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Keywords = Stimulus-Stimulus inhibition

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33 pages, 4098 KiB  
Systematic Review
Pharmacological Inhibition of the PI3K/AKT/mTOR Pathway in Rheumatoid Arthritis Synoviocytes: A Systematic Review and Meta-Analysis (Preclinical)
by Tatiana Bobkova, Artem Bobkov and Yang Li
Pharmaceuticals 2025, 18(8), 1152; https://doi.org/10.3390/ph18081152 (registering DOI) - 2 Aug 2025
Abstract
Background/Objectives: Constitutive activation of the PI3K/AKT/mTOR signaling cascade underlies the aggressive phenotype of fibroblast-like synoviocytes (FLSs) in rheumatoid arthritis (RA); however, a quantitative synthesis of in vitro data on pathway inhibition remains lacking. This systematic review and meta-analysis aimed to (i) aggregate [...] Read more.
Background/Objectives: Constitutive activation of the PI3K/AKT/mTOR signaling cascade underlies the aggressive phenotype of fibroblast-like synoviocytes (FLSs) in rheumatoid arthritis (RA); however, a quantitative synthesis of in vitro data on pathway inhibition remains lacking. This systematic review and meta-analysis aimed to (i) aggregate standardized effects of pathway inhibitors on proliferation, apoptosis, migration/invasion, IL-6/IL-8 secretion, p-AKT, and LC3; (ii) assess heterogeneity and identify key moderators of variability, including stimulus type, cell source, and inhibitor class. Methods: PubMed, Europe PMC, and the Cochrane Library were searched up to 18 May 2025 (PROSPERO CRD420251058185). Twenty of 2684 screened records met eligibility. Two reviewers independently extracted data and assessed study quality with SciRAP. Standardized mean differences (Hedges g) were pooled using a Sidik–Jonkman random-effects model with Hartung–Knapp confidence intervals. Heterogeneity (τ2, I2), 95% prediction intervals, and meta-regression by cell type were calculated; robustness was tested with REML-HK, leave-one-out, and Baujat diagnostics. Results: PI3K/AKT/mTOR inhibition markedly reduced proliferation (to –5.1 SD), IL-6 (–11.1 SD), and IL-8 (–6.5 SD) while increasing apoptosis (+2.7 SD). Fourteen of seventeen outcome clusters showed large effects (|g| ≥ 0.8), with low–moderate heterogeneity (I2 ≤ 35% in 11 clusters). Prediction intervals crossed zero only in small k-groups; sensitivity analyses shifted pooled estimates by ≤0.05 SD. p-AKT and p-mTOR consistently reflected functional changes and emerged as reliable pharmacodynamic markers. Conclusions: Targeted blockade of PI3K/AKT/mTOR robustly suppresses the proliferative and inflammatory phenotype of RA-FLSs, reaffirming this axis as a therapeutic target. The stability of estimates across multiple analytic scenarios enhances confidence in these findings and highlights p-AKT and p-mTOR as translational response markers. The present synthesis provides a quantitative basis for personalized dual-PI3K/mTOR strategies and supports the adoption of standardized long-term preclinical protocols. Full article
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13 pages, 986 KiB  
Article
Enhanced Cross-Audiovisual Perception in High-Level Martial Arts Routine Athletes Stems from Increased Automatic Processing Capacity
by Xiaohan Wang, Zeshuai Wang, Ya Gao, Wu Jiang, Zikang Meng, Tianxin Gu, Zonghao Zhang, Haoping Yang and Li Luo
Behav. Sci. 2025, 15(8), 1028; https://doi.org/10.3390/bs15081028 - 29 Jul 2025
Viewed by 151
Abstract
Multisensory integration is crucial for effective cognitive functioning, especially in complex tasks such as those requiring rapid audiovisual information processing. High-level martial arts routine athletes, trained in integrating visual and auditory cues for performance, may exhibit superior abilities in cross-audiovisual integration. This study [...] Read more.
Multisensory integration is crucial for effective cognitive functioning, especially in complex tasks such as those requiring rapid audiovisual information processing. High-level martial arts routine athletes, trained in integrating visual and auditory cues for performance, may exhibit superior abilities in cross-audiovisual integration. This study aimed to explore whether these athletes demonstrate an expert advantage effect in audiovisual integration, particularly focusing on whether this advantage is due to enhanced automatic auditory processing. A total of 165 participants (81 male, 84 female) were included in three experiments. Experiment 1 (n = 63) used a cross-audiovisual Rapid Serial Visual Presentation (RSVP) paradigm to compare the martial arts routine athlete group (n = 31) with a control group (n = 33) in tasks requiring target stimulus identification under audiovisual congruent and incongruent conditions. Experiment 2 (n = 52) manipulated the synchronicity of auditory stimuli to differentiate between audiovisual integration and auditory alerting effects. Experiment 3 (n = 50) combined surprise and post-surprise tests to investigate the role of automatic auditory processing in this expert advantage. Experiment 1 revealed that martial arts routine athletes outperformed the control group, especially in semantically incongruent conditions, with significantly higher accuracy at both lag3 (p < 0.001, 95% CI = [0.165, 0.275]) and lag8 (p < 0.001, 95% CI = [0.242, 0.435]). Experiment 2 found no significant difference between groups in response to the manipulation of auditory stimulus synchronicity, ruling out an alerting effect. In Experiment 3, martial arts routine athletes demonstrated better performance in reporting unexpected auditory stimuli during the surprise test, indicating enhanced automatic processing capacity. Additionally, a significant improvement in working memory re-selection was observed in the martial arts routine group. The expert advantage effect observed in martial arts routine athletes is attributable to enhanced cross-audiovisual integration, independent of an auditory alerting mechanism. Long-term training improves the efficiency of working memory re-selection and the ability to inhibit conflicting information, suggesting that the expanded capacity for automatic auditory processing underpins their multisensory integration advantage. Full article
(This article belongs to the Section Cognition)
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15 pages, 3934 KiB  
Article
Methyl Viologen@β-Zeolite with Absorption/Fluorescence Dual-Mode and Photo/Chemical Synergistic Stimuli-Responsive Chromism
by Jingxuan Han, Shaoning Li, Huihui Li, Yu Li, Jiaqiao Qin, Fuxiang Wang and Qinhe Pan
Molecules 2025, 30(13), 2872; https://doi.org/10.3390/molecules30132872 - 6 Jul 2025
Viewed by 333
Abstract
In this work, methyl viologen (MV) was adsorbed into the nanopores of Si/Al H-β-zeolite via cation exchange. The resulting MV@β-zeolite possessed absorption/fluorescence dual-mode and photo/chemical synergistic stimuli-responsive chromism. Owing to the acidic surrounding provided by β-zeolite, the chromism of MV required the synergistic [...] Read more.
In this work, methyl viologen (MV) was adsorbed into the nanopores of Si/Al H-β-zeolite via cation exchange. The resulting MV@β-zeolite possessed absorption/fluorescence dual-mode and photo/chemical synergistic stimuli-responsive chromism. Owing to the acidic surrounding provided by β-zeolite, the chromism of MV required the synergistic stimuli of UV irradiation and a chemical reductant (such as Na2SO3). UV irradiation induced single electron transfer from the chemical reductant to MV@β-zeolite, leading to enhanced absorption at 610 nm together with a daylight color change from pale yellow to blue. Meanwhile, the nanopores of β-zeolite inhibited aggregation-caused quenching of MV, enabling MV to emit cyan fluorescence at 500 nm. After the single electron transfer of the chemical reductant under UV irradiation, the cyan fluorescence of MV@β-zeolite was quenched. Additionally, MV@β-zeolite exhibited a short stimulus response time (250 s) and good color change reversibility. These findings in this work provide valuable insights into the design of multi-mode and synergistic stimuli-responsive viologen-based chromic materials, particularly for applications in secure high-throughput information storage, high-level anti-counterfeiting and multi-target multi-mode sensing. Full article
(This article belongs to the Special Issue Novel Organic-Inorganic Hybrid Porous Photochromic Materials)
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12 pages, 1087 KiB  
Review
Antioxidants as Modulators of NETosis: Mechanisms, Evidence, and Therapeutic Potential
by Fabiola Zambrano, Pamela Uribe, Mabel Schulz, Carlos Hermosilla, Anja Taubert and Raúl Sánchez
Int. J. Mol. Sci. 2025, 26(11), 5272; https://doi.org/10.3390/ijms26115272 - 30 May 2025
Viewed by 744
Abstract
Neutrophil extracellular trap (NET) formation is a process known as NETosis and is a critical innate immune response mechanism that can become pathologically dysregulated in various inflammatory, autoimmune, infectious, and neoplastic diseases. Reactive oxygen species (ROS) play a central role in NETosis induction, [...] Read more.
Neutrophil extracellular trap (NET) formation is a process known as NETosis and is a critical innate immune response mechanism that can become pathologically dysregulated in various inflammatory, autoimmune, infectious, and neoplastic diseases. Reactive oxygen species (ROS) play a central role in NETosis induction, making antioxidants a promising therapeutic approach. This review outlines the molecular mechanisms underlying NET formation and highlights three principal antioxidant-based inhibitory strategies: NADPH oxidase (NOX) inhibition, ROS scavenging, and myeloperoxidase (MPO) inhibition. Evidence supports the use of agents such as diphenylene iodonium (NOX inhibitor), N-acetylcysteine and glutathione (ROS scavengers), and thiocyanate (MPO inhibitor), which significantly reduce NETosis in vitro and in vivo. Moreover, natural compounds like resveratrol show pleiotropic effects by modulating neutrophil activation, ROS production, and protease activity. Combination therapies that enhance total antioxidant capacity are particularly effective, though their translation to clinical practice faces challenges such as stimulus specificity, bioavailability, and maintaining immune competence. Antioxidant-based therapies thus represent a promising avenue for targeted NETosis modulation. Future research should focus on improving delivery systems, identifying NET-specific biomarkers, and integrating antioxidants into broader immunomodulatory strategies. Full article
(This article belongs to the Special Issue Antioxidants: The Molecular Guardians Against Oxidative Stress)
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22 pages, 1299 KiB  
Article
Combined Effects of Biochar and Rhamnolipid on Phenanthrene Biodegradation in Agricultural Soil: Bioavailability and Microbial Community Dynamics
by Meng Zhang, Yuke Kang, Jie Ran, Jichao Song, Zhongyi Wang, Jiawang Li and Liyuan Chen
Agriculture 2025, 15(11), 1116; https://doi.org/10.3390/agriculture15111116 - 22 May 2025
Viewed by 487
Abstract
The present study investigated the combined effects of wheat straw biochar (BC) and biosurfactant rhamnolipid (RL) on the biodegradation kinetics of phenanthrene by indigenous microorganisms in agricultural soil, focusing on dynamic responses of both bioavailability and community structure. The combined treatment (BC + [...] Read more.
The present study investigated the combined effects of wheat straw biochar (BC) and biosurfactant rhamnolipid (RL) on the biodegradation kinetics of phenanthrene by indigenous microorganisms in agricultural soil, focusing on dynamic responses of both bioavailability and community structure. The combined treatment (BC + RL, 60.63%) significantly enhanced phenanthrene biodegradation compared to RL alone (54.74%) and the control (45.98%), while BC amendment alone (42.55%) notably inhibited biodegradation by reducing phenanthrene bioavailability despite increasing bacterial abundance, enzyme activity, and community diversity. Both RL and BC + RL treatments promoted bioavailability by transforming phenanthrene from tightly bound (very slowly desorbing fraction, Fvslow) to readily bioavailable fractions (rapidly and slowly desorbing fractions, Frapid and Fslow), as revealed by sequential Tenax extraction. The RL-mediated increase in phenanthrene bioavailability to microbes by 11.93–17.90% via solubilization greatly enriched PAH-degrading bacterial genera and the nidA gene, contributing to enhanced biodegradation. The BC + RL combination outperformed the single application of RL in improving phenanthrene biodegradation due to their synergy in stimulating microbial population and activity (e.g., Bacillus, Massilia, Sphingomonas, and polyphenol oxidase) as a growth stimulus. These findings demonstrate that BC and RL co-application enhances PAH removal through improved bioavailability and optimized microbial communities, offering a promising strategy for soil bioremediation to ensure agricultural product safety. Full article
(This article belongs to the Section Ecosystem, Environment and Climate Change in Agriculture)
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24 pages, 5413 KiB  
Review
Recent Advances in Ionic Mechanisms in Pituitary Cells: Implications for Electrophysiological and Electropharmacological Research
by Sheng-Nan Wu, Ya-Jean Wang, Zi-Han Gao, Rasa Liutkevičienė and Vita Rovite
J. Clin. Med. 2025, 14(9), 3117; https://doi.org/10.3390/jcm14093117 - 30 Apr 2025
Viewed by 989
Abstract
Pituitary cells are specialized cells located within the pituitary gland, a small, pea-sized gland situated at the base of the brain. Through the use of cellular electrophysiological techniques, the electrical properties of these cells have been revealed. This review paper aims to introduce [...] Read more.
Pituitary cells are specialized cells located within the pituitary gland, a small, pea-sized gland situated at the base of the brain. Through the use of cellular electrophysiological techniques, the electrical properties of these cells have been revealed. This review paper aims to introduce the ion currents that are known to be functionally expressed in pituitary cells. These currents include a voltage-gated Na+ current (INa), erg-mediated K+ current (IK(erg)), M-type K+ current (IK(M)), hyperpolarization-activated cation current (Ih), and large-conductance Ca2+-activated K+ (BKCa) channel. The biophysical characteristics of the respective ion current were described. Additionally, we also provide explanations for the effect of various drugs or compounds on each of these currents. GH3-cell exposure to GV-58 can increase the magnitude of INa with a concurrent rise in the inactivation time constant of the current. The presence of esaxerenone, an antagonist of the aldosterone receptor, directly suppresses the magnitude of peak and late INa. Risperidone, an atypical antipsychotic agent, is effective at suppressing the IK(erg) amplitude directly, and di(2-ethylhexyl)-phthalate suppressed IK(erg). Solifenacin and kynurenic acid can interact with the KM channel to stimulate IK(M), while carisbamate and cannabidiol inhibit the Ih amplitude activated by sustained hyperpolarization. Moreover, the presence of either rufinamide or QO-40 can enhance the activity of single BKCa channels. To summarize, alterations in ion currents within native pituitary cells or pituitary tumor cells can influence their functional activity, particularly in processes like stimulus–secretion coupling. The effects of small-molecule modulators, as demonstrated here, bear significance in clinical, therapeutic, and toxicological contexts. Full article
(This article belongs to the Special Issue Advances in Pituitary Adenomas)
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16 pages, 3409 KiB  
Article
Simultaneous Regularity Contrast and Luminance Polarity
by Frederick A. A. Kingdom, Hua-Chun Sun, Elena Gheorghiu and Martin S. Silva
Vision 2025, 9(1), 23; https://doi.org/10.3390/vision9010023 - 13 Mar 2025
Viewed by 560
Abstract
Texture regularity, for example, the repeating pattern of a carpet, brickwork, or tree bark, is a ubiquitous feature of the visual world. The perception of regularity has generally been studied using multi-element textures whose regularity is manipulated by the addition of random jitter [...] Read more.
Texture regularity, for example, the repeating pattern of a carpet, brickwork, or tree bark, is a ubiquitous feature of the visual world. The perception of regularity has generally been studied using multi-element textures whose regularity is manipulated by the addition of random jitter to the elements’ nominal positions. Here, we investigate the selectivity of regularity perception for the luminance contrast polarities of the elements. Our psychophysical tool was simultaneous regularity contrast, or SRC, the phenomenon in which the perceived regularity of a central test texture is shifted away from that of the surrounding regularity. Stimuli were composed of arrays of dark and/or white Gaussian elements. Surround and center test textures consisted of either the same (“congruent”) or opposite (“incongruent”) polarities. In addition, we tested a “mixed” condition consisting of a random mixture of polarities in both the surround and test. The perceived regularity of the test was measured using a match stimulus with the same polarity dimension as the test. The regularity of the match stimulus was adjusted on each trial using a forced-choice staircase procedure and the point-of-subjective equality between the match and test regularities was estimated from the resulting psychometric functions. SRC was observed in both congruent and incongruent conditions, but with the mixed condition, the perceived regularity of the test was shifted toward rather than away from the surround regularity, an example of assimilation, not contrast. The analysis revealed no significant difference in the magnitude of SRC between the congruent and incongruent conditions, suggesting that SRC could be mediated solely by polarity agnostic mechanisms, although there are other possible explanations for the “null” result. However, trend analysis using a non-linear (sigmoidal-shaped) function indicated a significant difference between the congruent and incongruent conditions, which, together with the mixed polarity results, suggests the presence of at least some polarity selective mechanisms. Previous reports have suggested that regularity perception is encoded by the “peakedness” in the distribution of spatial-frequency-tuned linear filter responses. We modelled SRC quantitatively by incorporating peakedness with spatial-frequency-selective surround inhibition and found that the model gave a good account of the SRC data. Possible reasons for the assimilation effect—with the mixed polarity condition are discussed. Full article
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17 pages, 1522 KiB  
Article
Role of lncRNA XIST/miR-146a Axis in Matrix Degradation and Apoptosis of Osteoarthritic Chondrocytes Through Regulation of MMP-13 and BCL2
by Sara Cheleschi, Nicola Mondanelli, Iole Seccafico, Roberta Corsaro, Elena Moretti, Giulia Collodel and Antonella Fioravanti
Biology 2025, 14(3), 221; https://doi.org/10.3390/biology14030221 - 20 Feb 2025
Cited by 1 | Viewed by 2292
Abstract
Growing evidence demonstrates the critical roles of long non-coding RNAs (lncRNAs) in osteoarthritis (OA) pathogenesis. The lncRNA XIST is one of the most commonly studied; however, its function remains unclear. This study aimed to research the molecular mechanism of XIST in human OA [...] Read more.
Growing evidence demonstrates the critical roles of long non-coding RNAs (lncRNAs) in osteoarthritis (OA) pathogenesis. The lncRNA XIST is one of the most commonly studied; however, its function remains unclear. This study aimed to research the molecular mechanism of XIST in human OA chondrocytes. Cells were transfected with small interfering RNA against XIST or with a microRNA (miR)-146a inhibitor in the presence of interleukin (IL)-1β. Viability was detected using MTT; apoptosis using cytometry; and XIST, miR-146a, B-cell lymphoma (BCL)2, and metalloproteinase (MMP)-13 expression using real-time PCR. The analysis of p50 and p65 nuclear factor (NF)-κB was conducted using PCR and immunofluorescence. Our findings showed that XIST was highly expressed in OA chondrocytes when compared to T/C-28a2 lines. Furthermore, XIST silencing significantly promoted survival and limited apoptosis, with a concomitant over expression of BCL2, reduction in MMP-13 mRNA, and NF-κB activation after IL-1β stimulus. Conversely, miR-146a was significantly down-regulated in OA cells, while its levels were increased following XIST silencing; moreover, miR-146a inhibition induced opposite results to those caused by XIST. Finally, the down-regulation of XIST was correlated to the over-expression of miR-146a, with a consequent modulation of BCL2, MMP-13, and NF-κB. This study suggests an influence of the XIST/miR-146a axis on the viability, apoptosis, and matrix degradation occurring in OA. Full article
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23 pages, 2583 KiB  
Article
Pearl Millet Cover Crop Extract Inhibits the Development of the Weed Ipomoea grandifolia by Inducing Oxidative Stress in Primary Roots and Affecting Photosynthesis Efficiency
by Gislaine Cristiane Mantovanelli, Adriano Antônio Silva, Letycia Lopes Ricardo, Fernanda Lima Kagami, Jéssica Dario de Almeida, Mauro Cezar Barbosa, Márcio Shigueaki Mito, Isabela de Carvalho Contesoto, Paulo Vinicius Moreira da Costa Menezes, Gabriel Felipe Stulp, Beatriz Pereira Moreno, Francielli Alana Pereira Valeze, Rubem Silvério de Oliveira Junior, Debora Cristina Baldoqui and Emy Luiza Ishii Iwamoto
Plants 2025, 14(2), 222; https://doi.org/10.3390/plants14020222 - 15 Jan 2025
Cited by 1 | Viewed by 1081
Abstract
The cover crop Pennisetum glaucum (L.) R.Br. (pearl millet) reduces the emergence of weed species in the field through a mechanism that is not fully known. The identification of the allelopathic activity of pearl millet can contribute to the development of no-tillage techniques [...] Read more.
The cover crop Pennisetum glaucum (L.) R.Br. (pearl millet) reduces the emergence of weed species in the field through a mechanism that is not fully known. The identification of the allelopathic activity of pearl millet can contribute to the development of no-tillage techniques to produce crops without or with low doses of herbicides. This issue was investigated by testing the effects of extracts from the aerial parts of pearl millet on the germination and growth of the weeds Bidens pilosa L., Euphorbia heterophylla L., and Ipomoea grandifolia (Dammer) O’Donell under laboratory conditions. The ethyl acetate fraction (EAF) at a concentration of 2000 µg mL−1 was inactive on Bidens pilosa; it inhibited root length (−72%) and seedling fresh weight (−41%) of E. heterophylla, and in I. grandifolia the length of primary root and aerial parts and the fresh and dry weight of seedlings were reduced by 63%, 32%, 25%, and 12%, respectively. In roots of I. grandifolia seedlings, at the initial development stage, EAF induced oxidative stress and increased electrolyte leakage. At the juvenile vegetative stage, a lower concentration of EAF (250 µg mL−1) induced a stimulus in seedling growth (+60% in root length and +23% in aerial parts length) that was associated with increased photosynthetic efficiency. However, at higher concentrations (1000 µg mL−1), it induced the opposite effects, inhibiting the growth of root (−41%) and aerial parts (−25%), with reduced superoxide dismutase activity and photosynthetic efficiency. The stilbenoid pallidol was identified as the main compound in EAF. The allelopathic activity of pearl millet may be attributed, at least in part, to the impairment of energy metabolism and the induction of oxidative stress in weed seedlings, with pallidol possibly involved in this action. Such findings demonstrated that the application of the EAF extract from pearl millet can be a natural and renewable alternative tool for weed control. Full article
(This article belongs to the Special Issue Allelopathy in Agroecosystems)
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17 pages, 4628 KiB  
Article
Sea Anemone Kunitz Peptide HCIQ2c1 Reduces Histamine-, Lipopolysaccharide-, and Carrageenan-Induced Inflammation via the Suppression of Pro-Inflammatory Mediators
by Aleksandra N. Kvetkina, Anna A. Klimovich, Yulia V. Deriavko, Evgeniy A. Pislyagin, Ekaterina S. Menchinskaya, Evgenia P. Bystritskaya, Marina P. Isaeva, Ekaterina N. Lyukmanova, Zakhar O. Shenkarev, Dmitriy L. Aminin and Elena V. Leychenko
Int. J. Mol. Sci. 2025, 26(1), 431; https://doi.org/10.3390/ijms26010431 - 6 Jan 2025
Cited by 1 | Viewed by 2674
Abstract
Inflammation is a physiological response of the immune system to infectious agents or tissue injury, which involves a cascade of vascular and cellular events and the activation of biochemical pathways depending on the type of harmful agent and the stimulus generated. The Kunitz [...] Read more.
Inflammation is a physiological response of the immune system to infectious agents or tissue injury, which involves a cascade of vascular and cellular events and the activation of biochemical pathways depending on the type of harmful agent and the stimulus generated. The Kunitz peptide HCIQ2c1 of sea anemone Heteractis magnifica is a strong protease inhibitor and exhibits neuroprotective and analgesic activities. In this study, we investigated the anti-inflammatory potential of HCIQ2c1 in histamine- and lipopolysaccharide (LPS)-activated RAW 264.7 macrophages as well as in LPS-induced systemic inflammation and carrageenan-induced paw edema models in CD-1 mice. We found that 10 μM HCIQ2c1 dramatically decreases histamine-induced intracellular Ca2+ release and LPS-induced reactive oxygen species (ROS) production in RAW 264.7 macrophages. Moreover, HCIQ2c1 significantly inhibited the production of LPS-induced tumor necrosis factor α (TNF-α), inducible NO-synthase (iNOS), and 5-lipoxygenase (5-LO) but slightly influenced the IL-1β and cyclooxygenase-2 (COX-2) expression level in macrophages. Furthermore, intravenous administration by HCIQ2c1 at 0.1 mg/kg dose reduced LPS-induced TNF-α, IL-1β, COX-2, and iNOS gene expression in CD-1 mice. The subplantar administration of HCIQ2c1 at 0.1 mg/kg dose to mice significantly reduced carrageenan-induced paw edema by a factor of two, which is comparable to the effect of diclofenac at 1 mg/kg dose. Thus, peptide HCIQ2c1 has a strong anti-inflammatory potential by the attenuation of systemic and local inflammatory effects through the inhibition of intracellular Ca2+ release, the production of ROS and pro-inflammatory cytokines, and enzymes involved in arachidonic acid metabolism. Full article
(This article belongs to the Special Issue The Structures and Biologic Activity of Marine Natural Products)
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19 pages, 8887 KiB  
Article
LPA3: Pharmacodynamic Differences Between Lysophosphatidic Acid and Oleoyl-Methoxy Glycerophosphothionate: Biased Agonism, Two Sites
by K. Helivier Solís, M. Teresa Romero-Ávila, Ruth Rincón-Heredia, Juan Carlos Martínez-Morales and J. Adolfo García-Sáinz
Receptors 2024, 3(4), 555-573; https://doi.org/10.3390/receptors3040029 - 20 Dec 2024
Cited by 2 | Viewed by 1135
Abstract
Background: Lysophosphatidic acid (LPA) receptor 3 (LPA3) is involved in many physiological and pathophysiological actions of this bioactive lipid, particularly in cancer. The actions of LPA and oleoyl-methoxy glycerophosphothionate (OMPT) were compared in LPA3-transfected HEK 293 cells. Methods: [...] Read more.
Background: Lysophosphatidic acid (LPA) receptor 3 (LPA3) is involved in many physiological and pathophysiological actions of this bioactive lipid, particularly in cancer. The actions of LPA and oleoyl-methoxy glycerophosphothionate (OMPT) were compared in LPA3-transfected HEK 293 cells. Methods: Receptor phosphorylation, ERK 1/2 activation, LPA3-β-arrestin 2 interaction, and changes in intracellular calcium were analyzed. Results: Our data indicate that LPA and OMPT increased LPA3 phosphorylation, OMPT being considerably more potent than LPA. OMPT was also more potent than LPA to activate ERK 1/2. In contrast, OMPT was less effective in increasing intracellular calcium than LPA. The LPA-induced LPA3-β-arrestin 2 interaction was fast and robust, whereas that induced by OMPT was only detected at 60 min of incubation. LPA- and OMPT-induced receptor internalization was fast, but that induced by OMPT was more marked. LPA-induced internalization was blocked by Pitstop 2, whereas OMPT-induced receptor internalization was partially inhibited by Pitstop 2 and Filipin and entirely by the combination of both. When LPA-stimulated cells were rechallenged with 1 µM LPA, hardly any response was detected, i.e., a “refractory” state was induced. However, a conspicuous and robust response was observed if OMPT was used as the second stimulus. Conclusions: The differences in these agents’ actions suggest that OMPT is a biased agonist. These findings suggest that two binding sites for these agonists might exist in the LPA3 receptor, one showing a very high affinity for OMPT and another likely shared by LPA and OMPT (structural analogs) with lower affinity. Full article
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15 pages, 1548 KiB  
Article
Pharmacodynamic Model of the Hemodynamic Effects of Propofol and Remifentanil and Their Interaction with Noxious Stimulation
by Maite Garraza-Obaldia, Sebastian Jaramillo, Zinnia P. Parra-Guillen, José F. Valencia, Pedro L. Gambús and Iñaki F. Trocóniz
Pharmaceutics 2024, 16(12), 1615; https://doi.org/10.3390/pharmaceutics16121615 - 19 Dec 2024
Cited by 1 | Viewed by 1290
Abstract
Background: Despite the known impact of propofol and remifentanil on hemodynamics and patient outcomes, there is a lack of comprehensive quantitative analysis, particularly in surgical settings, considering the influence of noxious stimuli. The aim of this study was to develop a quantitative [...] Read more.
Background: Despite the known impact of propofol and remifentanil on hemodynamics and patient outcomes, there is a lack of comprehensive quantitative analysis, particularly in surgical settings, considering the influence of noxious stimuli. The aim of this study was to develop a quantitative semi-mechanistic population model that characterized the time course changes in mean arterial pressure (MAP) and heart rate (HR) due to the effects of propofol, remifentanil, and different types of noxious stimulation related to the clinical routine. Methods: Data from a prospective study were used; the study analyzed the effects of propofol and remifentanil general anesthesia on female patients in physical status of I-II according to the American Society of Anesthesiologists (ASA I-II) undergoing gynecology surgery. Patients were consecutively assigned to different administration schemes of propofol and remifentanil targeted at different effect-site concentrations. Esophageal instrumentation, laryngeal mask airway insertion, hysteroscopy, and tetanus stimuli were applied. Data from patients with chronic hypertension were discarded. Results: MAP and HR observations from 77 patients were analyzed. The hemodynamic effects were described using turn-over models incorporating feedback mechanisms. Analyses revealed that propofol and remifentanil elicited effects on the turn-over of MAP and HR, respectively, with estimates of plasma drug concentrations causing an inhibition-half of the maximum effect (C50) of 8.79 µg∙mL−1 and 4.57 ng∙mL−1. Hysteroscopy exerted an increase in MAP (but not in HR), which was well-characterized by the model, with a predicted typical increase of 28 mmHg and a dissipation half-life of 33 min. The impact of other noxious stimuli on MAP or HR could not be identified. Model simulations indicated that propofol and remifentanil, titrated to inhibit the motor response to noxious stimuli, regardless of dose combinations, cause a significant risk of hypotension, especially following induction and at the end of surgery (when surgical intervention is completed, before the awakening phase). Conclusions: The developed semi-mechanistic and fully identifiable model provides quantitative information on how propofol, remifentanil, and surgical stimulus (hysteroscopy) interact to produce the hemodynamic changes (of MAP and HR) commonly observed in clinical practice. Full article
(This article belongs to the Special Issue Mechanism-Based Pharmacokinetic and Pharmacodynamic Modeling)
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15 pages, 2414 KiB  
Article
Interaction of Sensitivity, Emotions, and Motivations During Visual Perception
by Sergey Lytaev
Sensors 2024, 24(22), 7414; https://doi.org/10.3390/s24227414 - 20 Nov 2024
Cited by 1 | Viewed by 1967
Abstract
When an organism is exposed to environmental stimuli of varying intensity, the adaptive changes in the CNS can be explained by several conceptual provisions: the law of motivation–activation by Yerkes and Dodson, the laws of force and pessimal protective inhibition, and the theory [...] Read more.
When an organism is exposed to environmental stimuli of varying intensity, the adaptive changes in the CNS can be explained by several conceptual provisions: the law of motivation–activation by Yerkes and Dodson, the laws of force and pessimal protective inhibition, and the theory of emotion activation. Later, reinforcement sensitivity theory was developed in the fields of psychology and psychophysics. At the same time, cortical prepulse inhibition (PPI), the prepulse inhibition of perceived stimulus intensity (PPIPSI), and the augmentation/reduction phenomenon were proposed in sensory neurophysiology, which expanded our understanding of consciousness. The aim of this study was to identify markers of levels of activity of cognitive processes under normal and in psychopathological conditions while amplifying the information stimulus. For this purpose, we changed the contrast level of reversible checkerboard patterns and mapped the visual evoked potentials (VEPs) in 19 monopolar channels among 52 healthy subjects and 39 patients with a mental illness without an active productive pathology. Their cognitive functions were assessed by presenting visual tests to assess invariant pattern recognition, short-term visual memory, and Gestalt perception. The personalities of the healthy subjects were assessed according to Cattell’s 16-factor questionnaire, linking the data from neurophysiological and cognitive studies to factors Q4 (relaxation/tension) and C (emotional stability). According to the N70 and N150 VEP waves, the healthy subjects and the patients were divided into two groups. In some, there was a direct relationship between VEP amplitude and contrast intensity (21 patients and 29 healthy persons), while in the others, there was an inverse relationship, with a reduction in VEP amplitude (18 patients and 23 healthy persons). The relationship and mechanisms of subjects’ cognitive abilities and personality traits are discussed based on the data acquired from the responses to information stimuli of varied intensity. Full article
(This article belongs to the Section Intelligent Sensors)
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28 pages, 2702 KiB  
Review
A Systematic Review and Meta-Analysis of Conditioned Pain Modulation in Children and Young People with Chronic Pain
by Christina Liossi, Helen Laycock, Kanmani Radhakrishnan, Zara Hussain and Daniel Eric Schoth
Children 2024, 11(11), 1367; https://doi.org/10.3390/children11111367 - 11 Nov 2024
Viewed by 2846
Abstract
Background/Objectives: Conditioned pain modulation (CPM) is a psychophysical experimental measure of the endogenous pain inhibitory pathway in humans, wherein one pain stimulus (the conditioning stimulus) is used to inhibit an individual’s perception of a second painful (test) stimulus. Research provides evidence of impaired [...] Read more.
Background/Objectives: Conditioned pain modulation (CPM) is a psychophysical experimental measure of the endogenous pain inhibitory pathway in humans, wherein one pain stimulus (the conditioning stimulus) is used to inhibit an individual’s perception of a second painful (test) stimulus. Research provides evidence of impaired endogenous inhibitory pain responses in adults with chronic pain. CPM is now increasingly applied in paediatric research and clinical practice. The primary aim of this systematic review was to examine the efficacy of CPM in paediatric chronic pain populations (6–24-year-olds) compared to pain-free children and young people (CYP). Methods: The protocol was registered on PROSPERO (CRD42020221927). A systematic search of seven databases was conducted from database inception to 20th June 2024. Study inclusion criteria were as follows: (i) recruited a sample of CYP aged 6 to 24 (inclusive) with chronic pain or who were pain-free; and (ii) applied a CPM paradigm comprising both a painful test and conditioning stimuli that were sufficiently detailed to allow for replication,(iii) adhered to a study design of randomised control trial, case control or cohort study, including cross-sectional or longitudinal; (iv) available in the English language. Study exclusion criteria were: (i) The CPM paradigm used a non-painful test or conditioning stimulus only; and (ii) was only available as an abstract, letter, poster, editorial, case report, or review with or without meta-analyses. Risk of bias was assessed using the Appraisal Tool for Cross Sectional Studies (AXIS). Meta-analyses were conducted in Comprehensive Meta Analysis 3.0 using random effects models to compare the overall CPM responses in CYP with chronic pain conditions to healthy control CYP. Results: Thirty-two studies were eligible for inclusion, six of which were included in one or more meta-analysis (n = 407 chronic pain, n = 205 control). Meta-analysis revealed significantly weaker CPM responses in CYP with a variety of chronic pain conditions compared to healthy controls (standardized mean difference (SMD) = 0.352), and significantly weaker CPM responses in CYP with abdominal pain conditions compared to healthy controls (SMD = 0.685). No significant difference in CPM response was found between CYP with migraine and healthy controls (SMD = −0.201). Conclusions: Variable results were found across individual studies, and the meta-analysis of the small number of eligible studies provides tentative evidence for impaired CPM in CYP with chronic pain compared to healthy controls. Further research is clearly needed. In particular, studies should present CPM results separately for different age groups, ethnic groups, and sexes, as these variables shape clinical pain responses. Full article
(This article belongs to the Special Issue Advances in Pediatric Anesthesia, Pain Medicine and Intensive Care)
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31 pages, 1150 KiB  
Review
How Do ROS Induce NETosis? Oxidative DNA Damage, DNA Repair, and Chromatin Decondensation
by Dhia Azzouz and Nades Palaniyar
Biomolecules 2024, 14(10), 1307; https://doi.org/10.3390/biom14101307 - 16 Oct 2024
Cited by 18 | Viewed by 3522
Abstract
Neutrophil extracellular traps (NETs) are intricate, DNA-based, web-like structures adorned with cytotoxic proteins. They play a crucial role in antimicrobial defense but are also implicated in autoimmune diseases and tissue injury. The process of NET formation, known as NETosis, is a regulated cell [...] Read more.
Neutrophil extracellular traps (NETs) are intricate, DNA-based, web-like structures adorned with cytotoxic proteins. They play a crucial role in antimicrobial defense but are also implicated in autoimmune diseases and tissue injury. The process of NET formation, known as NETosis, is a regulated cell death mechanism that involves the release of these structures and is unique to neutrophils. NETosis is heavily dependent on the production of reactive oxygen species (ROS), which can be generated either through NADPH oxidase (NOX) or mitochondrial pathways, leading to NOX-dependent or NOX-independent NETosis, respectively. Recent research has revealed an intricate interplay between ROS production, DNA repair, and NET formation in different contexts. UV radiation can trigger a combined process of NETosis and apoptosis, known as apoNETosis, driven by mitochondrial ROS and DNA repair. Similarly, in calcium ionophore-induced NETosis, both ROS and DNA repair are key components, but only play a partial role. In the case of bacterial infections, the early stages of DNA repair are pivotal. Interestingly, in serum-free conditions, spontaneous NETosis occurs through NOX-derived ROS, with early-stage DNA repair inhibition halting the process, while late-stage inhibition increases it. The intricate balance between DNA repair processes and ROS production appears to be a critical factor in regulating NET formation, with different pathways being activated depending on the nature of the stimulus. These findings not only deepen our understanding of the mechanisms behind NETosis but also suggest potential therapeutic targets for conditions where NETs contribute to disease pathology. Full article
(This article belongs to the Section Cellular Biochemistry)
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