Search Results (96)

Pregnane X receptor (PXR) is an important nuclear receptor that regulates diverse physiological functions, including drug metabolism. Although PXR activation is potentially involved in adverse events, the full scope of its impact has yet to be elucidated. In this study, we developed a machine learning model to predict the activity of PXR agonists and applied the model to drugs listed in the US Food and Drug Administration Adverse Event Reporting System database. Analysis of the predicted agonist–active drug interactions and adverse event reports revealed statistically significant risks (lnROR > 1 and −logp > 1.3) for multiple cardiac disorders. These findings suggest that PXR activity is involved in cardiovascular adverse effects and may contribute to drug safety through the early identification of risks. Full article

Transcription factors (TFs) are proteins that control gene expression by binding to specific DNA sequences and are essential for cell development, differentiation, and homeostasis. Dysregulation of TFs is implicated in numerous diseases, including cancer, autoimmune disorders, and neurodegeneration. While TFs were traditionally considered “undruggable” due to their lack of well-defined binding pockets, recent advances have made it possible to modulate their activity using diverse pharmacological strategies. Major TF families include NF-κB, p53, STATs, HIF-1α, AP-1, Nrf2, and nuclear hormone receptors, which take part in the regulation of inflammation, tumor suppression, cytokine signaling, hypoxia and stress response, oxidative stress, and hormonal response, respectively. TFs can perform multiple functions, participating in the regulation of opposing processes depending on the context. NF-κB, for instance, plays dual roles in immunity and cancer, and is targeted by proteasome and IKKβ inhibitors. p53, often mutated in cancer, is reactivated using MDM2 antagonist Nutlin-3, refunctionalizing compound APR-246, or stapled peptides. HIF-1α, which regulates hypoxic responses and angiogenesis, is inhibited by agents like acriflavine or stabilized in anemia therapies by HIF-PHD inhibitor roxadustat. STATs, especially STAT3 and STAT5, are oncogenic and targeted via JAK inhibitors or novel PROTAC degraders, for instance SD-36. AP-1, implicated in cancer and arthritis, can be inhibited by T-5224 or kinase inhibitors JNK and p38 MAPK. Nrf2, a key antioxidant regulator, can be activated by agents like DMF or inhibited in chemoresistant tumors. Pharmacological strategies include direct inhibitors, activators, PROTACs, molecular glues, and epigenetic modulators. Challenges remain, including the structural inaccessibility of TFs, functional redundancy, off-target effects, and delivery barriers. Despite these challenges, transcription factor modulation is emerging as a viable and promising therapeutic approach, with ongoing research focusing on specificity, safety, and efficient delivery methods to realize its full clinical potential. Full article

Background: Malaria remains a significant global health burden, particularly in sub-Saharan Africa, accounting for high rates of illness and death. The growing resistance to frontline antimalarial therapies underscores the urgent need for novel drug targets and therapeutics. Bromodomain-containing proteins, which regulate gene expression through chromatin remodeling, have gained attention as potential targets. Plasmodium falciparum bromodomain protein 1 (PfBDP1), a 55 kDa nuclear protein, plays a key role in recognizing acetylated lysine residues and facilitating transcription during parasite development. Methods: This study investigated ex vivo PfBDP1 gene mutations and identified potential small molecule inhibitors using computational approaches. Malaria-positive blood samples were collected. Genomic DNA was extracted, assessed for quality, and amplified using PfBDP1-specific primers. DNA sequencing and alignment were performed to determine single-nucleotide polymorphism (SNP). Structural modeling used the PfBDP1 crystal structure (PDB ID: 7M97), and active site identification was conducted using CASTp 3.0. Virtual screening and pharmacophore modeling were performed using Pharmit and AutoDock Vina, followed by ADME/toxicity evaluations with SwissADME, OSIRIS, and Discovery Studio. GROMACS was used for 100 ns molecular dynamics simulations. Results: The malaria prevalence rate stood at 12.24%, and the sample size was 165. Sequencing results revealed conserved PfBDP1 gene sequences compared to the 3D7 reference strain. Virtual screening identified nine lead compounds with binding affinities ranging from −9.8 to −10.7 kcal/mol. Of these, CHEMBL2216838 had a binding affinity of −9.9 kcal/mol, with post-screening predictions of favorable drug-likeness (8.60), a high drug score (0.78), superior pharmacokinetics, and a low toxicity profile compared to chloroquine. Molecular dynamics simulations confirmed its stable interaction within the PfBDP1 active site. Conclusions: Overall, this study makes a significant contribution to the ongoing search for novel antimalarial drug targets by providing both molecular and computational evidence for PfBDP1 as a promising therapeutic target. The prediction of CHEMBL2216838 as a lead compound with favorable binding affinity, drug-likeness, and safety profile, surpassing those of existing drugs like chloroquine, sets the stage for preclinical validation and further structure-based drug design efforts. These findings are supported by prior experimental evidence showing significant parasite inhibition and gene suppression capability of predicted hits. Full article

Gallium-68 (⁶⁸Ga) radiopharmaceuticals are increasingly used in nuclear medicine due to their rapid production capabilities and exceptional specificity in molecular imaging applications. Several of these tracers have demonstrated remarkable clinical efficacy across various oncological conditions, including prostate cancer, neuro-endocrine tumours, and cancers expressing fibroblast activation protein. Commercial kits allow the use of the standardised production protocol, but extemporaneous preparations are the economic and flexible alternatives, particularly within hospital-based radiopharmacy settings. However, such preparations need meticulous conformity to quality control measures and regulation to ensure safety and effectiveness. This review provides an analysis of current methodologies employed in ⁶⁸Ga extemporaneous preparations and examines pertinent regulatory frameworks. Further clinical validation trials and technical advancement remain essential to facilitate the routine clinical practice’s widespread usage and long-term feasibility of such preparations. Full article

Ferulic acid (FA), a hydroxycinnamic acid derivative, is a key bioactive component in traditional medicinal plants including Angelica sinensis and Asafoetida. Accumulating evidence supports its therapeutic efficacy in inflammatory disorders, such as rheumatoid arthritis (RA) and ulcerative colitis (UC). FA exerts anti-inflammatory effects through (1) the regulation of inflammatory cytokine levels; (2) modulation of signaling pathways such as nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and janus kinase/signal transducer and activator of transcription (JAK/STAT); (3) amelioration of oxidative stress; and (4) regulation of immune cell homeostasis. At the pharmacokinetic level, studies show that FA is rapidly absorbed but exhibits low bioavailability, mainly due to the influence of metabolic pathways and food matrix characteristics. This review systematically summarizes the literature on the anti-inflammatory effects of FA, covering molecular mechanisms, pharmacokinetic characteristics, and application scenarios. Preclinical studies show that FA has low toxicity and good safety, demonstrating potential for development as a novel anti-inflammatory drug. However, its clinical translation is hindered by bottlenecks such as low bioavailability and insufficient human clinical data. Future research should prioritize developing novel drug delivery systems and conducting large-scale clinical trials to facilitate its clinical translation. Full article

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by persistent inflammation and progressive joint destruction. Recent data underscore oxidative stress as a primary factor in the pathophysiology of rheumatoid arthritis, intensifying inflammatory processes and tissue damage via the overproduction of reactive oxygen species (ROS) and compromised antioxidant defenses. Current therapies, including disease-modifying antirheumatic drugs (DMARDs), primarily target immune dysregulation but fail to address oxidative stress, necessitating novel adjunctive treatment strategies. This review explores the potential of antioxidant-based therapies as complementary approaches to RA management. Natural compounds such as curcumin, resveratrol, sulforaphane, and propolis exhibit strong anti-inflammatory and antioxidative properties by modulating redox-sensitive pathways, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and nuclear factor erythroid 2-related factor 2(Nrf2)/heme oxygenase (HO-1). N-acetylcysteine (NAC) replenishes intracellular glutathione, enhancing cellular resilience against oxidative stress. Additionally, molecular hydrogen (H₂) selectively neutralizes harmful ROS, reducing oxidative damage and inflammation. The role of vitamin supplementation (D, B12, C, and K) in regulating immune responses and protecting joint structures is also discussed. This review aims to evaluate the efficacy and potential clinical applications of antioxidant therapies in RA, emphasizing their role in mitigating oxidative damage and improving treatment outcomes. While preliminary findings are promising, further clinical trials are needed to establish standardized dosing, long-term safety, and their integration into current RA treatment protocols. Full article

Epigenetic modulation plays a crucial role in neuroprotection by regulating cellular responses to stress, inflammation, and oxidative damage, particularly in neurodegenerative diseases. Recognizing the therapeutic potential of epigenetic regulators, this study investigated the synergistic neuroprotective effects of curcumin-enriched turmeric extract combined with L-ascorbic acid, focusing on its modulation of epigenetic pathways in oxidative stress-induced neuronal damage. SH-SY5Y neuronal cells were treated with the combination at 20 and 40 µg/mL, and subsequently exposed to 200 µM hydrogen peroxide (H₂O₂) to induce oxidative stress. Cell viability was assessed using the MTT assay, while neuroprotective mechanisms were evaluated by analyzing the markers of epigenetic modulation, oxidative stress, inflammation, and apoptosis. The combination significantly enhanced cell viability, upregulated sirtuin-1 (SIRT1), and reduced DNA methyltransferase 1 (DNMT1) expression, indicating effective epigenetic modulation. Enhanced antioxidant defenses were observed, as evidenced by increased activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), along with decreased malondialdehyde (MDA) and reactive oxygen species (ROS) levels, alleviating oxidative stress. Additionally, it suppressed nuclear factor kappa B (NF-κB) activity and its downstream mediator interleukin-6 (IL-6), thereby mitigating inflammation. The treatment also increased anti-apoptotic Bcl-2 expression while reducing pro-apoptotic markers, including caspase-3 and caspase-9, suggesting inhibition of the intrinsic apoptotic pathway. These findings highlight the novel neuroprotective effects of this combination, demonstrating its ability to modulate epigenetic pathways while reducing oxidative stress, suppressing inflammation, and preventing undesired apoptosis. Its multifaceted neuroprotective properties make it a promising functional ingredient in functional foods for neurodegenerative disease intervention. However, further investigations, including animal studies and clinical trials, are essential to evaluate its safety and therapeutic potential. Full article

Morinda citrifolia L. (M. citrifolia), commonly referred to as noni, a Polynesian medicinal plant with over 2000 years of traditional use, has garnered global interest for its rich repertoire of antioxidant phytochemicals, including flavonoids (kaempferol, rutin), iridoids (aucubin, asperulosidic acid, deacetylasperulosidic acid, asperuloside), polysaccharides (nonioside A), and coumarins (scopoletin). This comprehensive review synthesizes recent advances (2018–2023) on noni’s bioactive constituents, pharmacological properties, and molecular mechanisms, with a focus on its antioxidant potential. Systematic analyses reveal that noni-derived compounds exhibit potent free radical scavenging capacity (e.g., 2,2-Diphenyl-1-picrylhydrazyl/2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonicacid) (DPPH/ABTS) inhibition), upregulate endogenous antioxidant enzymes (Superoxide Dismutase (SOD), Catalase (CAT), Glutathione Peroxidase (GPx)), and modulate key pathways such as Nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (Nrf2/Keap1) and Nuclear Factor kappa-B (NF-κB). Notably, polysaccharides and iridoids demonstrate dual antioxidant and anti-inflammatory effects via gut microbiota regulation. This highlights the plant’s potential for innovation in the medical and pharmaceutical fields. However, it is also recognized that further research is needed to clarify its mechanisms of action and ensure its safety for widespread application. We emphasize the need for mechanistic studies to bridge traditional knowledge with modern applications, particularly in developing antioxidant-rich nutraceuticals and sustainable livestock feed additives. This review underscores noni’s role as a multi-target antioxidant agent and provides a roadmap for future research to optimize its health benefits. Full article

Plant secondary metabolites are known to be valuable agents to hamper inflammation owing to their multiple mechanisms of action. This study investigates the molecular mechanisms underlying the anti-inflammatory effects of vicenin-2 in lipopolysaccharide (LPS)-stressed THP-1 cells. After ascertaining the safety of vicenin-2 in our in vitro model, we assessed the anti-inflammatory potential of this flavonoid. Indeed, it counteracted the increase of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 levels, as well as the overexpression of both inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 caused by the exposure of THP-1 cells to LPS. Acknowledged the role of SIRT1 in the inflammatory process, we focused our attention on this enzyme. Our results showed that LPS dramatically decreased the expression of SIRT1, whereas vicenin-2 restored the levels of this enzyme to those of unexposed cells. These effects were also observed in terms of acetylated p53, a SIRT1 substrate. Notably, we observed that vicenin-2 did not act as a direct activator of SIRT1. Therefore, we investigated the potential involvement of AMP-activated protein kinase (AMPK), an upstream activator of SIRT1. Of note, by blocking AMPK by dorsomorphin, the protective effects of vicenin-2 on SIRT1 expression and activity were lost, suggesting the engagement of this kinase. Consequently, the blockage of AMPK caused a downstream loss of the anti-inflammatory effect of vicenin-2, which was no longer able to decrease both the activation of nuclear factor (NF)-κB and the production of cytokines induced by LPS. Finally, docking simulation suggested that vicenin-2 might act as an activator of Ca²⁺/calmodulin-dependent protein kinase kinase β (CaMKKβ), one of the regulators of AMPK. Overall, our results suggest that the anti-inflammatory effects of vicenin-2 may be due to the interaction with the CaMKKβ-AMPK-SIRT1 axis. Full article

At present, the operation control modes of pressurized water reactor (PWR) nuclear power plants in service mainly include Mode-A, Mode-G, and MSHIM. Mode-A is mainly applicable to base load operation and cannot realize load tracking. In the process of Mode-G load tracking, it is necessary to adjust boron, and it cannot realize load tracking without boron regulation. Although MSHIM implements unregulated boron load tracking, a large number of control rods are inserted into the core during base load operation, which reduces the safety margin and causes certain economic losses. In recent years, China National Nuclear Corporation Limited proposed the Mode-C operation control mode, which attempts to concentrate the advantages of the above operation mode and avoid its disadvantages. When Mode-C is adopted, only one set of control rods is inserted into the reactor core to complete the nuclear power plant control task for the base load and other operations that do not require frequent reactor power regulation. For load tracking and other operations requiring frequent reactor power regulation, control rods are used instead of adjusting soluble boron to control core reactivity. Reactivity compensation and power distribution control in the load-tracking process are completed through control rods. When Mode-C mode is adopted, the reactivity control method under base load and load tracking conditions is different from other mature operating modes. It is impossible to directly adopt the ready-made reactor power control system scheme, which brings challenges to the practical engineering application of Mode-C. To solve the above problems, based on the idea of single-variable automatic control and bivariable automatic control in Mode-C under different load demand conditions, this paper carries out research on the strategy of the reactor power control system and puts forward two specific control schemes. Through the control simulation program based on the one-dimensional core model, the simulation model of the control object and control system is established, and the closed-loop simulation verification of the control strategy is completed. The simulation results show that the designed reactor power control system can realize automatic control of the full power operating range and non-adjustable boron load tracking, reduce the operator’s burden, and meet the expected operation effect of the Mode-C operating mode. Full article

Radon exposure is a major health concern associated with an increased risk of lung cancer, particularly in smokers, highlighting the need for effective mitigation measures in enclosed spaces by improving indoor air quality (IAQ), thus ensuring more sustainable buildings. The Euratom Directive, a key piece of EU legislation, sets standards for the protection of workers and the general public from ionizing radiation throughout Europe. It requires member states to implement safety measures, set exposure limits, monitor radon levels, and develop emergency plans and mitigation strategies for nuclear accidents and radiation incidents. The directive also sets reference and action levels for indoor radon. The aim of this article is to analyze the legislation on indoor radon exposure in European countries and to evaluate the impact of the directive on the standardization of the action and intervention levels. By conducting a comprehensive legislative review, this study will compare the action levels, assess the directive’s ability to harmonize the regulations, and identify legislative trends and developments. In addition, it will examine the factors contributing to the discrepancies between countries and highlight areas for improvement to ensure adequate protection against the risks of radon exposure and thereby increase the sustainability of buildings. Full article

The Spent Fuel Pool (SFP) is part of the fuel handling and storage system and is generally arranged in an independent building on the Nuclear Island (NI) of Nuclear Power Plants (NPPs). According to the HAF102—Safety Regulations for Nuclear Power Plants Design, it is necessary to ensure the smooth implementation of the safety functions of the SFP under various operating conditions. If the SFP is arranged inside containment, its protection requirements for external events will be significantly reduced, but new requirements will be raised for accident response measures inside containment, namely, that the system performs safety functions to ensure the long-term cooling of both the reactor core and spent fuel components. The reactor type that employs passive principles to realize the above functions requires a reasonable design of the layout of the Passive Safety System (PSS) to ensure nuclear safety. Based on existing reactor schemes, this article analyzes the design of a full-range passive concept for these reactors with an SFP built-in containment. The main focus of this article is on the long-term natural circulation process of PSS in containment under conditions of hypothetical accidents, and the arrangement of system items. Conceptual plans for the operation and layout of the safety system are obtained, which can provide references for the research and design of NPPs with SFP built-in containment. Full article

(6S,9R)-vomifoliol (VO) is a natural norisoprenoid of the megastigmane type derived from Gaultheria procumbens, an aromatic, evergreen shrub whose leaves, fruits, and aerial parts are used in traditional phytotherapy to treat oxidative stress and inflammation-related disorders. The plant is known as a rich source of essential oil and polyphenols. However, the levels of other constituents of G. procumbens, including VO, have yet to be explored. There is also a knowledge gap in the pharmacological potential of VO in the context of inflammation. Therefore, the present study aimed to investigate the accumulation of VO in leaves, stems, and fruits of G. procumbens and to determine its antioxidant and anti-inflammatory effects in non-cellular in vitro and cell-based models of human immune cells ex vivo. The GC-FID-MS (gas chromatography coupled with flame ionisation detector and mass spectrometer) analysis revealed the leaves as the richest source of VO (0.36 mg/g dw of the plant material) compared to other G. procumbens organs. In non-cellular activity tests, VO showed comparable to positive control anti-inflammatory activity against lipoxygenase, with significantly weaker impact on hyaluronidase and cyclooxygenase-2, and no effect on cyclooxygenase-1 isozyme. VO at 5–75 μM revealed a significant and dose-dependent ability to reduce the reactive oxygen species (ROS) level, downregulate the release of pro-inflammatory cytokines [tumour necrosis factor-α (TNF-α), interleukin-8 (IL-8), IL-6, and IL-1β] and tissue-remodelling enzymes (elastase-2, metalloproteinase-9), and up-regulate the secretion of anti-inflammatory cytokine IL-10 in bacterial lipopolysaccharide (LPS)- and N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP)-stimulated human neutrophils and peripheral blood mononuclear cells (PBMCs) ex vivo. Furthermore, a significant reduction in IL-6, lipoxygenase (LOX), nuclear factor κ-light-chain-enhancer of activated B cells 1 (NF-κB1), and NF-κB2 gene expression in LPS-stimulated peripheral blood lymphocytes was demonstrated by real-time PCR. The cellular safety of VO at 5–75 μM was confirmed by flow cytometry, with the viability of neutrophils and PBMCs after incubation with VO at 93.8–98.4%. The results encourage further studies of VO as a promising non-cytotoxic natural anti-inflammatory agent and support the use of leaves of G. procumbens in the adjuvant treatment of oxidative stress and inflammation-related diseases of affluence. Full article

With the development of modernization, traditional fossil energy reserves are decreasing, and the power industry, as one of the main energy consumption forces, has begun to pay attention to increasing the proportion of clean energy generation. With the deepening of electrification, the peak-valley difference of residential electricity consumption increases, but photovoltaic and wind power generation have fluctuations and are manifested as reverse peak regulation. Thermal power plants as the main force of peak regulation gradually reduce the market share, making nuclear power plants bear the heavy responsibility of participating in peak regulation. The traditional method of adjusting operating power by inserting and removing control rods has great safety risks and wastes resources. Therefore, this paper proposes a new energy storage system that can keep the nuclear power plant running at full power and produce hydrogen to synthesize ammonia from excess power. A comprehensive evaluation model of energy storage based on z-score data standardization and objective parameter assignment AHP (analytic hierarchy process) analysis method was established to evaluate energy storage systems according to a multi-index system. With an AP1000 daily load tracking curve as the input model, the simulation model built by Aspen Plus V14 was used to calculate the operating conditions of the system. In order to provide a construction basis for practical engineering use, Haiyang Nuclear Power Plant in Shandong Province is taken as an example. The system layout scheme is proposed according to the local environmental conditions. The accident tree analysis method is combined with ALOHA 5.4.1.2 (Areal Locations of Hazardous Atmospheres) hazardous chemical analysis software and MARPLOT 5.1.1 geographic information technology. A qualitative and quantitative assessment of risk factors and the consequences of leakage, fire, and explosion accidents caused by hydrogen and ammonia storage processes is carried out to provide guidance for accident prevention and emergency rescue. The design of an “Electric-Hydrogen-Ammonia” energy storage system proposed in this paper provides a new idea for zero-carbon energy storage for the peak shaving of nuclear power plants and has a certain role in promoting the development of clean energy. Full article

Nuclear power plants (NPPs) rely on critical, complex systems that require continuous monitoring to ensure safe operation under both normal and abnormal conditions. Despite the potential of artificial intelligence (AI) to enhance predictive capabilities in these systems, limited research has been conducted on the application of AI algorithms within NPPs. This presents a knowledge gap in the integration of AI for improving safety, reliability, and decision making in NPP. In this study, we explore the use of AI methods, including machine learning and real-time data analytics, applied to NPP components to address the nonlinearity and dynamic behavior inherent in reactor operations. Through the implementation of AI and Internet of Things (IoT) devices, we propose a system that enables early warning and real-time data transmission to regulatory authorities and decision-makers, ensuring better coordination during incidents. Lessons from past nuclear accidents, such as Chernobyl, emphasize the importance of timely information dissemination to mitigate risks. However, this integration also presents challenges, including cybersecurity risks and the need for updated regulations to address AI use in safety-critical environments. The results of this study highlight the urgent need for further research on the application of AI in NPPs, with a particular focus on addressing these challenges to ensure safe implementation. Full article