoxification genes. Gene knockout approaches have demonstrated its universal ...cytoprotective features. While Nrf2 has been the topic of intensive research in cancer biology since its discovery in 1994, understanding the role of Nrf2 in cardiovascular disease has just begun. The literature concerning Nrf2 in experimental models of atherosclerosis, ischemia, reperfusion, cardiac hypertrophy, heart failure, and diabetes supports its cardiac protective character. In addition to antioxidant and detoxification genes, Nrf2 has been found to regulate genes participating in cell signaling, transcription, anabolic metabolism, autophagy, cell proliferation, extracellular matrix remodeling, and organ development, suggesting that Nrf2 governs damage resistance as well as wound repair and tissue remodeling. A long list of small molecules, most derived from natural products, have been characterized as Nrf2 inducers. These compounds disrupt Keap1-mediated Nrf2 ubquitination, thereby prohibiting proteasomal degradation and allowing Nrf2 protein to accumulate and translocate to the nucleus, where Nrf2 interacts with sMaf to bind to ARE in the promoter of genes. Recently alternative mechanisms driving Nrf2 protein increase have been revealed, including removal of Keap1 by autophagy due to p62/SQSTM1 binding, inhibition of βTrCP or Synoviolin/Hrd1-mediated ubiquitination of Nrf2, and de novo Nrf2 protein translation. We review here a large volume of literature reporting historical and recent discoveries about the function and regulation of Nrf2 gene. Multiple lines of evidence presented here support the potential of dialing up the Nrf2 pathway for cardiac protection in the clinic.
Transdermal delivery of large hydrophilic molecules is a long-standing challenge owing to the strong diffusive barrier properties of the skin. Using choline and geranic acid (CAGE) based ionic liquid ...(IL) as a delivery technology, we report a significant improvement of transdermal transport of dextrans of various molecular weights up to 150 kDa. In addition, it is the first time that we show CAGE decreased the size-dependence of transport and thus can be applied to a broad range of solutes. At the molecular scale, we conducted Fourier Transform Infrared (FTIR) spectroscopy studies which showed lipid extraction in the skin due to CAGE. Based on these experimental observations, we built a novel theoretical model that elucidates how CAGE-induced skin structural changes result in faster macromolecular diffusion for enhanced permeability. The fundamental understanding gained from this study demonstrates the potential of ionic liquids as an effective and noninvasive transdermal drug delivery method.
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•Choline-geranate ionic liquid increases transdermal permeability of macromolecules.•This chemical enhancer also slows down the decay of permeability vs. molecular size.•Enhancement mechanism is mainly due to lipid extraction in the stratum corneum.•Novel theory predicts a mixture of ionic liquids and water mediates faster diffusion.
ABSTRACT
Sublethal levels of oxidative stress are commonly associated with various pathophysiological conditions. Cardiomyocytes have the highest content of mitochondria among all cell types, ...allowing the study of mitochondria in cells surviving oxidative stress and address whether nuclear factor‐erythroid‐derived 2‐related factor 2 (Nrf2) can reverse these changes. Mitochondria normally exist in elaborated networks, which were replaced by predominately individual punctuate mitochondria 24 h after exposure to a nonlethal dose of H2O2. Electron microscopy revealed that cells surviving H2O2 show swelling of mitochondria with disorganized cristae and areas of condensation. Measurements of functional mitochondria showed a H2O2 dose‐dependent decrease over a course of 5 d. At the protein and mRNA levels, cells surviving H2O2 treatment show a reduction of mitochondrial components, cytochrome c, and cytochrome b. Nrf2 overexpression prevented H2O2 from inducing mitochondria morphologic changes and reduction of cytochrome b/c. Although Nrf2 is known as a transcription factor regulating antioxidant and detoxification genes, Nrf2 overexpression did not significantly reduce the level of protein oxidation. Instead, Nrf2 was found to associate with the outer mitochondrial membrane. Mitochondria prepared from the myocardium of Nrf2 knockout mice are more sensitive to permeability transition. Our data suggest that Nrf2 protects mitochondria from oxidant injury likely through direct interaction with mitochondria.—Strom, J., Xu, B., Tian, X., Chen, Q. M. Nrf2 protects mitochondrial decay by oxidative stress. FASEB J. 30, 66‐80 (2016). www.fasebj.org
Nrf2 gene encodes a transcription factor regulating the expression of antioxidant and detoxification genes. We test here whether Nrf2 plays a role for cardiac protection during ischemic injury in an ...effort to establish Nrf2 as a target for cardiac protection therapies. Cardiac ischemia induced by the left anterior descending (LAD) coronary artery ligation results in myocardial infarction (MI). Young mice surviving MI show minimal signs of heart failure. Mice lacking Nrf2 experience an accelerated progression to heart failure that occurs within 10days following induction of MI. Nrf2 knockout (Nrf2 KO) mice have a survival rate similar to wild type (WT) mice at 24h after MI, but a significantly higher mortality rate within 10days after MI (50% vs 86%). Morphological examination revealed maladaptive remodeling, including cardiac hypertrophy and dilated left ventricle in Nrf2 KO mice, which were absent in WT mice. Measurements of cardiac function revealed increased left ventricular mass and decreases in cardiac output in Nrf2 KO mice. In addition, Nrf2 KO mice show biomarkers of heart failure, such as elevated levels of β-MHC, ANF, and BNP mRNA in the myocardium. These data support that Nrf2 plays an important role in protecting the myocardium from ischemic injury. Lack of Nrf2 leads to rapid development of heart failure.
•We test whether Nrf2 serves to protect the heart from ischemic injury.•Nrf2 knockout mice have increased mortality following myocardial ischemia.•Heart failure develops in 10days following myocardial ischemia due to Nrf2 knockout.
Aims
This study aimed to investigate the antibacterial ability and action mechanism of dithiocyano‐methane against Aeromonas hydrophila, so as to provide a reference for its application in farm ...disinfection.
Methods and Results
After exposing the bacteria to dithiocyano‐methane, the minimum inhibitory concentration (MIC), minimum bactericide concentration (MBC), activities of alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase and electric conductivity in bacterial suspensions were determined, transmission electron microscope images on cellular structure and SDS‐PAGE profile of bacterial proteins were analysed and the expression of genes related to the above experimental observations was confirmed by real‐time quantitative PCR. The MIC and MBC of dithiocyano‐methane against three tested strains was 1·46 and 2·93 mg l−1 respectively. The results showed that dithiocyano‐methane significantly damaged bacterial cell structure, inhibited the biosynthesis of bacterial proteins and changed the integrity and permeability of bacterial cell wall and cell membrane.
Conclusions
Dithiocyano‐methane showed remarkable antibacterial ability against three tested strains, indicating it is a potential effective bactericidal agent for preventing animal diseases resulted from Aer. hydrophila.
Significance and Impact of the Study
To our best knowledge, this is the first report to examine the antibacterial ability and action mechanism of dithiocyano‐methane against bacteria. The results demonstrate the great potential of dithiocyano‐methane as a disinfectant against Aer. hydrophila in settings such as aquaculture ponds and livestock farms.
Pharmacogenomics of Statins: A View from ChatGPT Alpert, Joseph S.; Chen, Qin M.
The American journal of medicine,
March 2024, 2024-Mar, 2024-03-00, 20240301, Letnik:
137, Številka:
3
Journal Article
Skin diseases such as lupus, cancer, psoriasis, and hyperhidrosis can potentially be treated effectively by suppressing allele-specific genes using small interfering RNA (siRNA). Injections of siRNA ...into skin, though effective, are painful and cover small surface areas and thus are not suitable as a long-term treatment option. Topical delivery of siRNA is an attractive alternative option to mediate RNA interference (RNAi). However, the barrier function of the epidermis impedes effective permeation of siRNA into the skin. Herein, we describe topical delivery of siRNA using ionic liquids (ILs) capable of complexing with siRNA non-covalently and delivering it effectively. Using complementary and synergistic strategies of ionic liquids, we report delivery of effective doses of siRNA into skin. The first strategy involved the use of hydrophobic cations to robe the siRNA and the second strategy involved the use of choline-geranic acid ionic liquid (CAGE) to enhance its dermal penetration. In vitro studies in porcine skin confirmed the synergistic effect of these strategies in enhancing epidermal and dermal penetration. In vivo application of siRNA formulation to SKH-1E hairless mice significantly suppressed GAPDH expression with no clinical evidence of toxicity. This is a simple, personalized, and scalable platform for effective topical delivery of siRNA for treating genetic skin diseases.
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The study of skyrmion/antiskyrmion motion in magnetic materials is very important in particular for the spintronics applications. In this work, we study the dynamics of isolated skyrmions and ...antiskyrmions in frustrated magnets driven by magnetic field gradient, using the Landau-Lifshitz-Gilbert simulations on the frustrated classical Heisenberg model on the triangular lattice. A Hall-like motion induced by the gradient is revealed in bulk system, similar to that in the well-studied chiral magnets. More interestingly, our work suggests that the lateral confinement in nanostripes of the frustrated system can completely suppress the Hall motion and significantly speed up the motion along the gradient direction. The simulated results are well explained by Thiele theory. It is demonstrated that the acceleration of the motion is mainly determined by the Gilbert damping constant, which provides useful information for finding potential materials for skyrmion-based spintronics.
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