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In Vitro Models for Preclinical Drug Development
Published in Hyun Jung Kim, Biomimetic Microengineering, 2020
Jason Ekert, Sunish Mohanan, Julianna Deakyne, Philippa Pribul Allen, Nikki Marshall, Claire Jeong, Spiro Getsios
The innate immune response has liver tissue-specific components involved in the production of acute-phase proteins, nonspecific phagocytosis and cell killing as well as disposal of molecules after the whole response (Parker and Picut 2005). Hepatic sinusoids are involved in the nonspecific phagocytosis response and include five cell types: endothelial cells, Kupffer cells (macrophages), pit cells (liver-specific NK cells), fat-storing cells, and DCs (Parker and Picut 2005). The Kupffer cells are the liver’s resident macrophages and contribute to normal liver physiology by participating in acute and chronic responses of the liver to toxic compounds. Pit cells represent the liver-specific more mature NK cells and morphologically resemble large granular lymphocytes. These cells play a role in defending the liver against invading tumor cells. Pit cells have critical cell–cell interactions with both endothelial and Kupffer cells and depend on Kupffer cells to proliferate and also kill tumor cells.
Bioprinting of liver
Published in Ali Khademhosseini, Gulden Camci-Unal, 3D Bioprinting in Regenerative Engineering, 2018
Dong-Woo Cho, Hyungseok Lee, Wonil Han, Yeong-Jin Choi
Kupffer cells are a type of macrophage that inhabits the liver [46]. Their main responsibility is to protect the liver from pathologic conditions including infection, fibrosis, and liver cancer [47]. Moreover, they interact with hepatocytes and other nonparenchymal cells to support lipid metabolism and normal liver functions [48]. Primary Kupffer cells [49] and several established cell lines [50] are available, but only primary Kupffer cells have been used for liver bioprinting [42].
Microplastics and human health: Integrating pharmacokinetics
Published in Critical Reviews in Environmental Science and Technology, 2023
Excretion of microplastics is plausible since available data does not support long-term accumulation in tissues, including in the gut of marine mammals (Nelms et al., 2019) or internal tissues of older cats of dogs (Prata et al., 2022). Similarly, no evidence for accumulation in the human body has so far been described, to the best of the author’s knowledge. Clearance of preserved particles mainly occurs through the phagocytes of the reticuloendothelial system, primarily by Kupffer cells in the liver and to a lesser extent by macrophages in the spleen and bone marrow (Hartenstein & Martinez, 2019; Ogawara et al., 1999), in liver endothelial cells and hepatocytes followed by exocytosis in the bile (Handy et al., 2008; Ogawara et al., 1999), or trapping in the splenic interendothelial cell-slits (Moghimi et al., 1991). Kupffer cells play an important role in the phagocytosis of synthetic particles, including of larger sizes, removing 60 - 70% of 50 and 500 nm of polystyrene after intravenous administration in rats (Ogawara et al., 1999). Similarly, intravenous administration of polystyrene in rabbits were readily removed by the reticuloendothelial system in the liver or spleen (90% under 1 min), being observed in Kupffer cells and still found in the liver after 8 days, only significantly distributing to the lungs or heart after pharmacological suppression of the reticuloendothelial system (Illum et al., 1986). Moreover, significantly higher concentrations of microplastics were found in livers of patients with cirrhosis than patients without cirrhosis (median 8.4 vs. 0.7 M/g) (Horvatits et al., 2022), which could result from the inability of diseased liver to excrete microplastics.
Evaluation of cytotoxic potential, oral toxicity, genotoxicity, and mutagenicity of organic extracts of Pityrocarpa moniliformis
Published in Journal of Toxicology and Environmental Health, Part A, 2019
Tamiris Alves Rocha, Danielle Feijó de Moura, Marllyn Marques da Silva, Talita Giselly dos Santos Souza, Maria Aparecida da Conceição de Lira, Dayane de Melo Barros, Alexandre Gomes da Silva, Rafael Matos Ximenes, Emerson Peter da Silva Falcão, Cristiano Aparecido Chagas, Francisco Carlos Amanajás de Aguiar Júnior, Noêmia Pereira da Silva Santos, Marcia Vanusa da Silva, Maria Tereza dos Santos Correia
Histomorphometric analyses of the liver, kidneys, and spleen of mice exposed to organic extracts (EP1, EP2, and EP3) are presented in Table 5. Data demonstrated that there was a significant increase in total number of hepatocytes in animals treated with EP3 (Figure 6). This abnormal proliferation of hepatocytes may be indicative of possible regeneration of liver tissue to circumvent pathological and/or experimental conditions influenced by several factors (Marinho et al. 2017). Investigators showed that some medicinal plants induce hepatotoxicity owing to their constituent substances, especially when these substances are generated by extract from alcohols such as methanol (Paz et al. 2005; Santos et al. 2010). In addition, EP3 contained a higher amount of saponins when compared to other extracts, and the presence of saponins in this extract may account for elevation in number of hepatocytes (Diamantino 2018). The EP1 and EP3 extracts resulted in a rise in Kupffer cells, which may be an indication of inflammatory processes and liver damage (Figure 6). However, additional tests are required, using, for example, pro-inflammatory markers such as TNF and IL-6. These cells play a key role in phagocytosis of foreign particles and are of importance for maintaining liver function in pathological and physiological conditions (Arii and Imanura, 2000). In addition, Kupffer cells contribute significantly to the inflammatory response by eliminating harmful substances and modulating the immune response. Thus, the cellular activation of the inflammatory processes may be related to the morphological signs of activation and to the increase in the cellular population that release biologically active substances, such as cytokines, to promote the pathological process after activation (Eguchi, McCuskey, and McCuskey 1991; Tsutsui and Nishiguchi 2014). Thus, this increase in number of Kupffer cells may be related to the pathogenesis of hepatic injury due to exposure to toxins, chemicals, and/or pharmacological agents (Ito et al. 2003; Kolios, Valatas, and Kouroumalis 2006; Luckey and Petersen 2001; Ono et al. 2004).
Investigation of novel sorafenib tosylate loaded biomaterial based nano-cochleates dispersion system for treatment of hepatocellular carcinoma
Published in Journal of Dispersion Science and Technology, 2021
Raj J. Ahiwale, Bothiraja Chellampillai, Atmaram P. Pawar
The findings from the study demonstrate that STNCs increased the bioavailability of ST, thereby elevating its therapeutic efficacy. STNCs induced additional cytotoxicity as compared to free ST. The tumor retention effect is evidently due to the extravasation of STNCs through porous capillary endothelium of tumor, which is caused due to enhanced permeability and retention effect.[83] The enhanced permeability and retention effect (EPR effect) causes, upsurge in the uptake of STNCs entrapped therapeutic agent (ST). Augmented anticancer activity of STNCs can be attributed to higher uptake of the ST via two mechanisms: 1) phagocytosis or 2) direct interaction i.e., the fusion between STNCs and the cancer cell membrane followed by controlled release of the drug[84] (Fig: Graphical abstract). The fusion process of the natural membrane facilitates through calcium-induced perturbation of negatively charged lipid membranes. The speculation for the mechanism of action of the STNCs can also be narrated similarly, where the junction of the calcium-rich thoroughly ordered membrane of STNCs with a natural membrane leads to perturbation and reordering of the cell membrane.[85] This merging occurs between the outer layer of the STNCs and the cell membrane. Further, it results, in some amount of the encochleated material to get transferred into the cytoplasm of the cancerous hepatocytes. The STNCs then break free of the previous cell and becomes available for second fusion event, either with the same hepatocyte or another. Alternatively, the liver is reported to carry out phagocytosis via Kupffer cells.[86] Soji T et al. (1992) demonstrated hepatocytes are also responsible for selective phagocytic action for phospholipid related particles. This study illustrates Kupffer cells nevertheless being responsible for phagocytosis failed to recognize the phospholipid coated silicon particles. They did so due to the membrane of phospholipid blocks the receptor sites on Kupffer cells, which is required to initiate its phagocytosis.[87] On the same grounds, it can be hypothesized that STNCs being formulated using DOPS-Na phospholipid, a major component of nano-cochleates, bypass the Kupffer cells and facilitates its phagocytosis by hepatocytes and is taken up by endocytosis to fuze from within the endocytic vesicle. Thereby causing pronounced cytotoxicity to the tumor. Moreover, similar results were obtained by Poudel I et al. (2018) which reported improved cytotoxicity of Docetaxel loaded Nano-cochleate as compared to free Docetaxel.[88] Bothiraja C et al. (2017) also demonstrated the enhanced cytotoxic effect of doxorubicin-loaded Nano-cochleate when compared to free doxorubicin.[89]