3/24/2023 0 Comments Groove agent 3![]() ![]() As a consequence, it is a matter of great relevance to investigate in detail the binding modes of the chromophore with DNA, and the nature of the electronically excited states that participate in the induction of DNA damage, for example, charge-transfer states. One of the main processes involved in the activation of apoptosis in cancer cells is the oxidative stress on DNA once a photosensitizer is excited by light. The design of more efficient photosensitizers is a matter of great importance in the field of cancer treatment by means of photodynamic therapy. Although several MD studies have been performed to unveil the energetics of the noncovalent binding process of anthraquinone derivatives with DNA, in particular the intercalation binding mode, to our knowledge a detailed study considering the effect of the DNA surrounding environment on the electronic structure of an anthraquinone derivative has not been performed to this date. Moreover, MD in conjunction with hybrid quantum mechanics/molecular mechanics (QM/MM) approaches have been applied to unravel in a comprehensive manner the binding modes with DNA and the nature of the excited states that give rise to photochemoterapeutic reactivity of organic photosensitizers, such as acetophenone, palmatine, methylene blue, Nile red and Nile blue, and chelerythrine, to cite a few. ![]() For example, molecular dynamics (MD) simulations have been employed to study the binding modes and determine the corresponding binding free energies of some representatives of the above mentioned photosensitizer families. These findings suggest that the npc2 mutant zebrafish may be a model of NPC disease. Histological analysis of adult npc2–/– zebrafish revealed that pathological changes in the nervous system, kidney, liver, and pancreas correlated with inflammatory responses (i.e., the upregulation of il1, nfκβ, and mpeg i.e., hallmarks of NPC disease). These behavioral changes correlated with downregulation of the mcu (mitochondrial calcium uniporter) gene, ppp3ca (calcineurin) gene, and genes that are involved in myelination (mbp and mpz). The npc2–/– larvae exhibited low mobility and a high anxiety-related response. We found that live npc2–/– larvae exhibited stronger Nile blue staining. Five-day-old npc2 mutants were morphologically indistinguishable from wildtype larvae. ![]() Using CRISPR/Cas9 technology, we knocked out the zebrafish homolog of NPC2. The present study generated and characterized a zebrafish mutant that lacks Npc2 protein that may be useful for studies at the organismal, cellular, and molecular levels and both small-scale and high-throughput screens. The molecular mechanisms that are responsible for NPC disease pathology are far from being understood. The time of onset and severity of symptoms of NPC disease are highly variable. Abnormal lysosomal storage leads to cell damage, neurological problems, and premature death. Niemann-Pick type C (NPC) disease is an autosomal recessive lysosomal storage disease that is caused by a mutation of the NPC1 or NPC2 gene, in which un-esterified cholesterol and sphingolipids accumulate mainly in the liver, spleen, and brain. ![]()
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