Impact Of Regulation Research Articles

Holothuria polii Extract as a Potential Anticoccidial Agent: Evidence of Its MUC2 Regulatory Impact in Murine Jejunum.

Eimeria is a parasite that causes coccidiosis in a variety of animals, leading to nutritional imbalances, issues with food digestion and absorption, low weight, and intestinal inflammation of varying degrees in its hosts. Anticoccidial medication resistance has become a significant obstacle to disease control efforts, leading to a renewed focus on discovering novel chemicals for alternative therapeutic approaches. The purpose of this study was to determine the efficacy of Holothuria polii extract (HpE) in treating eimeriosis in mice. Five groups of mice were studied, with E. papillata sporulated oocysts (1 × 103) used to infect three groups experimentally. The first group was treated with 200 mg/kg of HpE, the second group with Amprolium (120 mg/kg), and the third group was left untreated as a control. The fourth and fifth groups were uninfected, with one of them treated with 200 mg/kg of HpE and the other used as a negative control. The results revealed that HpE has 10 phytochemical compounds according to GC-MS analysis. Treatment with HpE resulted in a substantial decrease in oocyst output in feces. Also, the parasitic stages showed morphometric alterations, with reductions in the measurements compared with the infected, untreated mice. Moreover, expression of the mucin gene (MUC2) was higher in treated mice compared to infected ones, with significant increases in goblet cell numbers, which provided additional evidence for the activity of HpE as an anticoccidial product. In conclusion, there are a wide variety of natural products and many have been employed in folk medicine for treating a range of parasitic diseases.

Regulatory impact of a governmental approach for artificial intelligence technology implementation in Vietnam

This study assesses Vietnam’s state-level implementation of artificial intelligence (AI) technology and analyses the government’s efforts to encourage AI implementation by focusing on the National Strategy on AI Development Program. This study emphasizes the possibility of implementing AI at the state level in Vietnam and the importance of conducting continuous reviews and enhancements to achieve sustainable and inclusive AI growth. Impact evaluations were conducted in public organizations alone, and implication evaluations were considered optional. AI impact assessments were constrained by societal norms that necessitated establishing relationships among findings. There is a lack of official information regarding the positive impact of Vietnam’s AI policy on the development of AI infrastructure, research, and talent pools. The study’s findings highlight the necessity of facilitating extensive AI legislation, and strengthening international cooperation. The study concludes with the following recommendations for improving Vietnam’s AI policy: implementing a strong AI governance structure and supporting AI education and awareness.

Caspase-8 in inflammatory diseases: a potential therapeutic target.

Caspase-8, a renowned cysteine-aspartic protease within its enzyme family, initially garnered attention for its regulatory role in extrinsic apoptosis. With advancing research, a growing body of evidence has substantiated its involvement in other cell death processes, such as pyroptosis and necroptosis, as well as its modulatory effects on inflammasomes and proinflammatory cytokines. PANoptosis, an emerging concept of cell death, encompasses pyroptosis, apoptosis, and necroptosis, providing insight into the often overlapping cellular mortality observed during disease progression. The activation or deficiency of caspase-8 enzymatic activity is closely linked to PANoptosis, positioning caspase-8 as a key regulator of cell survival or death across various physiological and pathological processes. Aberrant expression of caspase-8 is closely associated with the development and progression of a range of inflammatory diseases, including immune system disorders, neurodegenerative diseases (NDDs), sepsis, and cancer. This paper delves into the regulatory role and impact of caspase-8 in these conditions, aiming to elucidate potential therapeutic strategies for the future intervention.

Методический подход к согласованию стратегических приоритетов государственной региональной политики развития старопромышленных регионов Российской Федерации

The formation of strategic priorities of the state regional policy for the development of old-industrial regions is complicated by the multiplicity of its actors and the need to coordinate spatial and sectoral priorities of regulatory impact. The article presents a methodological approach to coordinating the priorities of spatial and sectoral development of old industrial regions in the format of a scheme reflecting the logic and sequence of actions aimed at achieving strategic goals of regional development in accordance with the strategic national priorities of the Russian Federation. The methodological approach was tested on the example of the Saratov region, one of the old industrial regions of Russia with growth potential within the framework of the industrial development model. The necessity of using two approaches in the coordination process is justified: the first should be used to achieve the strategic priorities of the federal Center in a coordinated manner, on the one hand, and the old industrial regions and enterprises and organizations of the "industrial core", on the other (coordination "vertically"); the second — in order to coordinate the regional priorities of spatial and sectoral development of the old industrial region (horizontal alignment). Proposals are presented for the formation of a list of agreed priorities for the spatial and sectoral development of the Saratov region, the implementation of which will contribute to the transformation of the region into a point of growth of the national economy of Russia.

Harmony and Tensions Between Desa Adat and The Bali Provincial Government: Exploring Implications of Regulation on Customary Village of 2019

The Bali Provincial Government collaborates with desa adat (customary village) to enhance their strength and resilience, notably through the enactment of Province of Bali Regulation Number 4 of 2019. However, excessive regulatory impact may diverge from this goal. This study explores the ideological framework shaping interactions between desa adat and the government post-regulation. Using a qualitative methodology, data were collected through literature review, observations, and in-depth interviews. The findings draw on theories of hegemony, ideology, discourse, and the power of knowledge. Hidden ideologies of power, capital, and religion influence these interactions. The regulation's uniform framework on diverse desa adat leads to resistance and inefficiency, reflecting hegemonic control and the use of ideology and knowledge to legitimize power. This article contributes to developing legislation that empowers the desa adat while maintaining their unique characteristics.

Assessing cap-and-trade regulation's impact on dual-channel green supply chains under disruption

The rise of online shopping has intensified focus on the dual-channel supply chain, highlighting the need to balance profitability and eco-friendliness under competition and disruptions. This study investigates how cap-and-trade regulations affect the performance of a dual-channel green supply chain amidst disruptions. It explores the interplay between pricing and greening strategies under cap-and-trade conditions and varying market demand disruptions. The model features a Stackelberg game between a manufacturer of eco-friendly products and a retailer, applied to both centralized and decentralized systems. Findings reveal that cap-and-trade regulations affect centralized and decentralized supply chains differently. Centralized systems show higher sensitivity in greenness levels to disruptions compared to decentralized ones. Lower greening cost coefficients lead to higher greenness levels in both models, but centralized systems outperform decentralized ones when cap-and-trade regulations are absent. However, the performance of centralized systems deteriorates significantly during severe disruptions, whereas decentralized systems maintain profitability growth. Additionally, the study finds that increased greening costs reduce the optimal greenness level, impacting wholesale and sale prices. Centralized supply chains exhibit greater variability in carbon emissions and profits under disruption conditions, while decentralized systems show more stability and higher profitability, particularly in severe disruptions. The findings also indicate that a dynamic cap-and-trade system can enhance adaptability and efficiency in managing emissions during disruptions.

BPIFA1 alleviates allergic rhinitis by regulating the NF-κB signaling pathway and Treg/Th17 balance.

Allergic rhinitis (AR) is an allergic condition characterized by inflammation of the nasal mucosa. Bacterial permeability-increasing family member A1 (BPIFA1) exhibits anti-inflammatory properties; however, its impact on AR remains unclear. Aim of this study is to investigate the expression and function of BPIFA1 in AR and its influence on inflammation and immune regulation in a mouse model of AR induced by ovalbumin (OVA). The expression of BPIFA1 was analyzed using quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC). Morphological assessments of nasal mucosal tissues were conducted. Levels of inflammatory mediators in nasal lavage fluid (NALF) and serum were quantified using enzyme-linked immunosorbent assay (ELISA) kits. Protein expressions of BPIFA1, phosphorylated and total p65 (p-p65/p65), and IκBα were evaluated through Western blot analysis. The total cell counts, including epithelial cells, eosinophils, and lymphocytes in NALF, were determined using a hemocytometer. A mouse model of AR was established by OVA management. BPIFA1 expression was found to be reduced in the nasal mucosa tissues of patients with AR, suggesting a potential role in the disease's progression. We successfully developed a mouse model of AR, where BPIFA1 was similarly downregulated, indicating its possible involvement in modulating the NF-κB signaling pathway. Overexpression of BPIFA1 in this model attenuated inflammation and allergic responses by inhibiting the NF-κB pathway. Additionally, overexpression of BPIFA1 promoted the differentiation of regulatory T cells (Treg) and inhibited the differentiation of T helper 17 cells (Th17) in the NALF of AR mice, further demonstrating its regulatory impact on immune responses. The study confirmed that BPIFA1 upregulation reduced the levels of inflammatory cytokines TNF-α and IL-6, decreased infiltration of inflammatory cells, and modulated antigen-specific immunoglobulin levels and histamine in serum. BPIFA1 mitigated both inflammatory and allergic responses in AR mice induced by OVA through the modulation of the NF-κB signaling pathway and the balance between regulatory T cells (Treg) and T helper 17 cells (Th17). These findings suggest that BPIFA1 could serve as a novel biomarker and therapeutic target for AR, offering potential for the development of targeted treatments to improve patient outcomes.

An anti-money laundering authority for the European Union: a new center of gravity in AML enforcement

AbstractThe establishment of an Anti-Money Laundering Authority (AMLA) heralds a milestone in the European Union’s (EU) institutional framework for the enforcement of anti-money laundering and countering the financing of terrorism (AML/CFT) rules. This contribution explores the competence and powers of the new AML/CFT supervisor. While AMLA is a true enforcement actor with investigative and sanctioning powers to address breaches of AML/CFT requirements, the scope of AMLA’s enforcement powers will be limited. AMLA will nevertheless have an important regulatory impact and it will enhance the fight against cross-border financial crime by supporting the work of other bodies and agencies in the field.

SNPs in cytochromes P450 catalyzing cholesterol degradation in brain are associated with Parkinson's disease.

Besides being an essential structural component of plasma membranes and the precursor of many functional compounds and signaling molecules, cholesterol was also proposed to play a role in the etiology and/or manifestation of Parkinson's disease (PD). However, so far systematic investigations on the role of cholesterol and its metabolites present in the brain for the etiology of PD are missing. Here, we investigate for the first time the association of PD with SNPs in the genes of four cytochromes P450 (P450), CYP46A1, CYP39A1, CYP27A1 and CYP7B1, which are critical for the degradation of cholesterol in the brain. Analyzing 1,349 individuals from the PPMI data base, we found 24 SNPs in these four genes, which are significantly over- or under-represented in patients suffering from idiopathic PD (IPD). Studying each of the 362 IPD patients individually, we found that most patients (45%) showed only one associated SNP in one of the four P450 genes, while 31% displayed two associated SNPs and 18% three associated SNPs. The occurrence of some associated SNPs is in the same order of magnitude as SNPs in the GBA (beta-glucocerebrosidase) and thus might reflect a genetic predisposition for PD. As all 24 SNPs were located in introns and 3' untranslated regions, we evaluated the prospective regulatory impact of the surrounding genomic regions by using transcriptome and epigenome data from the Foundational Data Initiative for Parkinson Disease (FOUNDIN-PD). FOUNDIN-PD provides gene expression, open chromatin and DNA methylation data in a cohort of 89 induced pluripotent stem cell (iPSC) lines differentiated to dopaminergic (DA) neurons derived from people in the PPMI study. Indeed, two of the 24 SNPs, one in CYP7B1 (rs118111353) and the other one in CYP27A1 (rs74446825), were localized within a region of open chromatin in differentiated neurons. Interestingly, all iPSC lines with open chromatin in rs118111353 showed the reference allele. As all four P450, CYP46A1, CYP39A1, CYP27A1 and CYP7B1, are expressed in dopaminergic neurons, we discuss further functional studies to connect SNPs in regulatory regions with gene expression levels. Finally, potential possibilities for personalized therapeutic treatment of patients with SNPs in the four investigated P450 are discussed.

Identification of driving mechanisms of actual evapotranspiration in the Yiluo River Basin based on structural equation modeling

BackgroundActual evapotranspiration (ETa) is a crucial aspect of the hydrological cycle. It serves as a vital link between the soil–vegetation–atmosphere continuum. Quantifying the leading factors of regional ETa change and revealing the multi-factor compound driving mechanism of ETa evolution is necessary. Structural equation modeling (SEM) has been widely used to study the structural relationships between variables in large-scale areas. However, there is an urgent need for more in-depth exploration of these complex relationships at the grid scale. Therefore, the Yiluo River Basin, a representative area of soil and water conservation engineering demonstration in the Loess Plateau, was selected as the study area, and the SEM at the basin scale and grid-scale were constructed to carry out the research.ResultsThe data indicate that ETa decreased at 1.97 mm per year at the watershed scale from 1982 to 2020. Climate change had the greatest impact on the change of ETa in the watershed, with a total impact coefficient of over 0.9. The direct impact of climate change on ETa increased by 0.571 from 1982–1992 to 1993–2020. The direct impact coefficients of vegetation cover and soil moisture decreased by 0.402 and 0.102, respectively, while the impact coefficient of the water body factors increased by 0.096. At the scale of individual grid cells, the ETa in the watershed was affected by changes in watershed climate, vegetation, and soil moisture, with contributions ranging from − 0.31 to 0.22, − 1.09 to − 0.08, and 0.61 to 0.90, respectively. Spatially, vegetation and soil moisture had a stronger impact on ETa in the upstream area, while climate change had a negative effect, and the downstream region had the opposite effect. Furthermore, the regulatory impact of large reservoirs mitigated the response of water surface evaporation to climate change in the upstream region.ConclusionsThe application of SEM at different spatial and temporal scales has effectively quantified the driving mechanisms behind actual evapotranspiration in the Yiluo River Basin, while visually representing the spatial distribution characteristics of various influencing factors on ETa. This research provides a theoretical foundation for studying slope water consumption processes and circulation mechanisms.

A Systematic Scoping Review of the Collaborative Governance of Environmental and Cultural Flows

This study systematically reviews English-language papers about the collaborative governance of environmental and cultural flows. With mixed-methods analyses, we illustrate that the determination of environmental flow needs is common, with authors in 42 countries across 112 watersheds describing their management. In contrast, cultural flows (characterized by attention to both ecological and non-ecological needs, decision-making authority of Indigenous Nations, and Indigenous rights) were reported only in papers by authors in commonwealth, colonial countries: Australia, Canada, and New Zealand. Evaluated against the Organisation for Economic Co-operation and Development’s (OECD) Water Governance Principles, we found that the literature reported efforts that considered appropriate local and regional scales, information and data, regulatory frameworks, and capacity building of communities and authorities engaged in environmental and cultural flow initiatives. However, there was limited consideration of the roles of communities in policymaking, which was more common in jurisdictions with decentralized governance. In jurisdictions with democratic community-based initiatives, environmental and cultural flows have not been approached in merely technical processes to communicate hydro-social-ecological information to decision-makers. Instead, the initiatives have created the context for evaluating new developments at the watershed level in light of communities’ social and ecological water goals, collaborating during unique drought and flooding conditions, working to rebalance power in decision-making through water justice, creating ecological and Indigenous reserved water rights, granting legal personhood for rivers, and protecting water for the environment and dependent people in water markets. Going forward, we identify a need for greater attention to community roles in environmental and cultural flows protection in water governance including policy creation and evaluation, regulatory initiatives, strategic planning, and impact assessments.

Natural plant-derived polysaccharides targeting macrophage polarization: a promising strategy for cancer immunotherapy.

Tumor associated macrophages (TAMs) are the predominant innate immune cells in the tumor microenvironment (TME). Cytokines induce the differentiation of macrophages into distinct types of TAMs, primarily characterized by two phenotypes: M1-polarized and M2-polarized. Cancer growth is suppressed by M1-polarized macrophages and promoted by M2-polarized macrophages. The regulation of macrophage M1 polarization has emerged as a promising strategy for cancer immunotherapy. Polysaccharides are important bioactive substances found in numerous plants, manifesting a wide range of noteworthy biological actions, such as immunomodulation, anti-tumor effects, antioxidant capabilities, and antiviral functions. In recent years, there has been a significant increase in interest regarding the immunomodulatory and anti-tumor properties of polysaccharides derived from plants. The regulatory impact of polysaccharides on the immune system is mainly associated with the natural immune response, especially with the regulation of macrophages. This review provides a thorough analysis of the regulatory effects and mechanisms of plant polysaccharides on TAMs. Additionally, an analysis of potential opportunities for clinical translation of plant polysaccharides as immune adjuvants is presented. These insights have greatly advanced the research of plant polysaccharides for immunotherapy in tumor-related applications.

Three transposable elements exhibiting differential expression in pre-eclampsia overlap with enhancer regions

Transposable elements (TEs) play a crucial role in placental development and dysfunction. Our study examined TE expression in pre-eclampsia (PE) using RNA-seq datasets. We identified differentially expressed TEs and explored the genomic location of the most significant TEs, investigating their possible regulatory roles. Notably, three TEs overlapped with putative enhancer regions, suggesting a potential regulatory impact on gene expression. These findings highlight the regulatory potential of TEs and their importance in placental development, supporting that TE dysregulation may contribute to PE pathogenesis.

Discovering the Power of External Human-Machine Interface: An EEG Study on the Driving Anger Regulation

Driving with anger can result in hazardous driving behaviors, often arising from inadequate communication among Traffic Participants (TPs). Currently, external Human-Machine Interface (eHMI) technology provides a novel channel for enhancing communication among TPs, yet its role in regulating driving emotions remains uncertain. This study investigates the impact of eHMI technology on the regulation of driving anger. We simulated a driving scenario in which the preceding vehicle abruptly applied brakes to elicit anger from the following driver. Three eHMI formats (Symbol, Text, and Symbol + Text) positioned at the rear of the preceding vehicle were implemented to explain the sudden braking event and regulate drivers’ emotions. Objective electroencephalogram (EEG) signals and subjective assessment data were analyzed to assess the effects of eHMIs on driving anger regulation. The results indicate that driving with eHMIs exhibited significant regulatory quality of drivers’ anger. Among the three formats, Symbol + Text eHMI exerted a notable regulatory impact, while both Symbol and Text eHMI contributed to emotional regulation. This study illustrates the positive impact of eHMI on emotion regulation in traffic environments, providing valuable backing for traffic management authorities in developing guidelines and policies, and contributing to the standardization of future eHMI technologies.

The Protective Role of Interleukin-37 in Cardiovascular Diseases through Ferroptosis Modulation.

The role of ferroptosis and iron metabolism dysregulation in the pathophysiology of cardiovascular diseases is increasingly recognized. Conditions such as hypertension, cardiomyopathy, atherosclerosis, myocardial ischemia/reperfusion injury, heart failure, and cardiovascular complications associated with COVID-19 have been linked to these processes. Inflammation is central to these conditions, prompting exploration into the inflammatory and immunoregulatory molecular pathways that mediate ferroptosis and its contribution to cardiovascular disease progression. Notably, emerging evidence highlights interleukin-37 as a protective cytokine with the ability to activate the nuclear factor erythroid 2-related factor 2 pathway, inhibit macrophage ferroptosis, and attenuate atherosclerosis progression in murine models. However, a comprehensive review focusing on interleukin-37 and its protective role against ferroptosis in CVD is currently lacking. This review aims to fill this gap by summarizing existing knowledge on interleukin-37, including its regulatory functions and impact on ferroptosis in conditions such as atherosclerosis and myocardial infarction. We also explore experimental strategies and propose that targeting interleukin-37 to modulate ferroptosis presents a promising therapeutic approach for the prevention and treatment of cardiovascular diseases.

Scientific and Technological Innovation Effects on High-Quality Agricultural Development: Spatial Boundaries and Mechanisms

This study investigates the spatial boundaries and mechanisms of the effect of scientific and technological innovation (STI) on high-quality agricultural development (HQA) to enhance agricultural practices. By employing a double-fixed spatial Durbin model and analyzing panel data from 167 prefectural-level cities in major grain-producing regions spanning from 2004 to 2021, we revealed significant spatiotemporal variations in the impact of STI on HQA in both local and adjacent cities. Our findings remained robust after rigorous testing. The study identified the spillover range of STI to be 420 km, displaying a distinctive inverted U-shaped trend around 170 km. Mechanism analysis indicates that both agricultural industry upgrades and human capital levels within 420 km amplify the influence of STI on local HQA, with only the latter demonstrating spillover effects. Within 170 km, both factors effectively regulate HQA in adjacent cities, while beyond this distance, only human capital regulatory impact continues to exhibit spillover effects. These insights offer theoretical guidance for designing effective agricultural scientific and technology promotion policies aimed at elevating the quality of HQA.

Scoping Review on the Use of Music for Emotion Regulation.

With increasing interest in the emotional responses to music, some studies are specifically looking into music's regulatory function on emotion, known as "music emotion regulation (MER)". The purpose of this study was to examine the concepts on the regulatory impact of music on emotion using a scoping review procedure. Through an electronic database and manual searches based on the guidelines suggested by the JBI Manual for Evidence Synthesis, a total of 47 studies were identified and included for analysis. The results showed that there were some definitional challenges in each component of music emotion regulation. Most studies treated music as a single variable without exploring the regulatory mechanism of the intra-musical elements that constitute music. When examining the regulatory impact of music on emotion, emotion was inclusive of other terms ranging from feeling to mood. Most of the MER studies employed the terms used in the emotion regulation strategies; however, there were some regulatory processes that pertained solely to music's cathartic effect. Overall, the results showed that music emotion regulation (MER) was not clearly distinguished from music emotion (ME) studies. Future research should allocate more attention to the theoretical mechanism behind music's intrinsic regulatory effect in emotion regulation (MER) studies.

CircJPH1 regulates the NF-κB/HERC5 axis to promote the malignant progression of esophageal squamous cell carcinoma through binding to XRCC6

Esophageal squamous cell carcinoma (ESCC) is a prevalent and malignant cancer with an unknown pathogenesis and a poor prognosis; therefore, the identification of effective biomarkers and targets is crucial for its diagnosis and treatment. Circular (circ)RNAs are prominent functional biomarkers and therapeutic targets in various diseases, particularly cancer, due to their widespread expression and regulatory mechanisms. Our study aimed to investigate the therapeutic potential of circRNA for ESCC. We identified Hsa_circ_0137111 for the first time as one of the most significantly up-regulated genes in ESCC sequencing and named it circJPH1. The results of the present study demonstrated an enhanced expression of circJPH1 in ESCC tissues. Moreover, circJPH1-knockdown could significantly inhibit the proliferation, migration, and invasion of ESCC cells, while its overexpression promoted these characteristics. In addition, circJPH1 promoted ESCC cell tumor growth in vivo. For the first time, mass spectrometry and RNA pull-down analysis revealed the interaction of X-ray repair cross-complementary 6 (XRCC6) protein with circJPH1, thereby promoting its nuclear translocation. Consequently, the nuclear factor kappa-B (NF-κB) signaling pathway was activated, leading to an up-regulation of HECT and RLD domain containing E3 ubiquitin protein ligase 5 (HERC5), thereby promoting ESCC progression. In summary, the present study elucidated the regulatory impact of circJPH1 on ESCC progression in vitro and in vivo, thereby indicating its potential role in ESCC treatment.

Paeoniflorin inhibited GSDMD to alleviate ANIT-induced cholestasis via pyroptosis signaling pathway

BackgroundCholestasis (CT) is a group of disorders caused by impaired production, secretion or excretion of bile. This may result in the deposition of bile components in the blood and liver, which in turn causes damage to liver cells and other tissues. If untreated, CT can progress to severe complications, including cirrhosis, liver failure, and potentially life-threatening conditions. ObjectiveThis research was intended to elucidate the function and mechanism of Paeoniflorin (PF) in ameliorating ANIT-induced pyroptosis in CT. MethodsCT models were established in SD rats and HepG2 cells through ANIT treatment. Histological examination was conducted using haematoxylin and eosin (HE) staining to assess the histopathological alterations in the liver. Network pharmacology was employed to identify potential PF targets in CT treatment. To evaluate pyroptosis levels, various methods were used, including serum biochemical analysis, Enzyme-Linked Immunosorbent Assay (ELISA), immunofluorescence (IF), immunohistochemistry (IHC), Western blotting, transmission electron microscopy (TEM), and scanning electron microscopy (SEM). The HuProt™ 20K Chip was utilized to pinpoint potential PF-binding targets. PF's direct mechanisms in CT treatment were explored using molecular docking (MD), molecular dynamics simulations (MDS), Cellular Thermal Shift Assay (CETSA), and Surface Plasmon Resonance (SPR). ResultsPF administration was found to alleviate ANIT-induced liver pathology, enhance liver function markers, and improve cell viability. Network pharmacology and pyroptosis inhibitor studies suggested that PF might mitigate CT via the NLRP3-dependent pyroptosis pathway. This hypothesis was further supported by Western blotting, IF, and IHC analyses, which indicated PF's potential to inhibit NLRP3-dependent pyroptosis in CT. GSDMD was identified as a target through HuProt™ 20K Chip screening. The binding affinity of PF to GSDMD was validated through MD, MDS, CETSA, and SPR techniques. Additionally, the regulatory impact of GSDMD on downstream inflammatory pathways was confirmed by ELISA and IHC. CONCLUSION: PF exhibited a hepatoprotective effect in ANIT-induced CT, primarily by targeting GSDMD, thereby suppressing ANIT-induced pyroptosis and the subsequent release of inflammatory mediators.

The anti-inflammatory and tolerogenic potential of small spleen peptides.

Maintaining peripheral immune tolerance and preventing harmful autoimmune reactions is a fundamental task of the immune system. However, these essential functions are significantly compromised during autoimmune disorders, creating a major challenge in treating these conditions. In this context, we provide an overview of research on small spleen polypeptides (SSPs) that naturally regulate peripheral immune tolerance. Alongside outlining the observed effects of SSPs, we summarize here the findings on the cellular and molecular mechanisms that underlie their regulatory impact. Specifically, SSPs have demonstrated remarkable effectiveness in halting the progression of developing or established autoimmune disorders like psoriasis or arthritis in animal models. They primarily target dendritic cells (DCs), swiftly prompting the production of extracellular ATP, which is then degraded and sensed by adenosine receptors. This process triggers the mTOR signaling cascade, similar to powerful immune triggers, but instead of a rapid and intense reaction, it leads to a moderate yet significant activation of the mTOR signaling cascade. This induces a tolerogenic state in dendritic cells, ultimately leading to the generation of Foxp3+ immunosuppressor Treg cells. In addition, SSPs may indirectly attenuate the autoimmune response by reducing extracellular ATP synthesis in non-immune cells, such as endothelial cells, when exposed to elevated levels of proinflammatory cytokines. SSPs thus have the potential to contribute to the restoration of peripheral immune tolerance and may offer valuable therapeutic benefits in treating autoimmune diseases.