Assessment of toxicity using dehydrogenases activity and mathematical modeling

Dehydrogenase activity is frequently used to assess the general condition of microorganisms in soil and activated sludge. Many studies have investigated the inhibition of dehydrogenase activity by various compounds, including heavy metal ions. However, the time after which the measurements are carried out is often chosen arbitrarily. Thus, it can be difficult to estimate how the toxic effects of compounds vary during the reaction and when the maximum of the effect would be reached. Hence, the aim of this study was to create simple and useful mathematical model describing changes in dehydrogenase activity during exposure to substances that inactivate enzymes. Our model is based on the Lagergrens pseudo-first-order equation, the rate of chemical reactions, enzyme activity, and inactivation and was created to describe short-term changes in dehydrogenase activity. The main assumption of our model is that toxic substances cause irreversible inactivation of enzyme units. The model is able to predict the maximum direct toxic effect (MDTE) and the time to reach this maximum (T_MDTE). In order to validate our model, we present two examples: inactivation of dehydrogenase in microorganisms in soil and activated sludge. The model was applied successfully for cadmium and copper ions. Our results indicate that the predicted MDTE and T_MDTE are more appropriate than EC₅₀ and IC₅₀ for toxicity assessments, except for long exposure times.     

Necroptotic TNFα-Syndecan 4-TNFα Vicious Cycle as a Therapeutic Target for Preventing Temporomandibular Joint Osteoarthritis

Temporomandibular joint osteoarthritis (TMJOA) is a chronic degenerative disease for which the underlying mechanism still remains unclear. Compared with apoptosis and autophagy, necroptosis causes greater harm to tissue homeostasis by releasing damage-associated molecular patterns (DAMPs). However, the role of necroptosis and downstream key DAMPs in TMJOA is unknown. Here, rodent models of TMJOA were established by the unilateral anterior crossbite (UAC). Transmission electron microscopy (TEM) and immunohistochemistry of receptor interacting protein kinase 3 (RIPK3)/phosphorylation of mixed lineage kinase domain-like protein (pMLKL) were conducted to evaluate the occurrence of necroptosis in vivo. The therapeutic effects of blocking necroptosis were achieved by intra-articularly injecting RIPK3 or MLKL inhibitors and using RIPK3 or MLKL knockout mice. In vitro necroptosis of condylar chondrocyte was induced by combination of tumor necrosis factor alpha (TNFα), second mitochondria-derived activator of caspases (SMAC) mimetics and carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]- fluoromethylketone (z-VAD-fmk). The possible DAMPs released by necroptotic chondrocytes were screened by quantitative proteomics and blocked by specific antibody. Translucent cytosol, swollen organelles, and ruptured cell membranes, features of necroptosis, were frequently manifested in chondrocytes at the early stage of condylar cartilage degeneration in TMJOA, which was accompanied by upregulation of RIPK3/pMLKL. Inhibiting or knocking out RIPK3/MLKL significantly prevented cartilage degeneration. DAMPs released by necroptotic condylar chondrocytes, such as syndecan 4 (SDC4) and heat shock protein 90 (HSP90), were verified. Furthermore, blocking the function of SDC4 significantly attenuated the expression of TNFα in cartilage and synovium, and accordingly increased cartilage thickness and reduced synovial inflammation. Thus, the necroptotic vicious cycle of TNFα-SDC4-TNFα contributes to cartilage degeneration and synovitis, and can serve as a potential therapeutic target for treating TMJOA. © 2022 American Society for Bone and Mineral Research (ASBMR).     

Meta-Analysis of Saturated Fatty Acid Intake and Breast Cancer Risk

The associations between saturated fatty acid (SFA) consumption and risk of breast cancer (BC) remains inconclusive. Therefore, we conducted this meta-analysis to determine the quantitative relations between dietary SFA intake and incidence of BC.Literatures published up to April 2015 were systematically screened through Pubmed and Web of Science. Relevant publication quality was evaluated by conducting the Newcastle-Ottawa scale. We used fixed effects models or random effect models to calculate the summary relative risks (RRs) and odds ratios (ORs), and conducted sensitivity analyses and evaluated the publication bias.We identified a total of 52 studies (24 cohort studies and 28 case–control studies), with over 50,000 females diagnosed with BC. The associations between dietary SFA intake and risk of BC were 1.18 for case–control studies (high vs low intake, 95% confidence interval [CI] = 1.03–1.34) and 1.04 for cohort studies (95% CI = 0.97–1.11). When restricted analyses to population-based studies, positive associations were observed for both cohort (RR [95% CI] = 1.11 [1.01–1.21]) and case–control studies (OR [95% CI] = 1.26 [1.03–1.53]). Additionally, for case–control studies, significant positive associations between higher SFA intake and BC risk were observed for Asian (OR [95% CI] = 1.17 [1.02–1.34]) and Caucasian (OR [95% CI] = 1.19 [1.00–1.41]), as well as for postmenopausal women (OR = 1.33, 95% CI: 1.02–1.73). In contrast, higher dietary SFA intake was not associated with risk of BC among premenopausal women, in cohort studies or hospital-based studies.A positive association between higher dietary SFA intake and postmenopausal BC risk was observed in case–control but not in cohort studies. More studies are warranted to confirm these findings.