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RNAi as New Class of Nanomedicines
Published in Dan Peer, Handbook of Harnessing Biomaterials in Nanomedicine, 2021
Monika Dominska, Derek M. Dykxhoorn
One of the first approaches used to systemically deliver siRNAs involved rapid injection of siRNAs in a large volume of physiological buffer, termed hydrodynamic injection [11, 101, 108, 136, 163]. The rapid injection of large fluid volumes leads to right-sided heart failure resulting in an elevated venous pressure and the transient disruption of the plasma membrane of cells in highly vascular tissues, including lung, liver, spleen, and pancreas. This transient disruption of the plasma membrane facilitates the uptake of the siRNAs and the concomitant targeted silencing of gene expression. The ease of delivery to the liver and the susceptibility of the liver to variety of agents that induce acute or chronic liver injury (for example, viral infections, autoimmune hepatitis, toxins, and liver transplantation) has made the liver an attractive target for siRNA-mediated therapeutic gene silencing [15, 127, 136, 162]. The targeted silencing of Fas by hydrodynamic delivery of siRNAs protected mice from fulminant hepatitis induced by the intraperitoneal injection of a fas agonist antibody [136]. Although effective, this approach requires a high dose of siRNAs to achieve effective silencing with only a relatively small fraction of the siRNAs actually entering the target tissue. In addition, systemic hydrodynamic injection is too risky for human therapeutic applications.
Current and Rising Concepts in Immunotherapy: Biopharmaceuti cals versus Nanomedicines
Published in Raj Bawa, János Szebeni, Thomas J. Webster, Gerald F. Audette, Immune Aspects of Biopharmaceuticals and Nanomedicines, 2019
Our own research with human primary immune cells demonstrated an M2 polarization of MΦ by two tripeptides (RGD or GLF)-functionalized gold nanorods in vitro [77]. However, in vivo studies facilitating models for acute and chronic liver inflammation did not obtain therapeutic effects at comparable dosage and the coupled peptides even increased hepatic injury (Table 26.2) [13]. Subsequent studies of our research group put the focus on delivering anti-inflammatory drugs such as corticosteroids to achieve M2-polarization of MΦ [22]. Using liposomal dexamethasone (Lipodex), we were able to cure Concanavalin A-induced autoimmune hepatitis and found a tendency toward decreased fibrosis in the carbon tetrachloride (CCl4)-based model of chronic liver injury [23]. Treatment of inflammatory activation has been demonstrated using small interfering RNA (siRNA) administered by polymeric nanoparticles which inhibit M1 polarization of MΦ [80].
Assessment of Quercetin Isolated from Enicostemma Littorale Against Few Cancer Targets: An in Silico Approach
Published in A. K. Haghi, Ana Cristina Faria Ribeiro, Lionello Pogliani, Devrim Balköse, Francisco Torrens, Omari V. Mukbaniani, Applied Chemistry and Chemical Engineering, 2017
Prednisolone an active metabolite of prednisone which is a corticosteroid drug with predominant glucocorticoid receptor (GR), and low mineralocorticoid activity, making it useful for the treatment of a wide range of inflammatory and autoimmune conditions such as asthma ulcerative colitis, temporal arteritis and Crohn’s disease, Bell’s palsy, multiple sclerosis, cluster headaches, vasculitis, ALL and autoimmune hepatitis, systemic lupus erythematosus, and dermatomyositis.16 With high affinity prednisolone irreversibly binds GR α and β. Virtually α-GR and β-GR are found in all tissues varies in numbers between 3000 and 10,000 per cell depending on the tissue involved.39 Prednisolone can activate and influence biochemical behavior of most cells. The steroid/receptor complexes dimerize and interact with cellular DNA in the nucleus, binding to steroid-response elements and modifying gene transcription. They both induce synthesis of some genes and therefore some proteins and inhibit synthesis of others.60
Diagnostic accuracy of liver stiffness on two-dimensional shear wave elastography for detecting clinically significant portal hypertension: a meta-analysis
Published in Expert Review of Medical Devices, 2023
Bingtian Dong, Yuping Chen, Yongjian Chen, Huaming Wang, Guorong Lyu
Among the included studies, CLD etiologies of the patient populations mainly included 8 reports with 346 patients who had alcohol-related liver disease, 7 studies (188 patients) with hepatitis B virus (HBV), 6 studies (140 patients) with hepatitis C virus (HCV), 4 studies (66 patients) with nonalcoholic steatohepatitis (NASH), 2 studies (58 patients) with viral-related liver disease, 1 study (19 patients) with primary biliary cholangitis, 3 studies (12 patients) with viral- and alcohol-related liver disease, and 1 study with 8 patients who had autoimmune hepatitis. Moreover, 9 (100%) studies involved patients who had actual or previous hepatic decompensation, with a patient number of 493, accounting for about 51.6% of all patients included in our meta-analysis. See further details in Table 1 and Figure 2.
The roadmap towards cure of chronic hepatitis B virus infection
Published in Journal of the Royal Society of New Zealand, 2022
Although rapid inhibition of HBV antigen production by siRNAs and CAMs should help reconstitute HBV-specific immune responses, these may not be sufficient to reverse the T-cell exhaustion associated with life-long HBV infection. T cell effector function is inhibited in patients with chronic HBV infection by overexpression of inhibitory T cell receptors including PD1/PD-L1, CTLA-4, TIM-3, LAG-3, CD160, 2B4, TIGIT (Crawford and Wherry 2009; Chen et al. 2011; Boni, Barili, et al. 2019) Of these, PD-1 is the most highly expressed on HBV-specific T-cells within the liver of CHB patients whilst PD-L1 expression is increased on the hepatocytes (Liu et al. 2014). In woodchuck model, blockade of PD-L1 combined with DNA vaccination effectively controlled HBV viremia (Zhao et al. 2019). In patients with cancer, the new PD-1 and PD1 ligand inhibitors have been shown to restore antitumor activity of otherwise suppressed effector T cells and to improve survival. However, these checkpoint inhibitors are associated with an almost 10% incidence of immune-related adverse events (ir-AE), including autoimmune hepatitis, colitis and pneumonitis, which has raised concern about their use in patients with non-malignant diseases such as chronic HBV infection. In the first proof of concept study in CHB, a single dose of 0.3 mg/kg nivolumab (1/10 dose approved for cancer therapy) was safe and well-tolerated and led to HBsAg decline in 20/22 patients and sustained HBsAg loss in one patient (Gane, Verdon, et al. 2019). There are now multiple studies underway combining anti-PD1 with other new antiviral and immunomodulatory agents.
Noninvasive assessment of liver fibrosis in chronic hepatitis B carriers with sound touch elastography: study of surgical pathology specimens
Published in Expert Review of Medical Devices, 2020
Lulu Yang, Jiawu Li, Lin Ma, Hongjin Xiang, Du He, Changli Lu, Lin Tang, Yan Luo, Shigao Chen
Referring to the cutoff value of 7.31 kPa in the diagnosis of ≥ stage 2 by STE, a sensitivity of 90% was achieved, indicating a good capability for screening patients with significant fibrosis. This makes great sense in clinical practice because the presence of significant fibrosis is accepted as a strong indication for antiviral treatment for patients with CHB. In the differentiation of significant fibrosis by STE, Ren et al [18] examined 158 patients with CHB and found a lower cutoff point of 6.84 kPa, with a sensitivity of 96.6% and specificity of 59.8%. This variation could be explained by the different composition of fibrosis stages in the study population. On the other hand, Gatos et al [17] assessed STE for grading liver fibrosis in CLD patients and reported cutoff points of 7.15 kPa, 8.0 kPa, 9.05 kPa and 11.05 kPa for diagnosing ≥ stage 1, ≥ stage 2, ≥ stage 3 and stage 4 fibrosis, respectively. Generally, these diagnostic criteria are higher than ours results, especially in the diagnosis of cirrhosis. These differences might be related to etiology. This previously reported study included CLD patients with multiple etiologies, some of which, such as autoimmune hepatitis and primary biliary cholangitis, have been proven to present markedly higher LSMs than CHB at the same histological fibrosis level [19,20,33].