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Applications of Protein Nanoparticles as Drug Delivery Vehicle
Published in Adwitiya Sinha, Megha Rathi, Smart Healthcare Systems, 2019
Reema Gabrani, Ritu Ghildiyal, Neetigyata Pratap, Garima Sharma, Shweta Dang
Transferrin receptor 1 (TfR1), one of the known receptors, is overexpressed by various tumor tissues, and heavy chain ferritin, which is an iron storage protein, has the ability to bind these TfR1. Therefore, scientists developed a strategy to visualize cancer cells using iron oxide NPs encapsulated in a recombinant human heavy-chain ferritin. These NPs get attached with the overexpressed TfR1 and catalyzed the reaction in which peroxide substrate gets oxidized and assist in the differentiation between normal and cancer cells (Fan et al., 2012).
In Vivo Targeting of Magnetic Nanoparticles
Published in Nguyễn T. K. Thanh, Clinical Applications of Magnetic Nanoparticles, 2018
Laurent Adumeau, Marie-Hélène Delville, Stéphane Mornet
Other proteins present a high affinity for specific receptors overexpressed on a variety of tumour cells.147 Among them, transferrin, a glycoprotein of 80 kDa, has been extensively studied as a targeting ligand due to the presence of up-regulated endogenous transferrin receptor 1 (TfR1) on the surface of cancer cells.148 TfR1s were also targeted by a more exotic MNPs design involving encapsulation of iron oxide NPs within human ferritin protein shells called magnetoferritin.149 Some proteins are also used for bioconjugation because of their specific biorecognition interactions useful to control the orientation of a protein ligand in order to promote the binding site exposition. Once bound to the NP surface, protein G was used to immobilize in a well-oriented manner anti-horseradish peroxidase IgG via interactions with the Fc region of the Ab.150 Another representative example of affinity interactions is the well-known streptavidin–biotin binding, which displays the highest affinity constant (Kd= 4.10−14 M).151 Biotinylated herceptins (HER2/neu) were conjugated to commercially available streptavidin-conjugated superparamagnetic iron oxide NPs.152 HER2/neu receptors are highly expressed in 25% of breast cancers. This bioconjugated MRI contrast agent was used to correlate the different levels of HER2/neu expression on the breast cell membrane. Like the streptavidin–biotin system, the barnase/barstar-based recognition system also possesses a strong binding affinity, Kd, of the order of 10−14 M. One of them can be conjugated to an NP while the other can be fused to a protein of interest by genetic engineering, which allows the region-selective grafting of the protein of interest on the NP.153 However, the barnase is a bacterial protein lethal to the cell when expressed without its inhibitor barstar. Even if such strategies are useful to accurately control the orientation of protein ligands, these supramolecular structures are accompanied by a significant increase in the hydrodynamic diameter of NPs and may be at the origin of nonspecific interactions that can result in an increased uptake from the RES (see also Section 4.4.2). Enzymes are other proteins of interest with their catalytic activity under mild conditions. Immobilization of enzymes on magnetic NPs allows an efficient recovery of the enzyme complex, thereby preventing the enzyme contamination of the final product.154
Pathological Manifestations and Mechanisms of Metal Toxicity
Published in Debasis Bagchi, Manashi Bagchi, Metal Toxicology Handbook, 2020
Iron (Fe) hepatic overload in adults can have multiple etiologies, including hereditary hemochromatosis (when there is abnormal Fe absorption in the intestinal tract), excessive Iron intake, and repeated blood transfusions. Increased accumulation of Fe in any parenchymal organs is called hemosiderosis. When it becomes excessive and causes parenchymal lesions, such as increase fibrous connective tissue, it is called hemochromatosis. Hepatic hemochromatosis has been associated with increased risk of hepatocellular carcinoma (Anderson & Frazer, 2017; Curtis, 2013). However, hepatic Iron overload is also frequently observed with chronic liver disease regardless of its etiology. The {Rubino, 2015 #256} major route of Iron entry into the hepatocyte is via receptor-mediated endocytosis of transferrin by transferrin receptor-1 (TFR1). After internalization, the Iron is released into the lysosomal compartment and can be delivered into other organelles. Iron can cycle between two stable oxidation states, ferrous Iron (iron(II) or Fe2+) and ferric Iron (Iron(III) or Fe3+) (Sangkhae & Nemeth, 2017). When in excess, Fe is oxidized into the ferric form and can be sequestered within the ferritin (Bloomer & Brown, 2019). Increased levels of Fe can accelerate the Fenton reaction in which the ferrous form of Iron interacts with H2O2 and generates highly reactive hydroxyl radical (Fe2+ + H2O2 → Fe3+ + •OH + OH− & Fe3+ + H2O2 → Fe2+ + •OOH + H+). These ROS can lead to hepatocellular injury by disruptively reacting with biological structures such as unsaturated lipids in cellular membranes, DNA and RNA components, and other essential chemical groups in catalytic and signaling proteins (Rubino, 2015). Prolonged injury causes chronic stimulation of hepatic stellate cells (HSC) that become sources of transforming growth factor-beta (TGF-β) that, in turn, stimulates further proliferation of HSC and their differentiation into myofibroblasts producers of extracellular matrix that can lead to a fibrotic state. This state can progress into cirrhosis and ultimately cancer (Mehta, Farnaud, & Sharp, 2019). Iron has also been implicated with inflammatory pathways such as NF-ƙB in liver Kupffer cells that can increase inflammatory cytokines like, tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) (Bloomer & Brown, 2019). Increased Fe associated with increased intestinal absorption has also been reported as a possible factor in the etiology of nonalcoholic fatty liver disease (NAFLD) (Malik, Wilting, Ramadori, & Naz, 2017). A key hepatic hormone that regulates Iron systemic levels is hepcidin (HAMP or HEPC). Disturbances in HEPC are associated with many Iron overload disorders including chronic inflammatory diseases and cancer (Sangkhae & Nemeth, 2017).
Toxic and carcinogenic effects of hexavalent chromium in mammalian cells in vivo and in vitro: a recent update
Published in Journal of Environmental Science and Health, Part C, 2022
Shehnaz Islam, Sreejata Kamila, Ansuman Chattopadhyay
Adequate energy supply is crucial for the appropriate function of the cells. A disruption of energy metabolism can induce several physiological alterations that may lead to death. Loss of adenosine triphosphate (ATP) is a potential trigger of mitochondrial dysfunction by chronic Cr (VI) exposure.89 Intraperitoneal injections of potassium dichromate (K2Cr2O7, 2–6 mg/kg body weight) for 35 days in Wistar rats evoked haematological alterations, oxidative stress, disorganized structure and malfunction of the heart, cardiomyocyte apoptosis, ATP depletion, and mitochondria impairment in a dose-dependent manner.113 The concentrations of ATP were significantly reduced in Cr (VI)-treated groups along with depletion of sesn2 mRNA. The expression levels of mRNA and protein showed that Cr (VI) exposure causes impairment in the mitochondrial homeostasis, as evidenced by the elevated expression of Drp1 (mitochondrial fission regulator) and lower expressions of Mfn2 (mitochondrial fusion regulator) and PGC-1α (mitochondrial biogenesis regulator). Cr (VI)-induced loss of the mitochondrial membrane potential and ROS generation were observed in mouse spermatogonial stem cells.121 Cr (VI) oxidizes Fe2+ in the lumen of the small intestine and perturbs iron absorption. Ninety-day exposure to Cr (VI) through drinking water resulted in a dose-dependent decrease of iron levels in the duodenum, liver, serum, and bone marrow of Wistar rats with notable induction of transferrin receptor 1 (TFR1, tfr1) and divalent metal transporter 1 (DMT1, slc11a2) genes.110 Iron is transformed into its biologically available form in the mitochondrion by the iron-sulfur (Fe/S) cluster, which is involved in the electron transport system and production of ATP. Alteration in iron homeostasis due to Cr (VI) exposure might have adverse effects on mitochondrial functions.