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Optical Angiography at Diabetes
Published in Andrey V. Dunaev, Valery V. Tuchin, Biomedical Photonics for Diabetes Research, 2023
Dan Zhu, Jingtan Zhu, Dongyu Li, Tingting Yu, Wei Feng, Rui Shi
Alexis et al. [87] studied protein kinase Cβ (PKCβ)-mediated cerebrovascular breakdown in the retina in diabetic mice, and used a PKCβ inhibitor enzastaurin to re-seal the BBB. In their study, the effects of PKCβ antagonism on BBB integrity were examined. Fluorescein penetrance into the neuropil was evident on hippocampal sections from db/Veh mice, but in sections from db/Enz mice, NaFl fluorescence was confined to the vasculature in a pattern similar to Wt/Veh mice. Qualitative observations on hippocampal sections were upheld with direct quantification of NaFl in homogenates, as enzastaurin blocked increases in hippocampal NaFl penetrance. There was no effect of genotype or PKCβ antagonism on cortical NaFl concentrations, suggesting that there may be regional heterogeneity in susceptibility to BBB breakdown. Such results suggested that db/db mice exhibit PKCβ-mediated BBB breakdown.
Marine Drugs: A Source of Medicines for Neuroinflammatory Disorders
Published in Rohit Dutt, Anil K. Sharma, Raj K. Keservani, Vandana Garg, Promising Drug Molecules of Natural Origin, 2020
Arunachalam Muthuraman, Narahari Rishitha, Nallapilai Paramakrishnan
MS is an important common inflammatory neurological disease. The primary etiological factor of neuroinflammation is due to the action of the CNS immunological system via neuroimmune cells, i.e., astrocytes, and oligodendritic cells (Morrell, 1976). MS is characterized by a chronic process of demyelination and neurodegeneration of brain cells leads to produces the cognitive dysfunction, weakness of limbs, and development of muscular fatigue (Witte et al., 2014). The primary target site of inflammatory cytokines is BBB and also involves the recruitment of peripheral immune cells. The CNS recruited plasma cells and B-cells are readily supports the production of antibodies against the myelin sheath proteins. The degradation of myelin proteins affects the conduction system of CNS and PNS signals (Hemmer et al., 2002). The administration of anti-inflammatory, immunosuppressive drugs, and phytomedicines are producing ameliorative effects in MS disorders (Islam et al., 2008). However, the efficacy &potency of these medicines remain poor. In addition, chronic administration also causes unavoidable toxicity to the biological system (Martins and Fernandes, 2012). The marine drugs like lestaurtinib, enzastaurin, MS14, and dihydro-austrasulfone (DA) ameliorated the MS via immunosuppressive, anti-inflammatory, and neuroprotective actions (Ahmadi et al., 2010; Chen et al., 2014b; Gagalo et al., 2015; Tabatabai et al., 2007). Bryostatin-1 has potential ameliorative action on MS via suppression of matrix metalloprotein and antioxidant actions (Safaeinejad et al., 2018). Similarly, some of the marines drugs are documented to produce the potential neuroprotective action and amelioration of inflammatory brain disorders (Grosso et al., 2014; Tafreshi et al., 2008). The different marine sources are producing the anti-inflammatory and immuno-modulatory action in animals and in humans. From blue starfish (Linckia laevigata) derived marine drugs, i.e., linckoside B (IC50: 76 µM); linckoside F (IC50: 30 µM); linckoside G (IC50: <10 µM); linckoside H (IC50: <10 µM); linckoside I (IC50: 40 µM); linckoside J (IC50: 40 µM); linckoside K (IC50: 10 µM); LLG-5 (IC50: 59.3 µM); LLG-3 (IC50: 63.1 µM); and granulatoside A(IC50: 95 µM) are documented to produce the neuroprotection and neuro-immune modulatory actions with different IC50 values. Similarly, sea cucumber (Cucumaria echinata) derived marine drugs, i.e., CEG-6 (IC50: 43 µM); HLG-3 (IC50: 42 µM); CEG-8 (IC50: 40 µM); CEG-9 (IC50: 35.1 µM); SJG-1 (IC50: 39.1 µM); SJG-2 (IC50: 64.8 µM); and CG-1 (IC50: 43 µM) are also stated as neuroprotection from neuroinflammatory and neuro-immune modulatory actions (Grosso et al., 2014; Safaeinejad et al., 2018). Thus, these agents can be useful to treat MS. However, the detailed studies are essential to the clinical use of this medicine with full efficacy and less toxicity.
Validation of PRKCB Immunohistochemistry as a Biomarker for the Diagnosis of Ewing Sarcoma
Published in Fetal and Pediatric Pathology, 2023
Victor Zota, Gene P. Siegal, David Kelly, Julia A. Bridge, Anders Berglund, Katherine Bui, Farah Khalil, Damon R. Reed, Soner Altiok, Anthony Magliocco, Marilyn M. Bui
Compared to a known diagnostic marker, NKX2.2 IHC, which exhibits a nuclear staining pattern, both biomarkers identify the same target of EWSR1-FLI1 and were shown to be differentially upregulated in ES by array-based gene repression analyses [14, 26]. In addition to being a diagnostic biomarker, PRKCB has been shown to be a major therapeutic target in ES. Its inhibition has been shown either by small molecule inhibitors (such as enzastaurin) or by siRNA, which induces apoptosis in tumor cells. We hypothesize that PRKCB will also be used as a surrogate marker for PRKCB inhibitors, clinical trial patient preselection, and monitoring disease progression. The potential implication of PRKCB to serve as a therapeutic target in the treatment of ES by small molecule inhibitors warrants further investigation.
Changing paradigms for targeted therapies against diffuse infiltrative gliomas: tackling a moving target
Published in Expert Review of Neurotherapeutics, 2019
Candice D. Carpenter, Iyad Alnahhas, Javier Gonzalez, Pierre Giglio, Vinay K. Puduvalli
PDGFR is another RTK which function similar to EGFR in driving the growth of gliomas activating similar downstream pathways [108]. The Cancer Genome Atlas Research Network further reported PDGFR amplification in 13.1% in GBM samples [57]. Imatinib, a multikinase inhibitor which targets PDGFR, c-KIT, and BCR-ABL, was tested in recurrent GBM patients in several phase II and subsequently a phase III clinical trial, but there was no significant improvement in outcome when combined with hydroxyurea [109–111]. The PI3K is an important mediator of one of the main signaling pathways utilized upon RTK activation by multiple cell surface receptors including EGFR, PDGFR, and VEGFR and triggers activation of Akt and mTOR [112]. Efforts to directly inhibit Akt were limited by toxicity to normal tissue; hence, attempts to identify a targetable downstream member of the RTK pathways led to an assessment of the roles of mTOR and protein kinase C (PKC), key downstream hubs of RTK signaling. However, trials of enzastaurin, a PKC inhibitor, and everolimus, an mTOR inhibitor, did not show clinical benefit in patients with malignant glioma [113–115].
A safety profile of medications used to treat Waldenström’s macroglobulinemia
Published in Expert Opinion on Drug Safety, 2018
Ramón García-Sanz, Cristina Jiménez, Verónica González De La Calle, María Eugenia Sarasquete
Enzastaurin is another serine/threonine kinase inhibitor that targets not only the PI3K/AKT but also the protein kinase C pathway, and that has been shown to possess activity in WM preclinical models [94]. Forty-two previously treated patients were treated in a clinical trial with 250 mg oral enzastaurin twice daily (including a loading single dose of 375 mg three times on day 1, cycle 1) [95]. Eight 28-day courses were planned until progression or toxicity. In case of progression, high-dose dexamethasone was allowed. The ORR was modest (38%) and toxicity relevant, including one death from septic shock considered drug-related. A statistically significant association between response rate and interleukin 15 (IL-15) was observed, suggesting IL-15 as a biomarker for response, albeit more studies are needed to confirm this relationship.