Critical Target Research Articles

Pyroptosis was suppressed by 20-hydroxyecdysone through Lin28b-mediated let-7d in vascular endothelial cells.

20-hydroxyecdysone (20E), a natural polyhydroxylated steroid, has exhibited anti-inflammatory effects across various diseases. This study investigates the potential connection between 20E's anti-inflammatory properties and the RNA-binding protein Lin28b, which is notably upregulated in TNF-α-stimulated endothelial cells. Herein, we discovered that 20E can selectively downregulate Lin28b expression without affecting its paralog Lin28a. Notably, 20E treatment could significantly attenuate pyroptosis, an inflammatory form of programmed cell death, as evidenced by reduced IL-1β and LDH release, and fewer propidium iodide (PI)-positive cells. Subsequent protein analysis revealed that 20E inhibited the enhanced expressions of key pyroptosis-associated proteins, GSDMD, GSDMD-N, and GSDME-N. Besides, this suppression of Lin28b and pyroptosis may be partially mediated through TNFR1. Additionally, 20E upregulated let-7 miRNA, particularly let-7d, a critical downstream target of Lin28b. To elucidate the role of Lin28b in 20E-mediated pyroptosis attenuation, we performed Lin28b overexpression and silencing experiments. Overexpressing Lin28b negated 20E's inhibition of LDH release and PI-related fluorescence, exacerbating GSDMD and GSDME cleavage. Conversely, Lin28b knockdown augmented the suppressive effect of 20E on pyroptosis, which was reversed by a let-7d inhibitor. Co-transfection with let-7d mimic and Lin28b plasmid demonstrated let-7d's role in mitigating pyroptosis aggravated by Lin28b overexpression. Overall, this study demonstrates that 20E may mitigate GSDMD and GSDME-mediated pyroptosis in HUVECs through the Lin28b/let-7d-dependent signaling pathway. These results highlight the potential of 20E as a promising inhibitor of pyroptosis, offering new insights into its anti-inflammatory mechanisms.

Study on Public Perceptions and Disaster Prevention Framework of Tunnel Fires Based on Social Media and Artificial Intelligence

To investigate public perceptions regarding tunnel fire disasters and optimize the tunnel fire disaster prevention framework, this study takes the emerging social media platform Douyin as a case study, conducting an in-depth analysis of 2133 short videos related to tunnel fires on the platform. A computational communication method was used for analysis, Latent Dirichlet Allocation was used to cluster the discussion topics of these tunnel fire short videos, and a spatiotemporal evolution analysis of the number of videos posted, user comments, and emotional inclinations across different topics was performed. The findings reveal that there is a noticeable divergence in public opinion regarding emergency decision making in tunnel fires, related to the complexity of tunnel fire incidents, ethical dilemmas in tunnel fire escape scenarios, and insufficient knowledge popularization of fire safety practices. The study elucidates the public’s actual needs during tunnel fire incidents, and a dynamic disaster prevention framework for tunnel fires based on social media and artificial intelligence is proposed on this basis to enhance emergency response capabilities. Utilizing short videos on social media, the study constructs a critical target dataset under real tunnel fire scenarios. It proposes a computer vision-based model for identifying critical targets in tunnel fires. This model can accurately and in real-time identify key targets such as fires, smoke, vehicles, emergency exits, and people in real tunnel fire environments, achieving an average detection precision of 77.3%. This research bridges the cognitive differences between the general public and professionally knowledgeable tunnel engineers regarding tunnel fire evacuation, guiding tunnel fire emergency responses and personnel evacuation.

AlphaFold3 versus experimental structures: assessment of the accuracy in ligand-bound G protein-coupled receptors.

G protein-coupled receptors (GPCRs) are critical drug targets involved in numerous physiological processes, yet many of their structures remain unresolved due to inherent flexibility and diverse ligand interactions. This study systematically evaluates the accuracy of AlphaFold3-predicted GPCR structures compared to experimentally determined structures, with a primary focus on ligand-bound states. Our analysis reveals that while AlphaFold3 shows improved performance over AlphaFold2 in predicting overall GPCR backbone architecture, significant discrepancies persist in ligand-binding poses, particularly for ions, peptides, and proteins. Despite advancements, these limitations constrain the utility of AlphaFold3 models in functional studies and structure-based drug design, where high-resolution details of ligand interactions are crucial. We assess the accuracy of predicted structures across various ligand types, quantifying deviations in binding pocket geometries and ligand orientations. Our findings highlight specific challenges in the computational prediction of ligand-bound GPCR structures, emphasizing areas where further refinement is needed. This study provides valuable insights for researchers using AlphaFold3 in GPCR studies, underscores the ongoing necessity for experimental structure determination, and offers direction for improving protein-ligand interaction predictions in future computational models.

The CCL5/CCR5/SHP2 axis sustains Stat1 phosphorylation and activates NF-κB signaling promoting M1 macrophage polarization and exacerbating chronic prostatic inflammation

Background and objectiveChronic prostatitis (CP) is a condition markered by persistent prostate inflammation, yet the specific cytokines driving its progression remain largely undefined. This study aims to identify key cytokines involved in CP and investigate their role in driving inflammatory responses through mechanistic and therapeutic exploration.MethodsA 48-cytokine panel test was conducted to compare the plasma cytokine profiles between participants with CP-like symptoms (CP-LS) and healthy controls. Experimental autoimmune prostatitis (EAP) models were used for functional validation, with further mechanistic studies performed through in vivo and in vitro assays. Pharmacological inhibition was applied using maraviroc, and pathway inhibitors to assess therapeutic potential.ResultsOur analysis identified CCL5 as one of the most prominently elevated cytokines in CP-LS patients. Further validation in the EAP model mice confirmed elevated CCL5 levels, highlighting its role in driving prostatic inflammation. Mechanistic studies revealed that CCL5 interacts with the CCR5 receptor, promoting M1 macrophage polarization and activating key inflammatory signaling pathways, including Stat1 and NF-κB, as indicated by increased phosphorylation of Stat1 and p65. In vitro, CCL5 combined with LPS stimulation amplified these effects, further promoting M1 polarization. CCL5 also sustained Stat1 activation by inhibiting its dephosphorylation through reduced interaction with SHP2, leading to prolonged inflammatory signaling. Single-cell transcriptomics confirmed high CCR5 expression in macrophages, correlating with inflammatory pathways. Pharmacological inhibition of CCR5, or its downstream signaling, significantly reduced macrophage-driven inflammation both in vivo and in vitro.ConclusionThese findings establish the CCL5/CCR5 axis as a critical driver of persistant prostatic inflammation and present it as a potential therapeutic target for CP.Graphic The graphic abstract illustrates the central role of the CCL5/CCR5 axis in promoting chronic prostatitis progression. CCL5 binds to the CCR5 receptor on macrophages, enhancing M1 polarization and activating key inflammatory pathways, including Stat1 and NF-κB, as shown by the increased phosphorylation of Stat1 and p65. The interaction also inhibits SHP2-mediated Stat1 dephosphorylation, sustaining prolonged inflammatory signaling. Pharmacological inhibition of CCR5 or its downstream pathways attenuates macrophage-driven inflammation, highlighting this axis as a critical driver and potential therapeutic target for chronic prostatitis.

Tyrosine Hydroxylase Is Required for the Larval-Pupal Transformation and Immunity of Plutella xylostella: Potential for Pest Management.

Plutella xylostella has developed high levels of resistance to many commonly used insecticides. Tyrosine hydroxylase (TH) is essential for insect survival; thus, we evaluated whether TH could be a potential target for controlling P. xylostella. In this study, PxTH was identified; further qPCR analysis showed that PxTH increased its expression during larval pupation and was highly expressed in the head and epidermis of prepupa in P. xylostella. Subsequently, we found a significant decrease in insect pupation and eclosion rates after injection of dsPxTH or a feeding diet supplemented with 3-iodo-tyrosine (3-IT) as a TH inhibitor in P. xylostella. Moreover, this study suggested that PxTH enzyme activity and dopamine concentrations were significantly decreased, agreeing with the blockage of larval-pupal cuticle tanning, with thinner puparium and less melanization after feeding 3-IT. In addition, expression levels of four antimicrobial peptide genes were significantly inhibited after P. xylostella feeding with 3-IT, and injection of Escherichia coli resulted in 73.3% mortality, indicating that PxTH was required for immune responses. In summary, these results confirmed that PxTH was involved in the development and immunity of P. xylostella, suggesting a critical potential novel insecticide target for RNAi-based pest control.

GLP-1 Receptor Agonists Alleviate Diabetic Kidney Injury via β-Klotho-Mediated Ferroptosis Inhibition.

Semaglutide (Smg), a GLP-1 receptor agonist (GLP-1RA), shows renal protective effects in patients with diabetic kidney disease (DKD). However, the exact underlying mechanism remains elusive. This study employs transcriptome sequencing and identifies β-Klotho (KLB) as the critical target responsible for the role of Smg in kidney protection. Smg treatment alleviates diabetic kidney injury by inhibiting ferroptosis in patients, animal models, and HK-2 cells. Notably, Smg treatment significantly increases the mRNA expression of KLB through the activation of the cyclic adenosine monophosphate (cAMP) signaling pathway, specifically through the phosphorylation of protein kinase A (PKA) and cAMP-response element-binding protein (CREB). Subsequently, the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway is activated, reprograming the key metabolic processes of ferroptosis such as iron metabolism, fatty acid synthesis, and the antioxidant response against lipid peroxidation. Suppression of ferroptosis by Smg further attenuates renal inflammation and fibrosis. This work highlights the potential of GLP-1RAs and KLB targeting as promising therapeutic approaches for DKD management.

Machine Learning for Early Detection of Cognitive Decline in Parkinson’s Disease Using Multimodal Biomarker and Clinical Data

Background: Parkinson’s disease (PD) is the second most common neurodegenerative disease, primarily affecting the middle-aged to elderly population. Among its nonmotor symptoms, cognitive decline (CD) is a precursor to dementia and represents a critical target for early risk assessment and diagnosis. Accurate CD prediction is crucial for timely intervention and tailored management of at-risk patients. This study used machine learning (ML) techniques to predict the CD risk over five-year in early-stage PD. Methods: Data from the Early Parkinson’s Disease Longitudinal Singapore (2014 to 2018) was used to predict CD defined as a one-unit annual decrease or a one-unit decline in Montreal Cognitive Assessment over two consecutive years. Four ML methods—AutoScore, Random Forest, K-Nearest Neighbors and Neural Network—were applied using baseline demographics, clinical assessments and blood biomarkers. Results: Variable selection identified key predictors of CD, including education year, diastolic lying blood pressure, diastolic standing blood pressure, systolic lying blood pressure, Hoehn and Yahr scale, body mass index, phosphorylated tau at threonine 181, total tau, Neurofilament light chain and suppression of tumorigenicity 2. Random Forest was the most effective, achieving an AUC of 0.93 (95% CI: 0.89, 0.97), using 10-fold cross-validation. Conclusions: Here, we demonstrate that ML-based models can identify early-stage PD patients at high risk for CD, supporting targeted interventions and improved PD management.

Curcumol effectively improves obesity through GDF15 induction via activation of endoplasmic reticulum stress response

The escalating prevalence of obesity presents a formidable global health challenge, underscoring the imperative for efficacious pharmacotherapeutic interventions. However, current anti-obesity medications often exhibit limited efficacy and adverse effects, necessitating the exploration of alternative therapeutic approaches. Growth differentiation factor 15 (GDF15) has emerged as a promising target for obesity management, given its crucial role in appetite control and metabolic regulation. In this study, we aimed to investigate the efficacy of curcumol, a sesquiterpene compound derived from plants of the Zingiberaceae family, in obesity treatment. Our findings demonstrate that curcumol effectively induces the expression of GDF15 through the activation of the endoplasmic reticulum stress pathway. To confirm the role of GDF15 as a critical target for curcumol’s function, we compared the effects of curcumol in wild-type mice and Gdf15-knockout mice. Using a high-fat diet-induced obese murine model, we observed that curcumol led to reduced appetite and altered dietary preferences mediated by GDF15. Furthermore, chronic curcumol intervention resulted in promising anti-obesity effects. Additionally, curcumol administration improved glucose tolerance and lipid metabolism in the obese mice. These findings highlight the potential of curcumol as a GDF15 inducer and suggest innovative strategies for managing obesity and its associated metabolic disorders. In conclusion, our study provides evidence for the efficacy of curcumol in obesity treatment by inducing GDF15 expression. The identified effects of curcumol on appetite regulation, dietary preferences, glucose tolerance, and lipid metabolism emphasize its potential as a therapeutic agent for combating obesity and related metabolic disorders.

A estética do niilismo: a construção do personagem-narrador em Memórias Do Subsolo

The present article aims to investigate the relationship between nihilism and the construction of the narrator-character in Fyodor Dostoevsky's Notes from Underground. To this end, it analyzes the nihilistic aesthetics within the work, highlighting how the author, by positioning himself as a subject of his own creation, employs nihilism both as an aesthetic device and as a target of criticism, while simultaneously striving to transcend it. In this context, the Russian author understands nihilism not only as a representation of the human condition, as described by Nietzsche, or as a historical phenomenon that affected 19th-century Russia, but also as a creative force and political power that shapes his literary production.

Exploring the potential mechanisms of Acer tegmentosum Maxim in preventing alcoholic liver disease based on network pharmacology and molecular docking

To investigate the potential mechanisms of Acer tegmentosum Maxim (AT) in preventing Alcoholic liver disease (ALD), this study used network pharmacology and molecular docking methods to screen the main active ingredients of AT for preventing core target proteins related to ALD, conducted GO and KEGG pathway enrichment analysis and performed molecular docking and visualisation. The results showed that AT’s top five active components were kaempferol-3-rhamnoside, salidroside, linoleic acid, ethyl linoleate, and tyrosol. The top five core target proteins for preventing ALD with AT were SRC, AKT1, STAT3, MAPK1, and ESR1. Gene enrichment analysis indicated that AT may inhibit the occurrence of ALD by improving inflammation and cancer pathways, and the core components of AT were well combined with critical targets, further elucidated the preventive mechanism of ALD through multiple components, targets, and pathways. It can provide a new idea for studying the mechanism of AT active ingredients to prevent ALD.

Based on network pharmacology and molecular docking, the mechanism of action of Chinese herbal compound on mycoplasma synovial sac of chicken was studied

Mycoplasma synoviae (MS) is a wall-less pathogen primarily transmitted through the respiratory tract, causing synovitis and airsacculitis in poultry, which leads to substantial economic losses in the poultry industry. China has a long-standing tradition of Chinese medicine with abundant medicinal resources, renowned for its safety, efficacy, and holistic regulatory effects. This study aims to screen a traditional Chinese medicine (TCM) compound with anti-inflammatory and immunoregulatory properties and preliminarily validate its in vitro efficacy against MS infections. Based on the research foundation of this experiment and findings from previous studies, this study utilized network pharmacology analysis and molecular docking techniques to identify the anti-inflammatory and immunoregulatory effects of traditional Chinese medicinal herbs, including Rhizoma Coptidis, Honeysuckle (Flos Lonicerae Japonicae), Radix Codonopsis, and Radix Glycyrrhizae.The primary active components and potential targets were identified using the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) and other platforms. Protein-protein interaction (PPI) networks, Gene Ontology (GO) functional annotation, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were employed to identify critical therapeutic targets. The AutoDock software was used for molecular docking between active components and core targets. Subsequently, in vitro experiments were conducted to validate the effects of key active components on MS targets. The analysis revealed that this TCM compound contains 122 active components, including flavonoids (e.g., quercetin, trimethylisoflavone), chromones (e.g., anti-inflammatory coumarin A), and triterpenes (e.g., glycyrrhizic acid B). These components act on 739 pharmacological targets, and Venn analysis identified 23 intersection targets related to MS. Further analysis indicated that STAT3, IL6, and IL1B were potential core targets. KEGG pathway enrichment analysis showed that MAPK, FoxO, and Toll-like receptor signaling pathways played critical roles in the pathology and treatment of MS, while GO analysis emphasized the significance of the NF-κB signaling pathway and VEGF receptor pathway in immune regulation, inflammation, and tissue repair. Molecular docking results demonstrated that lignans and quercetin in this TCM compound exhibited strong binding affinities to IL1B, IL6, and STAT3, potentially modulating these key targets to exert anti-inflammatory and immunoregulatory effects. In vitro experiments further validated the significant inhibitory effects of quercetin and glycyrrhizic acid on MS infection. The findings suggest that this TCM compound may exert therapeutic effects on MS infection by regulating targets such as CASP3, TLR4, STAT3, IL6, and IL1B, and modulating signaling pathways including MAPK, NF-κB, and FoxO.

A massively parallel reporter assay library to screen short synthetic promoters in mammalian cells

Cellular responses to stimuli underpin discoveries in drug development, synthetic biology, and general life sciences. We introduce a library comprising 6144 synthetic promoters, each shorter than 250 bp, designed as transcriptional readouts of cellular stimulus responses in massively parallel reporter assay format. This library facilitates precise detection and amplification of transcriptional activity from our promoters, enabling the systematic development of tunable reporters with dynamic ranges of 50−100 fold. Our library proved functional in numerous cell lines and responsive to a variety of stimuli, including metabolites, mitogens, toxins, and pharmaceutical agents, generating robust and scalable reporters effective in screening assays, biomarkers, and synthetic circuits attuned to endogenous cellular activities. Particularly valuable in therapeutic development, our library excels in capturing candidate reporters to signals mediated by drug targets, a feature we illustrate across nine diverse G-protein coupled receptors (GPCRs), critical targets in drug development. We detail how this tool isolates and defines discrete signaling pathways associated with specific GPCRs, elucidating their transcriptional signatures. With its ease of implementation, broad utility, publicly available data, and comprehensive documentation, our library will be beneficial in synthetic biology, cellular engineering, ligand exploration, and drug development.

Tailoring glioblastoma treatment based on longitudinal analysis of post-surgical tumor microenvironment

Glioblastoma (GBM), an incurable primary brain tumor, typically requires surgical intervention followed by chemoradiation; however, recurrences remain fatal. Our previous work demonstrated that a nanomedicine hydrogel (GemC12-LNC) delays recurrence when administered post-surgery. However, tumor debulking also triggers time-dependent immune reactions that promote recurrence at the resection cavity borders. We hypothesized that combining the hydrogel with an immunomodulatory drug could enhance therapeutic outcomes. A thorough characterization of the post-surgical microenvironment (SMe) is crucial to guide combinatorial approaches.In this study, we performed cellular resolution imaging, flow cytometry and spatial hyperplexed immunofluorescence imaging to characterize the SMe in a syngeneic mouse model of tumor resection. Owing to our dynamic approach, we observed transient opening of the blood–brain barrier (BBB) during the first week after surgery. BBB permeability post-surgery was also confirmed in GBM patients. In our murine model, we also observed changes in immune cell morphology and spatial location post-surgery over time in resected animals as well as the accumulation of reactive microglia and anti-inflammatory macrophages in recurrences compared to unresected tumors since the first steps of recurrence growth. Therefore we investigated whether starting a systemic treatment with the SMAC mimetic small molecule (GDC-0152) directly after surgery would be beneficial for enhancing microglial anti-tumoral activity and decreasing the number of anti-inflammatory macrophages around the GemC12-LNC hydrogel-loaded tumor cavity. The immunomodulatory effects of this drug combination was firstly shown in patient-derived tumoroids. Its efficacy was confirmed in vivo by survival analysis and correlated with reversal of the immune profile as well as delayed tumor recurrence.This comprehensive study identified critical time frames and immune cellular targets within the SMe, aiding in the rational design of combination therapies to delay recurrence onset. Our findings suggest that post-surgical systemic injection of GDC-0152 in combination with GemC12-LNC local treatment is a promising and innovative approach for managing GBM recurrence, with potential for future translation to human patient.Graphical

An in vivo examination of the relationship between metabotropic glutamate receptor 5 and suicide attempts in people with borderline personality disorder

BackgroundBorderline Personality Disorder (BPD) is a serious psychiatric condition, associated with a high risk for suicide attempts and death by suicide. However, relatively little is known about the pathophysiology of BPD. The metabotropic glutamate receptor type 5 (mGlu5) has been specifically implicated in the pathophysiology of BPD and suicide attempts, with more general roles in emotion regulation, social and cognitive functioning, and pain processing. Here, we examined the relationship between mGlu5 availability, BPD, and suicide attempts in vivo for the first time. MethodsEighteen individuals with BPD, and 18 age-, sex-, and smoking-status matched healthy (HC) and 18 clinical comparison controls with major depressive disorder (MDD) completed comprehensive clinical assessments and participated in an [18F]FPEB positron emission tomography (PET) scan to measure mGlu5 availability. Volume of distribution (VT) in the frontolimbic circuit implicated in BPD pathophysiology was the PET outcome measure. ResultsWe observed significantly higher frontolimbic mGlu5 availability in BPD compared to both HC (p=.009, d=0.84, 18.43% difference), and MDD (p=.03, d=0.69, 15.21% difference). In the BPD, but not MDD group, higher mGlu5 availability was also associated with history of suicide attempts (SA; 19-25% higher, p’s=.005-.02). Further, mGlu5 availability was positively correlated with risk factors for suicide (e.g., sexual victimization, perceived burdensomeness) in BPD-SA group. ConclusionsResults show higher mGlu5 availability in BPD and suicide attempt for the first time. Our preliminary findings suggest mGlu5 may be a critical treatment target for BPD symptoms, including suicide attempts, and warrant further investigation in larger samples.

HUVECs’ Expressway Based on Magnesium Ion Doped Hierarchical Scaffold for Rapid Angiogenesis and Bone Ingrowth

AbstractDelayed union or nonunion remains an extremely challenging predicament even after the application of currently available engineering scaffolds for the treatment of critical‐sized bone defects. The angiogenesis throughout the artificial bone repair scaffold to achieve “angiogenic‐osteogenic coupling” is regarded as an effective approach to solving this issue. The newly formed blood vessels can accelerate the supply of oxygen and nutrients, thereby triggering subsequent bone regeneration. Therefore, scaffolds featuring an angiogenic microenvironment that promotes cell adhesion and migration should be designed for superior bone repair. Herein, a magnesium ion‐doped hierarchical scaffold is fabricated using a polymer blend system of chitosan/polyethyleneimine with inherent micro‐phase separation and complexation. Due to the microscopic sea‐island structure and the stable doped magnesium ions, the cell adhesion behavior underwent a significant transformation. Meanwhile, the pathways related to cell adhesion, migration, and angiogenesis are activated, and the critical target thrombospondin 1 is upregulated. Consequently, the cell adhesion capacity is augmented, 6 times the cell migration rate is attained, and the angiogenesis of human umbilical vein endothelial cells is significantly expedited. Eventually, rapid bone ingrowth and satisfactory bone defect repair are approximated in vivo, making the composite scaffold a promising clinical candidate for bone engineering.

Is polytrauma really just a simple accident? Recurrent characteristic of polytrauma

BackgroundPolytrauma was defined as a severe traumatic injury and believed that it was a sudden and unpredictable incident. Is polytrauma really just a simple accident? In order to comprehensively answer this question, the study sought to determine the frequency and specific risk factors associated with polytrauma recidivism, while also comparing the initial and subsequent injury events among recidivists.MethodsA multicenter, retrospective cohort study was conducted at four Advanced Trauma Centers’ emergency surgery or traumatic intensive care units (TICUs) between August 2020 and July 2023. A total of 2490 consecutive trauma patients who met the criteria consecutively were recruited and analyzed in the study. Risk factors for recurrent polytrauma were identified through the use of logistic regression analysis. A nomogram was created using the results from a multivariate logistic regression analysis and the rms package in R.ResultsIn polytrauma, the rate of recidivism was 44.6% (672/1507), then recidivists were predominantly male (80.4%) and frequently within the 45 to 54 year-old age range (51.3%). Recidivists in polytrauma patients overall had a median time to reinjury of 27 months, as measured by the interquartile range (IQR). The polytrauma patients in the recent traumatic event were often more severe than that in the initial event, as patients had higher ISS scores and lower GCS scores (P < 0.01). Moreover, polytrauma recidivism were associated with poorer prognosis and increased healthcare costs. Polytrauma patients with the specific characteristics were found to have a higher likelihood of experiencing a subsequent recurrence, including being male (OR = 3.82,95% CI: 2.21–6.83), aged 45–54 years old (OR = 2.62,95% CI: 2.13–6.32),experiencing sleep deprivation (OR = 2.38,95% CI: 1.32–4.25), working in construction (OR = 2.72,95% CI: 1.44–5.42), working as delivery staff (OR = 3.65,95% CI: 1.51–7.96) and being involved in an electric bicycle collision (OR = 2.85,95% CI: 1.31–5.64).ConclusionPolytrauma recidivism is associated with a high recurrence rate, poorer clinical outcomes, and elevated healthcare costs. Key predictive markers for recidivism include being male, aged 45–54 years, experiencing sleep deprivation, employment in construction or delivery roles, and involvement in electric bicycle collisions. These findings highlight polytrauma recidivists as a critical target for primary prevention efforts. Public health strategies should prioritize tailored interventions to reduce recidivism, aiming to mitigate morbidity, mortality, and associated healthcare burdens in this high-risk population.

Recycle or Not? An Exploration of Microplastic Generation During Plastic Processing via a Local Case Study.

Microplastic (MP), an emerging pollutant, has been identified as a critical target in tackling plastic pollution. Although a plethora of studies have explored MP generation from various sources, limited attention has been paid to plastic processing. This study investigated MP (10 μm-5 mm) generation in virgin and waste plastic extrusion processing. MPs at a density of 2.13 × 105-9.79 × 107 (approximately 0.01-10.85 g) were generated when processing 1 t of plastic. Feedstock sources, polymer types, and pelletizing techniques were found to influence the process. With a moderate weight (270.58-527.34 t) but enormous amount (1.34 × 1016-2.63 × 1016) of MPs generated globally in 2022, plastic processing is an underestimated but vital source of MPs, emphasizing the need for MP inspection and appropriate removal technologies in the industry, especially for virgin plastic processing and water ring pelletizing. Further simulation indicated that up to 84.35% of MPs could be removed using commonly available materials in the investigated plastic processing facility, with a higher removal efficiency for larger-sized particles. In this regard, plastic recycling was superior to virgin plastic processing with fewer and larger-sized MPs generated, which could facilitate MP removal and should be fostered.

Identification of chikusetsusaponin IVa as a novel lysine-specific demethylase 1 inhibitor that ameliorates high fat diet-induced MASLD in mice.

Diet-induced metabolic dysfunction steatotic liver disease (MASLD) is also called as non-alcoholic fatty liver disease (NAFLD) with limited effective strategies available. We previously have shown that chikusetsusaponin IVa (CHS), a dietary saponin from herbs in South American known for their metabolic benefits, mitigates diet-induced diabetes. In this study we investigated the beneficial effects of CHS on MASLD and the underlying mechanisms. MAFLD mouse model was established by the high-fat diet (HFD) for 6 weeks and then were treated with CHS (50 mg·kg-1·d-1, i.g.) for another 8 weeks. By conducting transcriptomic analysis in palmitic acid-treated HepG2 cells and primary hepatocytes as well as lipidomic analysis in liver tissues, we demonstrated that HFD activated the intestinal farnesoid X receptor (FXR) pathway, leading to the release of FGF15/19, which in turn promoted hepatic FXR-SHP binding with cAMP-responsive element-binding protein H (CREBH), thereby inhibiting CREBH-mediated fatty acid oxidation (FAO) and ketogenesis. Intriguingly, we found that CHS improved lipid metabolism in HFD mice by suppressing the enterohepatic crosstalk of FXR-SHP to enhance CREBH transactivation. Among these, lysine-specific demethylase 1 (LSD1)-mediated histone demethylation played a crucial role in lipid metabolic reprogramming. Moreover, we identified LSD1 as a critical cellular target of CHS, directly binding to Lys661 and Tyr761 of LSD1 to inhibit its histone demethylation activity. Our results suggest that targeting intestinal LSD1 with CHS could be a promising strategy for MAFLD treatment, offering new insights into the bioavailability and efficacy of natural products.

Potential MAO-B Inhibitors from Cissampelos Capensis L.f.: ADMET, Molecular Docking, Dynamics, and DFT Insights.

This study explores the therapeutic potential of three proaporphine alkaloids-cissamaline, cissamanine, and cissamdine, which were recently isolated from Cissampelos capensis L.f., against Parkinson's disease (PD). Using computational techniques, we investigated their efficacy as inhibitors of a key protein in PD. ADMET analysis demonstrated that these alkaloids conform to the Lipinski, Pfizer, Golden Triangle, and GSK rules, indicating favorable safety, oral bioavailability, and a high probability of passing the human intestinal and blood-brain barriers. They were neither substrates nor inhibitors of any CYP enzymes tested, indicating minimal metabolic interference and an enhanced safety profile. Molecular docking studies revealed binding energies of -9.05 kcal/mol (cissamaline), -9.95 kcal/mol (cissamanine), and -10.65 kcal/mol (cissamdine) against MAO-B, a critical PD target, surpassing the control (zonisamide, -6.96 kcal/mol). The molecular interaction analyses were also promising, with interactions comparable to the control. Molecular dynamics (MD) simulations confirmed stable protein-ligand interactions, with root-mean-square deviation (RMSD) values ranging from 1.03 Å to 3.92 Å, root-mean-square fluctuation (RMSF) values remaining below 1.14 Å, and radius of gyration (RGyr) values between 20.20 Å and 20.50 Å, indicating compact structures. Hydrogen bonding analysis revealed maximum hydrogen bond counts of 6 (cissamanine), 5 (cissamaline), and 4 (cissamdine), demonstrating robust interactions with MAO-B. Density Functional Theory (DFT) calculations revealed the highest electrophilicity (ω =0.151), highest electron affinity (EA =0.075), and smallest HOMO-LUMO gap (ΔE =0.130) for cissamanine, indicating enhanced reactivity. These results advocate for further in vitro and in vivo studies to evaluate the compounds' potential as PD therapeutics.

Ginkgetin Alleviates Inflammation and Senescence by Targeting STING.

Ginkgo biloba extract is reported to have therapeutic effects on aging-related disorders. However, the specific component responsible for this biological function and its mechanism of action remain largely unknown. This study finds that Ginkgetin, an active ingredient of Ginkgo biloba extract, can alleviate cellular senescence and improve pathologies in multiple tissues of aging mice. To reveal the molecular mechanism of Ginkgetin's anti-aging effect, a graph convolutional network-based drug "on-target" pathway prediction algorithm for prediction is employed. The results indicate that the cGAS-STING pathway may be a potential target for Ginkgetin. Subsequent cell biological and biophysical data confirmed that Ginkgetin directly binds to the carboxy-terminal domain of STING protein, thereby inhibiting STING activation and signal transduction. Furthermore, in vivo pharmacodynamic data showed that Ginkgetin effectively alleviates systemic inflammation in Trex1-/- mice and inhibits the abnormally activated STING signaling in aging mouse model. In summary, this study, utilizing an artificial intelligence algorithm combined with pharmacological methods, confirms STING serves as a critical target for Ginkgetin in alleviating inflammation and senescence. Importantly, this study elucidates the specific component and molecular mechanism underlying the anti-aging effect of Ginkgo biloba extract, providing a robust theoretical basis for its therapeutic use.