Boronate-Based Oxidant-Responsive Derivatives of Acetaminophen as Proinhibitors of Myeloperoxidase.

Myeloperoxidase (MPO) is an important component of the human innate immune system and the main source of a strong oxidizing and chlorinating species, hypochlorous acid (HOCl). Inadvertent, misplaced, or excessive generation of HOCl by MPO is associated with multiple human inflammatory diseases. Therefore, there is a considerable interest in the development of MPO inhibitors. Here, we report the synthesis and characterization of a boronobenzyl derivative of acetaminophen (AMBB), which can function as a proinhibitor of MPO and release acetaminophen, the inhibitor of chlorination cycle of MPO, in the presence of inflammatory oxidants, i.e., hydrogen peroxide, hypochlorous acid, or peroxynitrite. We demonstrate that the AMBB proinhibitor undergoes conversion to acetaminophen by all three oxidants, with the involvement of the primary phenolic product intermediate, with relatively long half-life at pH 7.4. The determined rate constants of the reaction of the AMBB proinhibitor with hydrogen peroxide, hypochlorous acid, or peroxynitrite are equal to 1.67, 1.6 × 104, and 1.0 × 106 M-1 s-1, respectively. AMBB showed lower MPO inhibitory activity (IC50 > 0.3 mM) than acetaminophen (IC50 = 0.14 mM) toward MPO-dependent HOCl generation. Finally, based on the determined reaction kinetics and the observed inhibitory effects of two plasma components, uric acid and albumin, on the extent of AMBB oxidation by ONOO- and HOCl, we conclude that ONOO- is the most likely potential activator of AMBB in human plasma.

Correlation between refractive error, muscle thickness, and bioelectrical activity of selected masticatory muscles.

OBJECTIVE: The aim of this study was to analyze the correlation between the refractive error, muscle thickness, and the bioelectrical activity of selected masticatory and neck muscles in subjects with myopia. METHODS: For bioelectrical activity analysis within the masticatory muscles, an 8-channel BioEMG III electromyograph was used. An M-Turbo ultrasound machine was used to analyze the masticatory and neck muscle thickness. RESULTS: Statistical analysis showed significant positive correlations between masseter muscle thickness at rest on the right side. Statistical analysis showed negative correlations between the digastric muscle and Activity Index within masticatory muscles at rest on the left side when the eyes were closed. CONCLUSIONS: As refractive error increases in myopic subjects, the resting tension on the temporal muscles increases, an increase in masseter muscle thickness is noted, and a decrease in bioelectrical activity on the digastric muscle at rest.

Influence of Soft Stabilization Splint on Electromyographic Patterns in Masticatory and Neck Muscles in Healthy Women.

This study investigates the influence of soft stabilization splints on electromyographic patterns in masticatory and neck muscles in healthy women. A total of 70 healthy women were qualified for the research. The resting and clenching electromyographic patterns of the temporalis (TA), masseter (MM), digastric (DA), and sternocleidomastoid (SCM) muscles were measured using the BioEMG III™ apparatus. The interaction between splint application and resting muscle activity affected the results in all examined muscles except the temporalis muscle. A large effect size was observed in masseter (2.19 µV vs. 5.18 µV; p = 0.00; ES = 1.00) and digastric (1.89 µV vs. 3.17 µV; p = 0.00; ES = 1.00) both-sided RMS activity. Significant differences between the two conditions were observed in all Functional Clenching Indices (FCI) for MM, SDM, and DA muscles. All FCI values for the MM and DA muscles were significantly lower with than without the splint. We observed an increase in all activity indices due to splint application, which suggests a masseter muscle advantage during measurement. The soft stabilization splint influenced resting and functional activity in the MM, SDM, and DA muscles. During tooth clenching, a soft stabilization splint changed the involvement proportions of the temporalis and masseter muscles, transferring the main activity to the masseter muscles. Using a soft stabilization splint did not affect the symmetry of the electromyographic activity of the masticatory and neck muscles.

The Difference in Electromyographic Activity While Wearing a Medical Mask in Women with and without Temporomandibular Disorders.

Wearing a medical mask influences resting activity of the temporalis anterior and masseter muscles in healthy young women. However, no studies link medical mask-wearing with masticatory muscle activity in patients with temporomandibular disorders (TMDs). Therefore, this study aims to compare electromyographic patterns while wearing a medical mask between women with and without temporomandibular disorders. Based on the Research Diagnostic Criteria for Temporomandibular Disorders, 115 adult women qualified for the study. Participants were divided into the following two groups: diagnosed TMDs (n = 55; mean age: 23.5 ± 2.3 years) and healthy women (n = 60; mean age: 23.7 ± 2.6 years). Examinations of the resting and functional electromyographic activity of the temporalis anterior (TA), superficial masseter (MM), anterior bellies of the digastric muscle (DA), and the middle part of the sternocleidomastoid muscle (SCM) were carried out using the BioEMG III™. Both groups showed statistically significant decreases in resting masticatory muscle activity during medical mask examination compared to no mask measurement. The significant differences in no mask measurement between both groups were noted regarding resting masticatory activity, clenching in the intercuspal position, and clenching on dental cotton rollers. During medical mask examination, women with TMDs showed differences in resting masticatory activity and clenching on dental cotton rollers compared to the healthy group. In all analyzed variables, both groups showed similar electromyographic patterns in the maximum mouth opening measurement during medical mask and no mask examination. A medical mask influences the resting bioelectric activity of the masticatory muscles in women with temporomandibular disorders and healthy women. We observed differences and some similarities in resting and functional electromyographic patterns within masticatory and neck muscles in both groups during medical mask and no mask examination.

The Chemistry of HNO: Mechanisms and Reaction Kinetics.

Azanone (HNO, also known as nitroxyl) is the protonated form of the product of one-electron reduction of nitric oxide (•NO), and an elusive electrophilic reactive nitrogen species of increasing pharmacological significance. Over the past 20 years, the interest in the biological chemistry of HNO has increased significantly due to the numerous beneficial pharmacological effects of its donors. Increased availability of various HNO donors was accompanied by great progress in the understanding of HNO chemistry and chemical biology. This review is focused on the chemistry of HNO, with emphasis on reaction kinetics and mechanisms in aqueous solutions.

Fluorescent probes for monitoring myeloperoxidase-derived hypochlorous acid: a comparative study.

MPO-derived oxidants including HOCl contribute to tissue damage and the initiation and propagation of inflammatory diseases. The search for small molecule inhibitors of myeloperoxidase, as molecular tools and potential drugs, requires the application of high throughput screening assays based on monitoring the activity of myeloperoxidase. In this study, we have compared three classes of fluorescent probes for monitoring myeloperoxidase-derived hypochlorous acid, including boronate-, aminophenyl- and thiol-based fluorogenic probes and we show that all three classes of probes are suitable for this purpose. However, probes based on the coumarin fluorophore turned out to be not reliable indicators of the inhibitors' potency. We have also determined the rate constants of the reaction between HOCl and the probes and they are equal to 1.8 × 104 M-1s-1 for coumarin boronic acid (CBA), 1.1 × 104 M-1s-1 for fluorescein based boronic acid (FLBA), 3.1 × 104 M-1s-1 for 7-(p-aminophenyl)-coumarin (APC), 1.6 × 104 M-1s-1 for 3'-(p-aminophenyl)-fluorescein (APF), and 1 × 107 M-1s-1 for 4-thiomorpholino-7-nitrobenz-2-oxa-1,3-diazole (NBD-TM). The high reaction rate constant of NBD-TM with HOCl makes this probe the most reliable tool to monitor HOCl formation in the presence of compounds showing HOCl-scavenging activity.

Masticatory Muscle Thickness and Activity Correlates to Eyeball Length, Intraocular Pressure, Retinal and Choroidal Thickness in Healthy Women versus Women with Myopia.

This study aims to examine the correlations between masticatory and neck muscle thickness and activity versus eyeball length, retinal thickness, choroidal thickness, and intraocular pressure in healthy women versus women with myopia. The study group consisted of 21 women aged 24 years and a control group of 19 women (mean age 23 years). For bioelectrical activity analysis within the temporalis anterior, the superficial part of the masseter muscle, the middle part of the sternocleidomastoid muscle, and the anterior belly of the digastric muscle, an eight-channel BioEMG III electromyograph were used. An M-Turbo ultrasound machine was used to analyze masticatory and neck muscle thickness. The eyeball length was examined by IOL Master 500; choroidal and retinal thickness by Optovue Angiovue; and intraocular pressure by Tono-Pen XL. Refractive errors are related to differences in muscle thickness and electromyographic activity. Bioelectrical activity within the temporalis anterior seems to be associated with ocular length, retinal thickness, and choroidal thickness in women with myopia.

Cervical Myofascial Pain Is Associated with an Imbalance of Masticatory Muscle Activity.

This study aimed to assess the relationship between the occurrence of cervical myofascial pain with active myofascial trigger points (MTrPs) within the upper trapezius muscle and the electromyographic asymmetry index (AsI) of masticatory muscles: temporalis anterior (TA), superficial part of the masseter muscle (MM), and anterior belly of the digastric muscle (DA). The study group comprised 100 subjects (80 women and 20 men) aged 18 to 30 years (mean 23 ± 2.6 years) reporting pain in the neck muscles, diagnosed with myofascial pain with active MTrPs only within the upper trapezius muscle. The control group comprised 60 healthy, pain-free subjects (42 women and 18 men) aged 20 to 30 years (mean 22.8 ± 2.6 years) without MTrPs in the upper trapezius muscle. The palpation measurement, based on the diagnostic criteria of Travell and Simons, was used to diagnose active MTrPs. The masticatory muscle activity was recorded using an 8-channel device for surface electromyography-BioEMG IIITM. Significant differences in electromyographic patterns between the group with MTrPs in the right side of upper trapezius muscle and the control group were observed within resting activity for the AsI TA (MTrPs: 8.64 vs. controls: -3.22; p = 0.001) and AsI MM (MTrPs: 7.05 vs. controls: -2.09; p = 0.018). Controls presented different electromyographic patterns during maximum voluntary clenching with cotton rolls between teeth within masseter muscle compared to the MTrPs group (MTrPs: 9.27 vs. controls: -0.43 vs. p = 0.041). Participants with MTrPs in the left side of upper trapezius muscle presented predomination of left-sided electromyographic patterns at rest within temporalis anterior in comparison to controls (MTrPs: -19.22 vs. controls: -3.22; p = 0.001). MTrPs within the trapezius muscle may be related to asymmetry within the masticatory muscle activity, suggesting that the presence of myofascial pain within the cervical muscles plays a role in the imbalance of the stomatognathic system. A unilateral active MTrPs within the trapezius muscle may increase the sEMG activity on the same side of the temporalis anterior and masseter muscles.

The Effects of Wearing a Medical Mask on the Masticatory and Neck Muscle Activity in Healthy Young Women.

The objective of this study was to analyze the influence of wearing a medical mask on masticatory and neck muscle activity in healthy young women. We recruited 66 healthy women aged from 18 to 30 years (mean 23.6 ± 2.3 years). The temporalis anterior (TA), the superficial part of the masseter muscle (MM), the anterior bellies of the digastric muscle (DA), and the middle part of the sternocleidomastoid muscle (SCM) potentials were recorded at rest and during functional activity using an eight-channel device for surface electromyography-BioEMG IIITM. There was a statistically significant decrease in mean TA activity during medical mask measurement compared to no mask examination at rest (2.16 µV vs. 2.58 µV; p = 0.05; ES = 0.2). Significant decreases in resting RMS values were also observed during the medical mask phase in comparison to no mask examination concerning the left MM (1.75 µV vs. 2.17 µV; p = 0.01; ES = 0.3), and mean bioelectrical activity of the MM (1.81 µV vs. 2.15 µV; p = 0.02; ES = 0.2). The differences between the two conditions did not reach the assumed significance level (p > 0.05) in terms of other indices. Wearing a medical mask has a small effect on decreasing the resting potentials of the temporalis anterior and masseter muscles without changing the parameters of activity and asymmetry within the stomatognathic system.

Kinetic Study on the Reactivity of Azanone (HNO) toward Cyclic C-Nucleophiles.

Azanone (HNO) is an elusive electrophilic reactive nitrogen species of growing pharmacological and biological significance. Here, we present a comparative kinetic study of HNO reactivity toward selected cyclic C-nucleophiles under aqueous conditions at pH 7.4. We applied the competition kinetics method, which is based on the use of a fluorescein-derived boronate probe FlBA and two parallel HNO reactions: with the studied scavenger or with O2 (k = 1.8 × 104 M-1s-1). We determined the second-order rate constants of HNO reactions with 13 structurally diverse C-nucleophiles (k = 33-20,000 M-1s-1). The results show that the reactivity of HNO toward C-nucleophiles depends strongly on the structure of the scavenger. The data are supported with quantum mechanical calculations. A comprehensive discussion of the HNO reaction with C-nucleophiles is provided.

Machine Learning augmented docking studies of aminothioureas at the SARS-CoV-2-ACE2 interface.

The current pandemic outbreak clearly indicated the urgent need for tools allowing fast predictions of bioactivity of a large number of compounds, either available or at least synthesizable. In the computational chemistry toolbox, several such tools are available, with the main ones being docking and structure-activity relationship modeling either by classical linear QSAR or Machine Learning techniques. In this contribution, we focus on the comparison of the results obtained using different docking protocols on the example of the search for bioactivity of compounds containing N-N-C(S)-N scaffold at the S-protein of SARS-CoV-2 virus with ACE2 human receptor interface. Based on over 1800 structures in the training set we have predicted binding properties of the complete set of nearly 600000 structures from the same class using the Machine Learning Random Forest Regressor approach.

The importance of multisection sagittal and coronal magnetic resonance imaging evaluation in the assessment of temporomandibular joint disc position.

OBJECTIVES: The aim of this study was to evaluate diagnoses of temporomandibular (TMJ) disc displacement by comparing evaluations done on the basis of central sagittal scans only, the most often used in temporomandibular disorder (TMD) patients, with a multisection evaluation done with both sagittal and coronal scans. MATERIALS AND METHODS: Multisection MRI analysis of 382 TMJs was conducted in 191 patients with disc displacement according to RDC/TMD criteria. Disc position in the intercuspal position (IP) was assessed two times using two different methods. The first method involved a TMJ disc position evaluation on the central slide in the oblique sagittal plane only. In the second method, the TMJ disc position was assessed on all oblique sagittal and coronal images. McNemar's χ2 test was used to evaluate the differences between the sensitivities of two methods. RESULTS: The first method (central oblique sagittal scans assessment) identified 148 TMJs (38.7%) with normal disc position compared with 89 TMJs (23.3%) with normal disc position found by the second method (all oblique sagittal and coronal scans assessment). The sensitivity of analysis in both planes was significantly higher than in the sagittal plane only (p < 0.001). CONCLUSIONS: The multisection analysis in the sagittal and coronal plane allows to distinguish the correct disc position from disc displacement and thus improve evaluation of TMJ internal derangement. CLINICAL RELEVANCE: The multisection sagittal and coronal images should be recommended as a standard in MRI of the TMJ disc displacement in patients with TMD to avoid false-negative diagnoses.