The concept of ferroptosis inhibition has gained growing recognition as a promising therapeutic strategy for addressing a wide range of diseases. Here, we present the discovery of four series of ortho-aminophenol derivatives as potential ferroptosis inhibitors beginning with the endogenous substance 3-hydroxyanthranilic acid (3-HA) by employing quantum chemistry techniques, in vitro and in vivo assays. Our findings reveal that these ortho-aminophenol derivatives exhibit unique intra-H bond interactions, compelling ortho-amines to achieve enhanced alignment with the aromatic π-system, thereby expanding their activity. Notably, compounds from all four series display remarkable activity against RSL3-induced ferroptosis, showcasing an activity 100 times more than that of 3-HA. Furthermore, these compounds also demonstrate robust in vivo efficacy in protecting mice from kidney ischemia-reperfusion injury and acetaminophen-induced hepatotoxicity. In summary, we provide four distinct series of active scaffolds that significantly expand the chemical space of ferroptosis inhibitors, serving as valuable insights for future structural modifications.
OBJECTIVE: This study aimed to investigate the differences in clinical features, diagnostic examination, treatment, and pathological results between adult-onset and pediatric-onset tethered cord syndrome (TCS). METHODS: The authors searched the PubMed, Embase, and Cochrane Library databases through January 2023 for reports on TCS, extracting information on clinical features, imaging data, treatment modalities, prognosis, and pathological research results. A total of 6135 cases from 246 articles were included in the analysis. This review was conducted in accordance with the 2020 PRISMA guidelines and registered on PROSPERO. RESULTS: The most common adult clinical manifestations were pain, urinary symptoms, and numbness; in children, they were urinary symptoms, skin lesions, bowel symptoms, and unspecific motor deficits. Surgical treatment was the primary approach for both adults and children, with a higher clinical improvement rate observed in adults. However, adults also had a higher rate of surgical complications than children. TCS pathological studies have not yet identified the differences between adults and children, and the pathogenesis of adult-onset TCS requires further investigation. CONCLUSIONS: Adult-onset and pediatric-onset TCS exhibit certain differences in clinical characteristics, diagnostic examinations, and treatments. However, significant differences have not been found in current pathological studies between adults and children. Systematic review registration no.: CRD42023479450 (www.crd.york.ac.uk/prospero).
Neural Tube Defects , Humans , Neural Tube Defects/surgery , Neural Tube Defects/diagnosis , Child , Adult , Age of Onset
Porcine reproductive and respiratory syndrome (PRRS) caused by the PRRS virus (PRRSV) is one of the most severe swine diseases causing great economic losses for the international swine industry. Non-structural protein 4 (NSP4) is critical to the life cycle of PRRSV and contains dominant B cell epitopes. This study prepared a monoclonal antibody against Nsp4, and 2D11, which contained the sequence 138KQGGGIVTRPSGQFCN153, was confirmed as the epitope. A 2D11-based double antibody sandwich enzyme-linked immunosorbent assay (dasELISA) was next developed with a cut value of 0.1987. A total of 1354 pig serum samples were detected by dasELISA and compared to a commercial ELISA kit (N-coated iELISA), resulting in a positive coincidence rate of 98.8% and negative coincidence rate of 96.9%. A total of 119 sera were positive by dasELISA while negative by iELISA. Higher positive rates by dasELISA were found in pig farms where PRRSV antibody levels varied widely. These results indicated that the dasELISA was a useful tool to detect PRRSV antibody in clinical samples.
Driver genomic mutations in tumors define specific molecular subtypes that display distinct malignancy competence, therapeutic resistance and clinical outcome. Although TP53 mutation has been identified as the most common mutation in hepatocellular carcinoma (HCC), current understanding on the biological traits and therapeutic strategies of this subtype has been largely unknown. Here, we reveal that fatty acid ß oxidation (FAO) is remarkable repressed in TP53 mutant HCC and which links to poor prognosis in HCC patients. We further demonstrate that carnitine palmitoyltransferase 1 (CPT1A), the rate-limiting enzyme of FAO, is universally downregulated in liver tumor tissues, and which correlates with poor prognosis in HCC and promotes HCC progression in the de novo liver tumor and xenograft tumor models. Mechanically, hepatic Cpt1a loss disrupts lipid metabolism and acetyl-CoA production. Such reduction in acetyl-CoA reduced histone acetylation and epigenetically reprograms branched-chain amino acids (BCAA) catabolism, and leads to the accumulation of cellular BCAAs and hyperactivation of mTOR signaling. Importantly, we reveal that genetic ablation of CPT1A renders TP53 mutant liver cancer mTOR-addicted and sensitivity to mTOR inhibitor AZD-8055 treatment. Consistently, Cpt1a loss in HCC directs tumor cell therapeutic response to AZD-8055. Conclusion: Our results show genetic evidence for CPT1A as a metabolic tumor suppressor in HCC and provide a therapeutic approach for TP53 mutant HCC patients.
An acetal-linked dimeric phthalocyanine has been synthesised and immobilised on the surface of gold nanobipyramids. The resulting nanocomposite serves as a highly sensitive probe for intracellular pH through its acid-responsive fluorescence and surface-enhanced Raman scattering signals. The phthalocyanine units released in the acidic intracellular environment can also effectively eliminate the cancer cells upon light irradiation, rendering this simple fabricated nanosystem a bimodal and bifunctional theranostic agent.
BACKGROUND: Acute kidney injury (AKI) is a common clinical syndrome with high morbidity and mortality rates. The use of pluripotent stem cells holds great promise for the treatment of AKI. Urine-derived stem cells (USCs) are a novel and versatile cell source in cell-based therapy and regenerative medicine that provide advantages of a noninvasive, simple, and low-cost approach and are induced with high multidifferentiation potential. Whether these cells could serve as a potential stem cell source for the treatment of AKI has not been determined. AIM: To investigate whether USCs can serve as a potential stem cell source to improve renal function and histological structure after experimental AKI. METHODS: Stem cell markers with multidifferentiation potential were isolated from human amniotic fluid. AKI severe combined immune deficiency (SCID) mice models were induced by means of an intramuscular injection with glycerol. USCs isolated from human-voided urine were administered via tail veins. The functional changes in the kidney were assessed by the levels of blood urea nitrogen and serum creatinine. The histologic changes were evaluated by hematoxylin and eosin staining and transferase dUTP nick-end labeling staining. Meanwhile, we compared the regenerative potential of USCs with bone marrow-derived mesenchymal stem cells (MSCs). RESULTS: Treatment with USCs significantly alleviated histological destruction and functional decline. The renal function was rapidly restored after intravenous injection of 5 × 105 human USCs into SCID mice with glycerol-induced AKI compared with injection of saline. Results from secretion assays conducted in vitro demonstrated that both stem cell varieties released a wide array of cytokines and growth factors. This suggests that a mixture of various mediators closely interacts with their biochemical functions. Two types of stem cells showed enhanced tubular cell proliferation and decreased tubular cell apoptosis, although USC treatment was not more effective than MSC treatment. We found that USC therapy significantly improved renal function and histological damage, inhibited inflammation and apoptosis processes in the kidney, and promoted tubular epithelial proliferation. CONCLUSION: Our study demonstrated the potential of USCs for the treatment of AKI, representing a new clinical therapeutic strategy.
Signal peptide (SP) is essential for protein secretion, and pathogenic variants in the SP of FIX have been identified in hemophilia B (HB). However, the underlying mechanism for the genotype-phenotype correlation of these variants has not been well studied. Here we systematically examined the effects of 13 pathogenic point variants in the SP of FIX using different approaches. Our results showed that these point variants lead to HB by missense variants and/or aberrant pre-mRNA splicing. The missense variants in h-region mainly affected the co-translational translocation function of the SP, and those in c-region caused FIX deficiency mainly by disturbing the co-translational translocation and/or cleavage of the SP. Almost absolute aberrant pre-mRNA splicing was only observed in variants of c.82T>G, but a slight change of splicing patterns was found in variants of c.53G>T, c.77C>A, c.82T>C, and c.83G>A, indicating that these variants might have different degree to affect pre-mRNA splicing. Although two 6-nt deletion aberrant pre-mRNA splicing products caused FIX deficiency by disturbing the SP cleavage, but they could produce some functional mature FIX and vitamin K could increase the secretion of functional FIX. Taken together, our data indicated that pathogenic variants in the SP of FIX caused HB through diverse molecular mechanisms or even a mixture of several mechanisms, and vitamin K availability could be partially attributed to varying bleeding tendencies in patients carrying the same variant in the SP.
Verbena officinalis L. as a medical plant has been used to treat many diseases. However, the quality control underlying V. officinalis remains to be studied. HPLC fingerprint analysis and the qualitative and quantitative analysis of water extract from V. officinalis were carried out, and it was found that the quality varies according to habitat and batch. Verbenalin could be a crucial component in the quality evaluation of V. officinalis. This study contributes to better understanding of quality control for V. officinalis.
The management of diabetic wound healing remains a severe clinical challenge due to the complicated wound microenvironments, including abnormal immune regulation, excessive reactive oxygen species (ROS), and repeated bacterial infections. Herein, we report an extracellular matrix (ECM)-mimetic coating derived from scallop byssal protein (Sbp9Δ), which can be assembled in situ within 30 min under the trigger of Ca2+ driven by strong coordination interaction. The biocompatible Sbp9Δ coating and genetically programmable LL37-fused coating exhibit outstanding antioxidant, antibacterial, and immune regulatory properties in vitro. Proof-of-concept applications demonstrate that the coating can reliably promote wound healing in animal models, including diabetic mice and rabbits, ex vivo human skins, and Staphylococcus aureus-infected diabetic mice. In-depth mechanism investigation indicates that improved wound microenvironments accelerated wound repair, including alleviated bacterial infection, lessened inflammation, appearance of abundant M2-type macrophages, removal of ROS, promoted angiogenesis, and re-epithelialization. Collectively, our investigation provides an in situ, convenient, and effective approach for diabetic wound repair.
Objective: This study evaluated the performance of attentional fusion model-based multiscale features in classifying intracerebral hemorrhage and the localization of bleeding focus based on weakly supervised target localization. Methods: A publicly available dataset provided by the American College of Neuroradiology (ASNR) was used, consisting of 750,000 computed tomography (CT) scans of the brain, manually marked by radiologists for intracranial hemorrhage and five hemorrhage subtypes. A multiscale feature classification and weakly supervised localization framework based on an attentional fusion mechanism were applied, which could be annotated at the slice level and provided intracranial hemorrhage classification and hemorrhage focus localization. Results: The designed framework achieved excellent performance for classification and localization. The area under the curve (AUC) for predicting bleeding was 0.973. High AUC values were observed for the five hemorrhage subtypes (epidural AUC = 0.891, subdural AUC = 0.991, subarachnoid AUC = 0.983, intraventricular AUC = 0.995, intraparenchymal AUC = 0.990). This model outperformed the average entry-level radiology trainee compared to previously reported data. Conclusion: The designed method quickly and accurately detected intracerebral hemorrhage, classifying hemorrhage subtypes and locating bleeding points with image-level annotation alone. The results indicate that this framework can significantly reduce diagnostic time while improving the detection of intracerebral hemorrhage in emergencies. It can thus be integrated into the diagnostic radiology workflow in the future.
Introduction: Transformer network is widely emphasized and studied relying on its excellent performance. The self-attention mechanism finds a good solution for feature coding among multiple channels of electroencephalography (EEG) signals. However, using the self-attention mechanism to construct models on EEG data suffers from the problem of the large amount of data required and the complexity of the algorithm. Methods: We propose a Transformer neural network combined with the addition of Mixture of Experts (MoE) layer and ProbSparse Self-attention mechanism for decoding the time-frequency-spatial domain features from motor imagery (MI) EEG of spinal cord injury patients. The model is named as EEG MoE-Prob-Transformer (EMPT). The common spatial pattern and the modified s-transform method are employed for achieving the time-frequency-spatial features, which are used as feature embeddings to input the improved transformer neural network for feature reconstruction, and then rely on the expert model in the MoE layer for sparsity mapping, and finally output the results through the fully connected layer. Results: EMPT achieves an accuracy of 95.24% on the MI EEG dataset for patients with spinal cord injury. EMPT has also achieved excellent results in comparative experiments with other state-of-the-art methods. Discussion: The MoE layer and ProbSparse Self-attention inside the EMPT are subjected to visualisation experiments. The experiments prove that sparsity can be introduced to the Transformer neural network by introducing MoE and kullback-leibler divergence attention pooling mechanism, thereby enhancing its applicability on EEG datasets. A novel deep learning approach is presented for decoding EEG data based on MI.
Background Studies on basilar artery occlusion are relatively few compared with those of anterior circulation stroke. The aim of the present study was to compare the efficacy of endovascular therapy (EVT) in patients with basilar artery occlusion classified as large artery atherosclerosis (LAA) and cardioembolism (CE), and to analyze the independent risk factors affecting the prognosis of EVT. Methods A total of 123 people were assigned to the LAA and CE groups (97 to the LAA and 26 to the CE). The primary outcome was a modified Rankin Scale (mRS) score of 2 or lower at 90 days. The primary safety outcome was mortality at 90 days. Secondary safety endpoints included the rates of symptomatic intracranial hemorrhage and reinfarction. Multiple logistic regression was used to screen out independent risk factors for EVT prognosis of the LAA and CE groups. Results In the analysis, the patients with LAA stroke had better collateral circulation (American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology [SIR] score of 2-4; 61.9 vs. 19.2%, p = 0.000), and higher angioplasty rate (32.0 vs. 3.8%, p = 0.002). The proportions of patients with a 90-day mRS score of 0 to 2 and 90-day mortality were not found to be statistically significant between the two groups. Multivariate logistic regression analysis indicated that age, SIR, white blood cell, blood glucose, and modified thrombolysis in cerebral infarction were independent risk factors for the poor prognosis of EVT in the LAA group. Conclusion Although there were differences in clinical characteristics and imaging features between LAA and CE, there was no evidence of a significant difference in prognosis after EVT. In addition, the National Institutes of Health Stroke Scale score was not among the independent risk factors affecting the prognosis of the LAA group.
Waterlogging stress (WS) hinders kernel development and directly reduces peanut yield; however, the mechanism of kernel filling in response to WS remains unknown. The waterlogging-sensitive variety Huayu 39 was subjected to WS for 3 days at 7 days after the gynophores touched the ground (DAG). We found that WS affected kernel filling at 14, 21, and 28 DAG. WS decreased the average filling rate and kernel dry weight, while transcriptome sequencing and widely targeted metabolomic analysis revealed that WS inhibited the gene expression in starch and sucrose metabolism, which reduced sucrose input and transformation ability. Additionally, genes related to ethylene and melatonin synthesis and the accumulation of tryptophan and methionine were upregulated in response to WS. WS upregulated the expression of the gene encoding tryptophan decarboxylase (AhTDC), and overexpression of AhTDC in Arabidopsis significantly reduced the seed length, width, and weight. Therefore, WS reduced the kernel-filling rate, leading to a reduction in the 100-kernel weight. This survey informs the development of measures that alleviate the negative impact of WS on peanut yield and quality and provides a basis for exploring high-yield and high-quality cultivation, molecular-assisted breeding, and waterlogging prevention in peanut farming.
Diamond is considered the most promising next-generation semiconductor material due to its excellent physical characteristics. It has been more than three decades since the discovery of a special structure named n-diamond. However, despite extensive efforts, its crystallographic structure and properties are still unclear. Here, we show that subdisordered structures in diamond provide an explanation for the structural feature of n-diamond. Monocrystalline diamond with subdisordered structures is synthesized via the chemical vapor deposition method. Atomic-resolution scanning transmission electron microscopy characterizations combined with the picometer-precision peak finder technology and diffraction simulations reveal that picometer-scale shifts of atoms within cells of diamond govern the subdisordered structures. First-principles calculations indicate that the bandgap of diamond decreases rapidly with increasing shifting distance, in accordance with experimental results. These findings clarify the crystallographic structure and electronic properties of n-diamond and provide new insights into the bandgap adjustment in diamond.
INTRODUCTION: Emerging antibiotic resistance among bacterial pathogens has forced an urgent need for alternative non-antibiotic strategies development that could combat drug resistant-associated infections. Suppression of virulence of ESKAPE pathogens' by targeting multiple virulence traits provides a promising approach. OBJECTIVES: Here we propose an iron-blocking antibacterial therapy based on a cationic heme-mimetic gallium porphyrin (GaCHP), which antibacterial efficacy could be further enhanced by photodynamic inactivation. METHODS: We used gallium heme mimetic porphyrin (GaCHP) excited with light to significantly reduce microbial viability and suppress both the expression and biological activity of several virulence traits of both Gram-positive and Gram-negative ESKAPE representatives, i.e., S. aureus and P. aeruginosa. Moreover, further improvement of the proposed strategy by combining it with routinely used antimicrobials to resensitize the microbes to antibiotics and provide enhanced bactericidal efficacy was investigated. RESULTS: The proposed strategy led to substantial inactivation of critical priority pathogens and has been evidenced to suppress the expression and biological activity of multiple virulence factors in S. aureus and P. aeruginosa. Finally, the combination of GaCHP phototreatment and antibiotics resulted in promising strategy to overcome antibiotic resistance of the studied microbes and to enhance disinfection of drug resistant pathogens. CONCLUSION: Lastly, considering high safety aspects of the proposed treatment toward host cells, i.e., lack of mutagenicity, no dark toxicity and mild phototoxicity, we describe an efficient alternative that simultaneously suppresses the functionality of multiple virulence factors in ESKAPE pathogens.
We report the synthesis of a longitudinally helical molecular nanocarbon, hexabenzoheptacene (HBH), along with its dimethylated derivative (HBH-Me), which are composed of six benzene rings periodically benzannulated to both zigzag edges of a heptacene core. This benzannulation pattern endows the resulting nanocarbons with a helical heptacene core and local aromaticity, imparting enhanced solubility and stability to the system. The chiral HBH-Me adopts a more highly twisted conformation with an end-to-end twist angle of 95°, enabling the separation of the enantiomers. Both HBH and HBH-Me can be facilely oxidized into their corresponding dications, which exhibit enhanced planarity and aromaticity upon loss of electrons. Notably, both longitudinally helical nanocarbons readily promote solid state packing into two-dimensional (2D) arrangement. Single-crystal microbelts of HBH-Me show hole mobility up to 0.62 cm2 V-1 s-1, illustrating the promising potential of these longitudinally helical molecules for organic electronic devices.
OBJECTIVES: Bile acids (BAs), as signaling molecules to regulate metabolism, have received considerable attention. Genipin is an iridoid compound extracted from Fructus Gradeniae, which has been shown to relieve adiposity and metabolic syndrome. Here, we investigated the mechanism of genipin counteracting obesity and its relationship with BAs signals in diet-induced obese (DIO) rats. METHODS: The DIO rats were received intraperitoneal injections of genipin for 10 days. The body weight, visceral fat, lipid metabolism in the liver, thermogenic genes expressions in brown fat, BAs metabolism and signals, and key enzymes for BAs synthesis were determined. KEY FINDINGS: Genipin inhibited fat synthesis and promoted lipolysis in the liver, and upregulated thermogenic gene expressions in brown adipose tissue of DIO rats. Genipin increased bile flow rate and upregulated the expressions of aquaporin 8 and the transporters of BAs in liver. Furthermore, genipin changed BAs composition by promoting alternative pathways and inhibiting classical pathways for BAs synthesis and upregulated the expressions of bile acid receptors synchronously. CONCLUSIONS: These results suggest that genipin ameliorate obesity through BAs-mediated signaling pathways.
RATIONALE: Medications are urgently needed to treat symptoms of drug withdrawal and mitigate dysphoria and psychiatric comorbidities that drive opioid abuse and relapse. ITI-333 is a novel molecule in development for treatment of substance use disorders, psychiatric comorbidities, and pain. OBJECTIVE: Characterize the preclinical profile of ITI-333 using pharmacological, behavioral, and physiological assays. METHODS: Cell-based assays were used to measure receptor binding and intrinsic efficacy of ITI-333; animal models were employed to assess effects on opioid reinstatement, precipitated oxycodone withdrawal, and drug abuse liability. RESULTS: In vitro, ITI-333 is a potent 5-HT2A receptor antagonist (Ki = 8 nM) and a biased, partial agonist at µ-opioid (MOP) receptors (Ki = 11 nM; lacking ß-arrestin agonism) with lesser antagonist activity at adrenergic α1A (Ki = 28 nM) and dopamine D1 (Ki = 50 nM) receptors. In vivo, ITI-333 blocks 5-HT2A receptor-mediated head twitch and MOP receptor-mediated effects on motor hyperactivity in mice. ITI-333 alone is a naloxone-sensitive analgesic (mice) which suppresses somatic signs of naloxone-precipitated oxycodone withdrawal (mice) and heroin cue-induced reinstatement responding without apparent tolerance or physical dependence after chronic dosing (rats). ITI-333 did not acutely impair gastrointestinal or pulmonary function (rats) and was not intravenously self-administered by heroin-maintained rats or rhesus monkeys. CONCLUSIONS: ITI-333 acts as a potent 5-HT2A receptor antagonist, as well a biased MOP receptor partial agonist with low intrinsic efficacy. ITI-333 mitigates opioid withdrawal/reinstatement, supporting its potential utility as a treatment for OUD.
