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Tanshinone Diterpenes
Published in Dilip Ghosh, Pulok K. Mukherjee, Natural Medicines, 2019
Mohamed-Elamir F. Hegazy, Tarik A. Mohamed, Abdelsamed I. Elshamy, Ahmed R. Hamed, Sara Abdelfatah, Soleiman E. Helaly, Nahla S. Abdel-Azim, Khaled A. Shams, Abdel-Razik H. Farrag, Abdessamad Debbab, Tahia K. Mohamed, El-Seedi Hesham R., Mohamed E.M. Saeed, Masaaki Noji, Akemi Umeyama, Paul W. Paré, Thomas Efferth
Dihydrotanshinone I and cryptotanshinone revealed significant activity with IC50 values of 16 and 36 mM, respectively, with IgE receptor-mediated tyrosine phosphorylation of PLCg2 and MAPK, suggesting that the dihydrofuran ring may be important for biological activity (Ryu et al. 1999; Choi and Kim 2004; Wang et al. 2007).
Zearalenone: Insights into New Mechanisms in Human Health
Published in Dongyou Liu, Handbook of Foodborne Diseases, 2018
Cornelia Braicu, Alina Andreea Zimta, Ioana Berindan-Neagoe
By exposure to 25 μM of ZEA, the gene expression profile of intestinal epithelial cells in pig displayed major modifications: 797 genes were upregulated, and 303 were down regulated. When co-exposed with Escherichia coli, the situation had worsened, with 991 upregulated and 800 downregulated genes. Several genes involved in tumor formation were reported to be deregulated. The most overexpressed genes were NFKBIA, SOX9, TNF, BTG2, and DDIT, and the most underexpressed ones were MAPK1, PDGFRB, PLCG2, ZAK, CD4, GLI2, CDK6, CCND1, and DKK1. When co-exposed with Escherichia coli, ZEA alters the IL-17A signaling pathway, leading to overproduction of NF-kB, an important factor in carcinogenesis. Three genes were double-checked through qRT-PCR: IL-6, IL-8, and TNF-α. The mRNA for all proteins was overtranscribed, especially in co-exposure, hence leading to the conclusion that ZEA enhances the immune response in intestinal cells [31].
Leukaemias of Mature B- and T/NK-Cells
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
The historical staging system introduced by Kanti Rai (New York) in 1975 was based on the notion that CLL cells first accumulate in the blood and bone marrow, followed by lymphoid tissues, finally leading to bone marrow failure. This acknowledged the Dameshek–Galton model of orderly disease progression in CLL and allowed patients with CLL to be categorized into three prognostic groups. The Rai staging system was modified by Jacques-Louis Binet (Paris) in 1981, based on multivariate analysis of a large cohort of French patients (Table 9.3). Typically, untreated patients with good prognosis, who comprise about 60–70% of all patients, have a 10-year overall survival of over 50%, which approached the survival of people matched for sex and age who do not have CLL; those with intermediate prognosis have an overall survival of about 2–4 years and those with poor prognosis disease about 1.0–1.5 years. These staging systems have of course served us well for over four decades, and in 2014, a new system, integrating the molecular genetics, was proposed by Robin Foá and colleagues, which allows us to classify patients with CLL into four prognostic groups. The MD Anderson Cancer Center CLL Group has also proposed a novel staging system (Table 9.4). The iwCLL 2018 guidelines recommend the assessment of del(17p) and TP53 for prognostic and predictive value and impact therapeutic decisions in the clinics, and also confirm the prognostic role of the IGHV mutational status. As illustration, TP53 abnormalities affect response to first-line therapy and is included in the CLL International Prognostic Index (CLL-IPI), which combines five parameters: age, clinical stage, IGHV mutational status, serum β2-microglobulin and TP53 status [normal versus del(17p) and/or TP53 mutation]. Other risk scores/models have also been suggested, which help assessment of the prognostic and predictive (to chemotherapy) impact of molecular biomarkers, such as SF3B1, NOTCH1 and ATM mutations, which influence the PFS and overall survival. Furthermore, the changes in the therapeutic landscape of CLL with targeted therapies targeting BTK kinases (ibrutinib), PI3K (idelalisib) and bcl2 (ventoclax), will be useful to monitor for the emergence of certain genes associated with resistance, for example BTKC481S and PLCG2. Many efforts are also assessing the prognostic usefulness of diverse recurrent gene mutations, including MYD88, BIRC3, KRAS, POT1, EGR2, MED12, BRAF, ZMYM3, IRF4, ASXL1, RPS15, SAMHD1 and SETD2.
Bruton’s tyrosine kinase as a promising therapeutic target for multiple sclerosis
Published in Expert Opinion on Therapeutic Targets, 2023
Darius Saberi, Anastasia Geladaris, Sarah Dybowski, Martin S. Weber
After antigen binding to the B cell receptor (BCR), Lck/Yes novel tyrosine kinase (Lyn), a member of the SRC kinase family phosphorylates the Igα and Igβ immunoreceptor tyrosine-based activation motifs (ITAMs), which then binds spleen tyrosine kinase (SYK). In the next step, SYK gets phosphorylated by Lyn and BTK is recruited from the cytosol to the plasma membrane [75]. In general, activation of BTK is characterized by phosphorylation at the position Y551 of BTK. This promotes the catalytic activity of BTK and subsequently results in its autophosphorylation at the position Y223 in its SH3 domain [71]. Active BTK phosphorylates phospholipase C gamma 2 (PLCγ2). Consequently, PLCγ2 generates two second messengers, inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). The activation of calcium channels by IP3 results in a transport of nuclear factor of activated T cells (NFAT) into the nucleus. The pathway of nuclear factor ‘kappa-light-chain-enhancer’ (NF-κB) of activated B cells and mitogen-associated protein kinase (MAPK) is activated by DAG. The expression of several genes that are essential for B cell survival and proliferation chemokine and cytokine expression is regulated by NFAT and NF-κB (Figure 1). In summary, this complex cascade leads to an increase in survival and accelerates the proliferation of B cells, and therefore highlights the pivotal role of BTK in B cells [76].
Approved and emerging Bruton’s tyrosine kinase inhibitors for the treatment of chronic lymphocytic leukemia
Published in Expert Opinion on Pharmacotherapy, 2022
Alycia Hatashima, Mehdi Karami, Mazyar Shadman
CLL patients with del(17p) and/or TP53 mutations historically have been a difficult-to-treat patient group as studies have reported an increased risk of relapse or death with CIT and inferior PFS in ibrutinib-treated relapsed or refractory patients [7,46,47]. In addition, these high-risk patients have been excluded or underrepresented in phase III trials, thus warranting studies focused on these individuals [14,18–21]. Ahn and colleagues conducted a phase II study of 34 previously untreated patients with TP53 alterations, and patients received continuous ibrutinib monotherapy [7]. The estimated 6-year PFS and OS were 61% and 79%, respectively. Thirty percent of patients achieved a complete response to therapy and the median time to progression was 53 months. Twelve patients had disease progression, and 83% of these patients were found to have mutations in BTK PLCG2.
Overcoming challenges in developing small molecule inhibitors for GPVI and CLEC-2
Published in Platelets, 2021
Foteini-Nafsika Damaskinaki, Luis A. Moran, Angel Garcia, Barrie Kellam, Steve P. Watson
The clustering of GPVI and CLEC-2 drives intracellular signaling cascades that lead to activation of platelets. GPVI is a single transmembrane protein belonging to the immunoglobulin family of receptors that is expressed in the membrane with the dimeric Fc receptor (FcR) γ-chain, with each chain having an immunoreceptor tyrosine-based activation motif (ITAM), characterized by two conserved YxxL sequences [29]. In contrast, the single transmembrane, lectin-like receptor, CLEC-2, has one YxxL sequence in its cytosolic tail, named a hemITAM (or hemi-ITAM) [30]. Clustering of GPVI or CLEC-2 leads to phosphorylation of the conserved tyrosines in the hemITAM or ITAM sequence by Src and Syk tyrosine kinases, leading to binding of the tandem SH2 domains in Syk and initiation of a downstream signaling cascade orchestrated through the protein adapter LAT. This acts as a binding template for other proteins facilitating a phosphorylation cascade, including various adapter and effector proteins, leading to activation of PI 3-kinase and PLCγ2 (Figure 1). PI 3-kinase generates the second messenger phosphatidylinositol 3,4,5-trisphosphate (PIP3) which binds to pleckstrin homology and SH2 domains. PLCγ2 generates the second messenger inositol 1,4, 5-trisphosphate (IP3) and 1,2-diacylglycerol, which release Ca2+ and activate protein kinase C, respectively.