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- Liukkonen, J, et al.
(author)
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Immunological and Microbiological Profiling of Cumulative Risk Score for Periodontitis
- 2020
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In: Diagnostics (Basel, Switzerland). - : MDPI AG. - 2075-4418. ; 10:8
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Journal article (peer-reviewed)abstract
- The cumulative risk score (CRS) is a mathematical salivary diagnostic model to define an individual’s risk of having periodontitis. In order to further validate this salivary biomarker, we investigated how periodontal bacteria, lipopolysaccharide (LPS), and systemic and local host immune responses relate to CRS. Subgingival plaque, saliva, and serum samples collected from 445 individuals were used in the analyses. Plaque levels of 28 microbial species, especially those of Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Porphyromonas endodontalis, Prevotella intermedia, and Tannerella forsythia, and serum and salivary levels of IgA and IgG against these five species were determined. Additionally, LPS activity was measured. High CRS associated strongly with all IgA/IgG antibody and LPS levels in saliva, whereas in serum the associations were not that obvious. In the final logistic regression model, the best predictors of high CRS were saliva IgA burden against the five species (OR 7.04, 95% CI 2.25–22.0), IgG burden (3.79, 1.78–8.08), LPS (2.19, 1.38–3.47), and the sum of 17 subgingival Gram-negative species (6.19, 2.10–18.3). CRS is strongly associated with microbial biomarker species of periodontitis and salivary humoral immune responses against them.
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3. |
- Virtanen, Anniina T., et al.
(author)
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Identification of Novel Small Molecule Ligands for JAK2 Pseudokinase Domain
- 2023
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In: Pharmaceuticals. - : MDPI AG. - 1424-8247. ; 16:1
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Journal article (peer-reviewed)abstract
- Hyperactive mutation V617F in the JAK2 regulatory pseudokinase domain (JH2) is prevalent in patients with myeloproliferative neoplasms. Here, we identified novel small molecules that target JH2 of JAK2 V617F and characterized binding via biochemical and structural approaches. Screening of 107,600 small molecules resulted in identification of 55 binders to the ATP-binding pocket of recombinant JAK2 JH2 V617F protein at a low hit rate of 0.05%, which indicates unique structural characteristics of the JAK2 JH2 ATP-binding pocket. Selected hits and structural analogs were further assessed for binding to JH2 and JH1 (kinase) domains of JAK family members (JAK1-3, TYK2) and for effects on MPN model cell viability. Crystal structures were determined with JAK2 JH2 wild-type and V617F. The JH2-selective binders were identified in diaminotriazole, diaminotriazine, and phenylpyrazolo-pyrimidone chemical entities, but they showed low-affinity, and no inhibition of MPN cells was detected, while compounds binding to both JAK2 JH1 and JH2 domains inhibited MPN cell viability. X-ray crystal structures of protein-ligand complexes indicated generally similar binding modes between the ligands and V617F or wild-type JAK2. Ligands of JAK2 JH2 V617F are applicable as probes in JAK-STAT research, and SAR optimization combined with structural insights may yield higher-affinity inhibitors with biological activity.
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