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Parasitic organisms with the liver organ : epidemiology, analysis and also medical management inside the Western circumstance.
Mitochondria possess multiple copies of mitochondrial DNA (mtDNA) that encode 37 genes and their transcription and replication get controlled by unique molecular codes different from that in the nuclear DNA. The mtDNA has been gaining increased attention as one of the critical therapeutic targets as mutations in them impair the function of mitochondria and cause mitochondrial diseases like MELAS. In this chapter, we describe artificial control of mitochondrial transcription based on mtDNA sequence information with a new type of compounds termed MITO-PIPs, which encompasses two domains pyrrole-imidazole polyamide as DNA recognition domain and mitochondrial penetrating peptide as the mitochondria-targeting domain. Because MITO-PIPs are amenable to tunability, they can be expanded as a synthetic strategy to modulate mitochondrial gene(s) on demand.Ca2+ handling by mitochondria is implicated in energy production, shaping of cytosolic Ca2+ rises, and determination of cell fate. It is therefore of crucial interest for researchers to directly measure mitochondrial Ca2+ concentration [Ca2+] in living cells. Synthetic fluorescent Ca2+ indicators, providing a straightforward loading technique, represents a tempting strategy. Recently, we developed a new highly selective mitochondria-targeted Ca2+ indicator named mt-fura-2 , obtained by coupling two triphenylphosphonium cation-containing groups to the molecular backbone of the cytosolic ratiometric Ca2+ indicator fura-2 .The protocols we describe here cover all the significant steps that are necessary to characterize the probe and apply it to biologically relevant contexts. The procedures reported are referred to mt-fura-2 but could in principle be applied to characterize other mitochondria-targeted Ca2+ probes . More in general, with the due modifications, this chapter can be considered as a handbook for the characterization and/or application of mitochondria-targeted chemical Ca2+ probes .Creatine kinase (CK) enzyme overexpression has been suggested to play a role in the process of tumorigenesis and metastasis. Cyclocreatine (CCR) is a substrate analog of creatine kinase (CK), where its phosphorylated form is a poor phosphate donor in comparison with native bioenergetic molecule, creatine phosphate (Cr-P). The compound CCR has been shown to markedly inhibit the growth of a broad spectrum of cancers, both in vitro and in vivo. Intracellularly, CCR is phosphorylated by CK to yield a synthetic phosphagen [(N-phosphorylcyclocreatine (CCR ~P)], with thermodynamic and kinetic properties distinct from those of creatine phosphate (Cr-P). Distinct inhibition of tumor growth and metastasis has been attributed to CCR accumulation as CCR ~P in tumor cells, especially in those expressing a high level of CK protein, with minimal adverse effects. Unfortunately, the clinical use of CCR against malignancies is quite limited due to its amphoteric nature, which accounts for most of its extremely low membrane perism to counteract uncontrolled neoplastic proliferation, in target cancer cells. Our novel liposomal delivery system of the CCR substrate analog demonstrated strong inhibition of malignant cell bioenergetics, leading to significant antineoplastic and proapoptotic actions, against different cancers.Research on mitochondria-targeted active molecules became a hot topic in the past decade. Development of mitochondria permeability transition pore (mPTP )-targeting agents with clinical applications is needed not only because of the importance of the target in several diseases but also due to the fact that the current developed molecules have shown poor clinical success. In fact, only a reduced percentage reach mitochondria , effectively preventing pathological mPTP opening. The mitochondrial-targeting strategies should be a promising solution to increase the selectivity of compounds to the mPTP , reducing also their potential side effects. Chemical conjugation of bioactive molecules with a lipophilic cation such as the triphenylphosphonium (TPP +) has been established as a robust strategy to specifically target mitochondria . AK7 Phytochemicals such as hydroxybenzoic acids are normal constituents of the human diet. These molecules display beneficial healthy effects, ranging from antioxidant action through diverse mechanisms to modulation of mitochondrial-related apoptotic system, although their therapeutic application is limited due to pharmacokinetic drawbacks. Accordingly, the development of a new antioxidant based on the dietary benzoic acid-gallic acid -is described as well as the demonstration of its mitochondriotropic characteristics.Resveratrol and quercetin are among the most studied plant polyphenols, and have many health-promoting actions. Strategies to accumulate them into mitochondria may be of therapeutic relevance, since these compounds are redox active and are well known to impact mitochondria and mitochondrial proteins. We report here the procedures to synthesize mitochondria-targeted resveratrol and quercetin derivatives; the synthetic strategies reported are however expected to be adaptable to other polyphenols with similar reactivity at the phenolic hydroxyls. Mitochondrial targeting can be achieved by conjugation with triphenylphosphonium , a lipophilic cation; this was linked via a butyl spacer forming an ether bond with one of the phenolic oxygens. The first step toward the synthesis of all mitochondriotropic derivatives described in this work is the production of a regiospecific -(4-O-chlorobutyl) derivative. Triphenylphosphonium (P+Ph3I-) is then introduced through two consecutive nucleophilic substitution steps -Cl → -I → -P+Ph3I-. Pure mono-substituted chlorobutyl regioisomers are obtained by purification from the reaction mixture in the case of resveratrol , while specific protection strategies are required for quercetin to favor alkylation of one specific hydroxyl.Functionalization of the remaining hydroxyls can be exploited to modulate the physicochemical properties of the derivatives (i.e., water solubility, affinity for cell membranes); we report here synthetic protocols to obtain acetylated and methylated analogs.A brief description of some methods to assess the accumulation of the derivatives in mitochondria is also given; the proposed techniques are the use of a TPP +-selective electrode (with isolated rat liver mitochondria ) and fluorescence microscopy (with cultured cells).
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