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Drug Repurposing and Novel Antiviral Drugs for COVID-19 Management
Published in Debmalya Barh, Kenneth Lundstrom, COVID-19, 2022
Shailendra Dwivedi, Aakanksha Rawat, Amit Ranjan, Ruchika Agrawal, Radhieka Misra, Sunil Kumar Gupta, Surekha Kishore, Sanjeev Misra
Previous studies on viral diseases including COVID-19 have shown that MSCs retain immune-regulatory potential by modifying immune responses with the help of proliferation and function of numerous immune cells, such as inhibiting the differentiation of monocytes into dendritic cells (DCs), changing the cytokine profiles of DCs with upregulation of regulatory cytokines, and suppression of inflammatory cytokines. Thus MSCs also induce tolerant phenotypes of naive and effector T cells, constraining antibody production by B cells, and diminishing NK cell proliferation and NK cell-mediated cytotoxicity [55]. These immunomodulatory activities are mediated by both cell–cell communications and secreted cytokines including interferon- 𝛾 (IFN-𝛾), indoleamine 2,3-dioxygenase (IDO), transforming growth factor-𝛽 (TGF-𝛽), IL-6, IL-10, and prostaglandin E2 [56]. Thus several COVID-19 trials on MSCs in the United States, China, Israel, Iran, Italy, and Iraq are in progress (Table 7.1).
The Contribution of Pets to Human and Veterinary Medicine
Published in Rebecca A. Krimins, Learning from Disease in Pets, 2020
Research at the University of California, Davis, demonstrated that blocking indolamine-2,3 dioxygenase rebound immune suppression would boost antitumor effects of radio-immunotherapy in both murine models and in dogs with naturally occurring tumors (Monjazeb et al. 2016). Continued research is currently underway further assessing indoleamine dioxygenase inhibitors and their role in cancer treatment (Zhu, Dancsok, and Nielsen 2019).
Subfamily Bombacoideae
Published in Mahendra Rai, Shandesh Bhattarai, Chistiane M. Feitosa, Wild Plants, 2020
Mariam I. Gamal El-Din, Fadia S. Youssef, Mohamed L. Ashour, Omayma A. Eldahshan, Abdel Nasser B. Singab
The inflammatory processes may also activate some biomarkers, such as cyclooxygenases, which are enzymes that allow the body to produce prostaglandins from arachidonic acid. This type of enzymes can act as dioxygenase or peroxidase, as they are peripheral membrane proteins having two isoforms (Salinas et al. 2007). COX1, present in most tissues, such as stomach, synthesize prostaglandins and perform maintenance of the gastric mucosa, which regulates the proliferation of normal cells and intervenes indirectly in physiological processes, such as protection and neutrophil migration to the epithelium. COX2, the other isoform, is formed from an increase of prostaglandins in tissues where an inflammatory response occurs. It is expressed after induction of inflammation caused by erosion of the mucosa (Díaz-Rivas et al. 2015). Inhibition of both COX-1 and COX-2 was found to be the basic mechanism of different anti-inflammatory plant extracts. However, selective COX-2 inhibitor mixes both the anti-inflammatory activity and minimum side effects usually related to COX-1 inhibition. The isoflavone compounds isolated from Ceiba pentandra stem bark were evaluated for their inhibition of cyclooxygenase-1-catalyzed prostaglandin biosynthesis together with the known flavan-3-ol, (+)-catechin (39). Vavain (45), vavain 3‘-O-β-D-glucoside (46), and (+)-catechin (39) demonstrated inhibitory effects with IC50 values of 97, 381, and 80 μM, respectively, compared to indomethacin activity (IC50 of 1.1 μM) (Noreen et al. 1998).
Single-center, observational study of AML/MDS-EB with IDH1/2 mutations: genetic profile, immunophenotypes, mutational kinetics and outcomes
Published in Hematology, 2023
Vasiliki Papadopoulou, Jacqueline Schoumans, Valentin Basset, Françoise Solly, Jérôme Pasquier, Sabine Blum, Olivier Spertini
IDH (isocitrate dehydrogenase) enzymes convert, via a two-step process, isocitrate to α-ketoglutarate (α-KG), within and outside of, the Krebs cycle [1]. α-KG produced from isocitrate can serve as a substrate (OH-donor) for dioxygenase-type enzymes. Dioxygenase-type enzymes include, among others, histone demethylases and DNA-5-methylcytosine hydroxylases like TET2. Therefore, as hydroxylation of the 5-methylcytosines of DNA is the first step to DNA demethylation [2,3], the activity of IDH1/2 enzymes, ultimately serves, among other purposes, to promote DNA and histone demethylation by providing to dioxygenases the substrate α-KG, and thus to activate certain gene expression signatures [4]. Mutations of IDH1/2 are frequent in gliomas and cartilaginous tumors [5,6] and occur recurrently in AML and MDS [7]. IDH1 mutations typically alter the R132 residue of the active site, while mutations in IDH2 similarly alter an active-site arginine at position 140 or 172 [4,7]. Disturbance of the active site leads to production of D-2-hydroxyglutarate (D-2-HG), instead of α-KG, a product with ability to inhibit dioxygenase-type enzymes, instead of serving as their substrate [8–10]. Therefore, both histone and DNA demethylation are ultimately inhibited by the non-physiological product D-2-HG and a hypermethylated genome/epigenome is expected, and has been shown, in IDH1/2-mutated malignancies [11–13].
Tumor microenvironment-responsive micelles assembled from a prodrug of mitoxantrone and 1-methyl tryptophan for enhanced chemo-immunotherapy
Published in Drug Delivery, 2023
Ru Wang, Nuannuan Li, Tianyu Zhang, Yiying Sun, Xiaoyan He, Xiaoyan Lu, Liuxiang Chu, Kaoxiang Sun
Chemotherapy is the main treatment method for breast cancer. The anthraquinone mitoxantrone (MX) (An et al., 2021) is efficacious against breast cancer. It can produce an anti-tumor effect by disturbing DNA synthesis (Evison et al., 2016; Granja et al., 2021). Some studies have shown that MX can also induce immunogenic-cell death (ICD) (Kepp et al., 2019). ICD can promote damage-associated molecular patterns (Zhou et al., 2019; Kim et al., 2022) in dying cancer cells, including exposure of calreticulin (CRT) (Mei et al., 2020) on the membrane surface, release of high mobility group box 1 (HMGB1), and secretion of adenosine triphosphate (ATP) (Li et al., 2020). All of these substances activate dendritic cells (Dudek et al., 2013) to devour dying tumor cells and recruit activated cytotoxic T cells to the tumor site. However, this process also induces overexpression of indole amine 2,3-dioxygenase (IDO) in tumor cells (Li et al., 2021) and activation of regulatory T cells (Tregs). These actions can further inhibit the functions of effector T cells and natural killer cells, thereby weakening the therapeutic effect of ICD (Li et al., 2021; Yang et al., 2022).
Adopting an alternative structure for clinical trials in immunotherapy
Published in Expert Review of Anticancer Therapy, 2021
Evanthia T. Roussos Torres, Alan L. Epstein
Murine tumor models that grow in immunocompetent mice can be viewed as individual patients with a unique combination of mechanisms that enable these tumors to grow in that strain of mouse. The effect of novel combinations of immune therapies with known and novel targeted therapies is often more easily studied preclinically [2]. Use of genomic sequencing [7], as well as imaging mass cytometry [8,9] and/or digital spatial profiling, also often leads to a deeper understanding of mechanisms of response and support future studies of less abundant immune cells such as MDSCs [10], natural killer cells, and other immune cell types that greatly contribute to the success of immunotherapy [11,12]. Identification of the exact means by which these tumors defeat immunity which can then be matched to the immune profile seen in individual patients or small groups of patients and can therefore be used to learn how to reverse immune lethargy to a vigorous anti-tumor response is a relatively new way of identifying therapeutic combinations. Again, the focus here should be on the dominant pathways. The disappointment of indoleamine 2,3-dioxygenase (IDO) as an immune intervention recently demonstrates that it is not a dominant pathway like suppressor cells, loss of HLA, and lack of co-stimulation in tumors [13]. It is of great importance to continue to learn from the mechanistic findings from preclinical research to guide the design of clinical trials involving immunotherapy.