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Progress in Antimalarial Drug Discovery and Development
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Anna C.C. Aguiar, Wilian A. Cortopassi, Antoniana U. Krettli
Plasmodium spp parasites have a complex life cycle, which initiates when highly motile sporozoite forms are inoculated into the dermis of the mammalian host during the mosquito bite (Figure 3). A proportion of the parasites enters blood capillaries, relying on gliding motility, a random process enabling them to reach and penetrate blood vessels in the bloodstream (Frenal et al. 2017). Other sporozoites are drained in the lymphatic system and reach the lymph node where most are degraded by dendritic leucocytes. Some sporozoites partially differentiate into exoerythrocytic stages in the skin (Amino et al. 2008). The parasites migrating through Kupffer cells avoid phagocytosis by these resident macrophages and are retained in hepatocytes, then differentiate and divide thereby originating thousands of new cells, the merozoits (Tavares et al. 2013). The migration through the hepatocytes is an essential step of the Plasmodium life cycle, after exocytosis of the sporozoite apical organelles, a prerequisite for infection (Mota et al. 2001). In addition, prior to hepatocyte invasion, the sporozoites must leave the circumsporozoite (CSP), a multifunctional protein that is involved in the mosquitoes’ sporogonic cycle, including invasion of the salivary glands. The specific arrest of sporozoites in the liver sinusoid depends on their gliding motility and the hepatocyte recognition and entry (Sultan 1999).
Mechanism of Hard-Nanomaterial Clearance by the Liver *
Published in Valerio Voliani, Nanomaterials and Neoplasms, 2021
Kim M. Tsoi, Sonya A. Macparland, Xue-Zhong Ma, Vinzent N. Spetzler, Juan Echeverri, Ben Ouyang, Saleh M. Fadel, Edward A. Sykes, Nicolas Goldaracena, Johann M. Kaths, John B. Conneely, Benjamin A. Alman, Markus Selzner, Mario A. Ostrowski, Oyedele A. Adeyi, Anton Zilman, Ian D. Mcgilvray, Warren C. W. Chan
where U is the average flow velocity and bi and λi are numerical coefficients. The sequestration probability, P, is a decreasing function of the dimensionless parameter /(DL, which measures the strength of advection relative to diffusion. Using values derived empirically and from the literature, we compared the computationally predicted probability of nanomaterial sequestration in two different locations: the liver sinusoid and the systemic circulation. The liver inlet (hepatic artery, portal vein) and outlet (inferior vena cava) were selected as representative of the systemic circulation. For a Poiseuille parabolic flow profile with fully absorbing walls, the model predicts a 102–103 times greater probability of nanomaterial sequestration in a liver sinusoid than in the extrahepatic circulation (see Fig. 17.2b). As many types of flow occur in vivo, we tested the model’s robustness by replacing the parabolic flow assumption with a flat flow profile. The prediction of higher nanomaterial sequestration within the sinusoid persists; however, the difference between regions is reduced. This finding extends to other types of flow, as the shape of the flow profile v(r) in Eq. 17.2 does not alter the expression for the sequestration probability P, only the numerical values of the coefficients, bi and λi. To validate our mathematical model and experimentally test our hypothesis, we isolated hepatic and peripheral blood mononuclear cells (PBMCs) from the quantum-dot-treated rats and determined nanomaterial uptake via flow cytometry. As predicted by the model, hepatic cells took up significantly more quantum dots than did PBMCs. The trend persisted when we looked specifically at cells in the monocyte-macrophage lineage (CD68+ cells), as 67.1 ± 15.7% of Kupffer cells and only 10.0 ± 6.3% of monocytes were quantumdot-positive (see Fig. 17.2e,f). The importance of flow dynamics is reinforced by the fact that, under static culture conditions, monocytes took up quantum dots with the same affinity as Kupffer cells.
Engineering extracellular vesicles with macrophage membrane fusion for ameliorating imiquimod-induced psoriatic skin inflammation
Published in Journal of Dermatological Treatment, 2023
Zeng Wang, Zhizhen Qin, Jiadie Wang, Xinqi Xu, Mengxin Zhang, Yuyue Liang, Yukun Huang, Zengyang Yu, Yu Gong, Luxian Zhou, Yiran Qiu, Minglu Ma, Dan Li, Bin Li
In the in vivo experiments, we noticed that EV treatment effectively ameliorated skin inflammation and reduced macrophage infiltration. In vitro experiments showed that EAM treatment led to slight decrease of macrophage population after prolonged treatment. Thus, the reduced macrophage infiltration was likely due to the decreased recruitment of macrophages to the lesional skin. As expected, after M2 polarization, we found that EV treatment significantly downregulated the IMQ primed IL-1β, IL-6, and TNF-α accumulation in skin. All these results suggested that the engineered EVs effectively interrupted the positive feedback loop of inflammation in psoriasis. We also found that EV treatment, especially EAM, restored liver sinusoid structure and alleviated renal injury induced by IMQ. Psoriasis is not restricted to the skin. The cytokine levels in serum significantly elevate in psoriasis patients (40), and psoriatic arthritis, a common complication of psoriasis, can cause great damage to distal joints (41). Recently, Van Raemdonck et al. have found that macrophages in the skin lesion are capable to trigger skin-to-joint crosstalk in psoriatic arthritis (42). All these results indicated the potential therapeutic application of our engineered EVs in the more extensive immune system.
Hemophilia A gene therapy: current and next-generation approaches
Published in Expert Opinion on Biological Therapy, 2022
Steven W. Pipe, Gil Gonen-Yaacovi, Oscar G. Segurado
FVIII is synthesized by hepatic and extrahepatic sources, likely of endothelial origin. Extrahepatic sources include Kupffer cells, monocytes, and monocyte-derived macrophages within the hematopoietic system. The liver is a major source, and while hepatocytes are the most abundant cell type comprising the liver, the liver sinusoid endothelial cells are the main source of liver-derived FVIII [29–31]. Upon its release into the circulation, the FVIII heterodimer forms a tight noncovalent complex with von Willebrand factor (vWF), the FVIII carrier protein produced and secreted by vascular endothelial cells. The half-life of FVIII in the absence of VWF is only 2 h compared to 12 h when bound to VWF [32]. The 2332-amino acid FVIII protein has 6 domains (A1-A2-B-A3-C1-C2), circulating as a 90-200 kDa heavy chain (A1-A2-B) and an 80-kDa light chain (A3-C1-C2). When the coagulation cascade is triggered by the presence of thrombin and activated factor X, vWF dissociates from FVIII and serine proteases act to cleave FVIII with release of the B domain, which has a potential regulatory role [27]. The activated form of FVIII (FVIIIa) functions as a cofactor for factor IXa within the factor X-activating complex and accelerates the proteolytic conversion of factor X to its activated form (Xa) in the presence of calcium ions and phospholipids [33–36]. High FVIII activity is associated with an increased risk of stroke, and low levels adversely affect bone metabolism [37].
Non-alcoholic fatty liver disease (NAFLD) models in drug discovery
Published in Expert Opinion on Drug Discovery, 2018
Banumathi K. Cole, Ryan E. Feaver, Brian R. Wamhoff, Ajit Dash
Feaver et al. recently developed a system for studying lipotoxic changes similar to that seen in NAFL/NASH, using the HemoShear liver platform [63]. This original platform exposes primary hepatocytes to liver sinusoid-derived hemodynamic and transport conditions in a 3D culture system resulting in the retention of differentiated cellular phenotype. As a result, the hepatocytes can be cultured in physiologically relevant levels of glucose and insulin in the system and exhibit drug toxicity responses at clinically relevant concentrations, often orders of magnitude lower than conventional static cultures [86–88]. The system has also been used to demonstrate steatohepatitic changes induced by drugs such as amiodarone [64]. While adapting the system to study NAFLD and NASH, Feaver et al. introduced macrophages and HSCs positioned relative to the human hepatocytes in a sinusoid-like configuration [63]. To model disease-like conditions, they combined oleic acid (65 µM) and palmitic acid (45 µM) levels derived from circulating levels in NASH patients [89] over the NASH-physiologically relevant levels of glucose and insulin in the system. Over days of exposure to the disease-like milieu, lipotoxic changes were observed, evidenced by measured functional end points reflective of increased lipid accumulation, decreased insulin response, increased inflammatory and fibrosis biomarkers, and stellate cell activation (Figure 2).