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ETHNOPHARMACOLOGICAL RELEVANCE: Thrombosis is a common cause of morbidity and mortality worldwide. Lagopsis supina (Stephan ex Willd.) Ikonn.-Gal. ex Knorring is an ancient Chinese herbal medicine used for treating thrombotic diseases. Nevertheless, the antithrombotic mechanisms and effective constituents of this plant have not been clarified. AIM OF THE STUDY: This work aimed to elucidate the pharmacodynamics and mechanism of L. supina against thrombosis. MATERIALS AND METHODS: Systematic network pharmacology was used to explore candidate effective constituents and hub targets of L. supina against thrombosis. Subsequently, the binding affinities of major constituents with core targets were verified by molecular docking analysis. Afterward, the therapeutic effect and mechanism were evaluated in an arteriovenous bypass thrombosis rat model. In addition, the serum metabolomics analysis was conducted using ultra-high performance liquid chromatography coupled with Q-Exactive mass spectrometry. RESULTS: A total of 124 intersected targets of L. supina against thrombosis were predicted. Among them, 24 hub targets were obtained and their mainly associated with inflammation, angiogenesis, and thrombosis approaches. Furthermore, 9 candidate effective constituents, including (22E,24R)-5α,8α-epidioxyergosta-6,22-dien-3ß-ol, aurantiamide, (22E,24R)-5α,8α-epidioxyergosta-6,9 (11),22-trien-3ß-ol, lagopsinA, lagopsin C, 15-epi-lagopsin C, lagopsin D, 15-epi-lagopsin D, and lagopsin G in L. supina and 6 potential core targets (TLR-4, TNF-α, HIF-1α, VEGF-A, VEGFR-2, and CLEC1B) were acquired. Then, these 9 constituents demonstrated strong binding affinities with the 6 targets, with their lowest binding energies were all less than -5.0 kcal/mol. The antithrombotic effect and potential mechanisms of L. supina were verified, showing a positively associated with the inhibition of inflammation (TNF-α, IL-1ß, IL-6, IL-8, and IL-10) and coagulation cascade (TT, APTT, PT, FIB, AT-III), promotion of angiogenesis (VEGF), suppression of platelet activation (TXB2, 6-keto-PGF1α, and TXB2/6-keto-PGF1α), and prevention of fibrinolysis (t-PA, u-PA, PAI-1, PAI-1/t-PA, PAI-1/u-PA, and PLG). Finally, 14 endogenous differential metabolites from serum samples of rats were intervened by L. supina based on untargeted metabolomics analysis, which were closely related to amino acid metabolism, inflammatory and angiogenic pathways. CONCLUSION: Our integrated strategy based on network pharmacology, molecular docking, metabolomics, and in vivo experiments revealed for the first time that L. supina exerts a significant antithrombotic effect through the inhibition of inflammation and coagulation cascade, promotion of angiogenesis, and suppression of platelet activation. This paper provides novel insight into the potential of L. supina as a candidate agent to treat thrombosis.
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Fibrinolíticos , Metabolômica , Simulação de Acoplamento Molecular , Farmacologia em Rede , Ratos Sprague-Dawley , Trombose , Animais , Fibrinolíticos/farmacologia , Fibrinolíticos/química , Fibrinolíticos/isolamento & purificação , Ratos , Masculino , Trombose/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/químicaRESUMO
Radiofrequency ablation (RFA), a form of thermal ablation, employs localized heat to induce protein denaturation in tissue cells, resulting in cell death. It has emerged as a viable treatment option for patients who are ineligible for surgery in various diseases, particularly liver cancer and other tumor-related conditions. In addition to directly eliminating tumor cells, RFA also induces alterations in the infiltrating cells within the tumor microenvironment (TME), which can significantly impact treatment outcomes. Moreover, incomplete RFA (iRFA) may lead to tumor recurrence and metastasis. The current challenge is to enhance the efficacy of RFA by elucidating its underlying mechanisms. This review discusses the clinical applications of RFA in treating various diseases and the mechanisms that contribute to the survival and invasion of tumor cells following iRFA, including the roles of heat shock proteins, hypoxia, and autophagy. Additionally, we analyze| the changes occurring in infiltrating cells within the TME after iRFA. Finally, we provide a comprehensive summary of clinical trials involving RFA in conjunction with other treatment modalities in the field of cancer therapy, aiming to offer novel insights and references for improving the effectiveness of RFA.
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Benefiting from advances in large-scale pre-training, foundation models, have demonstrated remarkable capability in the fields of natural language processing, computer vision, among others. However, to achieve expert-level performance in specific applications, such models often need to be fine-tuned with domain-specific knowledge. In this paper, we focus on enabling vision-language models to unleash more potential for visual understanding tasks under few-shot tuning. Specifically, we propose a novel adapter, dubbed as lusterAdapter, which is based on trainable multiple prototypes clustering algorithm, for tuning the CLIP model. It can not only alleviate the concern of catastrophic forgetting of foundation models by introducing anchors to inherit common knowledge, but also improve the utilization efficiency of few annotated samples via bringing in clustering and domain priors, thereby improving the performance of few-shot tuning. We have conducted extensive experiments on 11 common classification benchmarks. The results show our method significantly surpasses the original CLIP and achieves state-of-the-art (SOTA) performance under all benchmarks and settings. For example, under the 16-shot setting, our method exhibits a remarkable improvement over the original CLIP by 19.6%, and also surpasses TIP-Adapter and GraphAdapter by 2.7% and 2.2%, respectively, in terms of average accuracy across the 11 benchmarks. Code is available at https://github.com/uyzhang/Cluster-Adapter.
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Ferroptosis is an important pathological mechanism of chronic heart failure (CHF). This study aimed to investigate the protective mechanism of Astragaloside IV (AS-IV) on CHF rats by integrating bioinformatics and ferroptosis. CHF-related targets and ferroptosis-related targets were collected. After the intersection, the common targets were obtained. The PPI network of the common targets was constructed, and topological analysis of the network was carried out. The target with the highest topological parameter values was selected as the key target. The key target p53 was obtained through bioinformatics analysis, and its molecular docking model with AS-IV was obtained, as well as molecular dynamics simulation analysis. The rat models of CHF after myocardial infarction were established by ligation of left coronary artery and treated with AS-IV for 4 weeks. AS-IV treatment significantly improved cardiac function in CHF rats, improved cardiomyocyte morphology and myocardial fibrosis, reduced mitochondrial damage, decreased myocardial MDA and Fe2+ content, increased GSH content, inhibited the expression of p53 and p-p53, and up-regulated the expression of SLC7A11 and GPX4. In conclusion, AS-IV improved cardiac function in CHF rats, presumably by regulating p53/SLC7A11/GPX4 signaling pathway and inhibiting myocardial ferroptosis.
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Biologia Computacional , Ferroptose , Insuficiência Cardíaca , Saponinas , Triterpenos , Animais , Ferroptose/efeitos dos fármacos , Triterpenos/farmacologia , Saponinas/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , Ratos , Biologia Computacional/métodos , Masculino , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Simulação de Acoplamento Molecular , Doença Crônica , Modelos Animais de Doenças , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Simulação de Dinâmica Molecular , Miocárdio/metabolismo , Miocárdio/patologiaRESUMO
[This corrects the article DOI: 10.7150/thno.28219.].
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The study aimed to reveal the function of LXY30 peptide-modified bone marrow mesenchymal stem cell-derived exosomes (LXY30-Exos) in NSCLC. LXY30 peptide is a peptide ligand targeting α3ß1 integrin, and LXY30 specifically binds to Exos derived from different cells. We use transmission electron microscopy to identify LXY30-Exos and tracking analysis for particles, and the LXY30-Exos internalized by NSCLC cells in vitro and targeted NSCLC tumours in vivo were verified by multiple molecular technologies. The functions of LXY30-Exos-encapsulated miR-30c, miR-181b or miR-613 were assessed using cell proliferation, migration and cell apoptosis assays. Meanwhile, the safety of the above engineered Exos was evaluated in vivo. After LXY30-Exos were isolated and identified, LXY30-Exos were confirmed to be internalized by NSCLC cells in vitro and specifically targeted NSCLC tumours in vivo. Functionally, LXY30-Exos-encapsulated miR-30c, miR-181b or miR-613 weakened the proliferation, migration and cell cycle of NSCLC cells induced cellular apoptosis in vitro and restrained the tumour progression in vivo. Meanwhile, the safety of LXY30-Exos-encapsulated miR-30c, miR-181b or miR-613 was confirmed in vivo. Overall, miR-30c, miR-181b and miR-613 encapsulated in LXY30 peptide-modified BMSC-Exos relieved NSCLC.
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Apoptose , Carcinoma Pulmonar de Células não Pequenas , Movimento Celular , Proliferação de Células , Exossomos , Neoplasias Pulmonares , Células-Tronco Mesenquimais , MicroRNAs , Exossomos/metabolismo , MicroRNAs/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Células-Tronco Mesenquimais/metabolismo , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/terapia , Animais , Camundongos , Linhagem Celular Tumoral , Camundongos Nus , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: The incidence, risk factors, and outcomes of venous thromboembolism (VTE) in patients with chronic lymphocytic leukemia (CLL) and monoclonal B cell lymphocytosis (MBL) is not well described. OBJECTIVES: We aimed to determine the clinical characteristics, risk factors, and outcomes of incident VTE in patients with newly diagnosed MBL/CLL, and to compare the incidence to the age- and sex-matched general population. PATIENTS/METHODS: Using the Mayo Clinic CLL Database, we identified 946 patients with newly diagnosed MBL/CLL between 1998-2021. Incidence of VTE was identified by querying the EHR for VTE-specific ICD-9 and ICD-10 codes and reviewing results of radiographic studies. RESULTS: Eighty patients developed VTE. Incidence of VTE in patients with newly diagnosed MBL/CLL was â¼1% per year. In multivariable analyses, prior history of VTE (HR: 5.33, 95% CI: 1.93-14.68, P=0.001), and high/very-high-risk CLL-International Prognostic Index score (HR: 2.63, 95% CI: 1.31 - 5.26, P=0.006) were associated with an increased risk of VTE; receipt of CLL treatment or occurrence of non-hematologic malignancy was not. Development of VTE was associated with shorter overall survival (HR: 1.82, 95% CI: 1.30-2.55) after adjusting for age, sex, prior history of VTE, and Rai stage. Age- and sex-adjusted VTE incidence rate for patients with MBL/CLL and no prior history of VTE (n=904) was 1,254 per 100,000 person-years compared to 204 per 100,000 person-years in the general population, reflecting a 5.9-fold increase. CONCLUSIONS: Our study demonstrates a 6-fold increased risk of VTE in patients with MBL/CLL compared to the age- and sex-matched general population.
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Ulcerative colitis (UC) is a complex, refractory inflammatory bowel disease characterized impared intestinal mucosal barrier and imbalanced M1/M2 macrophage polarization mediating its progression. Formononetin (FN), a bioactive isoflavone with established anti-inflammatory and immunomodulatory properties, shows promise in mitigating UC, yet its therapeutic and underlying mechanisms remain unclear. In this study, colitis was induced in mice by administering 2.5% (w/v) dextran sulfate sodium (DSS) solution for 7 days. Oral (25, 50, and 100 mg/kg) FN for 10 days significantly ameliorated colitis symptoms in a dose-dependent manner, by mitigating body weight loss, reducing disease activity index (DAI), colonic weight, and colonic weight index, while enhancing survival rates and colonic length. Histological analysis revealed FN remarkably suppressed inflammatory damage in colonic tissues. Furthermore, FN modulated the expression of pro- and anti-inflammatory cytokines and enhanced antioxidant capacity. Notably, FN treatment significantly enhanced the expression of tight junction (TJ) proteins (claudin-1, ZO-1, occludin) at both protein and mRNA levels in the colon tissues, suggesting improved intestinal barrier function. Crucially, FN inhibited macrophage infiltration in colonic tissues and rebalanced M1/M2 macrophage polarization. While, macrophage depletion largely abrogated FN's protective effects against colitis, indicating a crucial role for macrophages in mediating FN's therapeutic response. Overall, FN effectively alleviated colitis primarily via modulating inflammatory cytokine expression, enhancing antioxidant capacity, upregulating TJs proteins expression, and remodeling M1/M2 macrophage polarization equilibrium. These findings suggest that FN could be the next candidate to unlocking UC's treatment challenge.
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Background: COVID-19 began in December 2019, rapidly spreading worldwide. China implemented a dynamic zero-COVID strategy and strict control measures after the outbreak. However, Guangzhou city ended closed-off management by the end of November 2022, leading to exposure to SARS-CoV-2. Despite most hospitalized patients being infected or co-infected with SARS-CoV-2, some remained uninfected. We report two cases of bacterial pneumonia with elevated globulin levels not infected with SARS-CoV-2, aiming to identify protection factors of SARS-CoV-2 infection and provide a scientific basis for SARS-CoV-2 prevention. Case presentation: Case 1, a 92-year-old male, admitted on October 21, 2022, developed worsening cough and sputum after aspiration, diagnosed with bacterial pneumonia with Pseudomonas aeruginosa, Escherichia coli (CRE) and carbapenem-resistant Acinetobacter baumannii (CRAB) infections. He was treated with imipenem anti-infective therapy and mechanical ventilation, then switched to a combination of meropenem, voriconazole and amikacin anti-infective therapy due to recurrent infections and septic shock, and died of sepsis on 8 January 2023. Case 2 is an 82-year-old male admitted on 30 September 2022, with recurrent cough, sputum, and shortness of breath, diagnosed with bacterial pneumonia with carbapenem-resistant Klebsiella pneumoniae (CRKP) and Mycobacterium pneumoniae infections. He was treated with ventilator-assisted ventilation, meropenem, amikacin, tigecycline and mucomycin nebulization and discharged with improvement on 26 October. He was readmitted on 21 November 2022 and diagnosed with bacterial pneumonia. He was treated with cefoperazone sulbactam, amikacin, meropenem and fluconazole and discharged on 31 December. Neither patient was infected with SARS-CoV-2 during hospitalization. Notably, their globulin levels were elevated before SARS-CoV-2 exposure, gradually decreasing afterward. Conclusions: Patients with bacterial pneumonia with high globulin levels likely have large amounts of immunoglobulin, and that immunoglobulin cross-reactivity causes this protein to be involved in clearing SARS-CoV-2 and preventing infection. Therefore, bacterial pneumonia patients with high globulin levels included in this study were not infected with SARS-CoV-2. After exposure to SARS-CoV-2, the amount of globulin in the patient's body was reduced because it was used to clear SARS-CoV-2. The results of this study are expected to provide a theoretical basis for the study of the mechanism of prevention and treatment of SARS-CoV-2 infection.
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COVID-19 , Pneumonia Bacteriana , SARS-CoV-2 , Humanos , Masculino , COVID-19/complicações , Pneumonia Bacteriana/tratamento farmacológico , Pneumonia Bacteriana/diagnóstico , Idoso de 80 Anos ou mais , Antibacterianos/uso terapêuticoRESUMO
Objective To analyze the clinical features of 17 patients with primary angiitis of the central nervous system (PACNS) and thus facilitate the early diagnosis and treatment,reduce the recurrence and mortality,and improve the prognoses of this disease. Methods We collected the data of patients with PACNS diagnosed by brain biopsy from January 2009 to June 2023 and analyzed their clinical presentations,laboratory and imaging manifestations,electrophysiological and pathological changes,and treatment regimens and prognosis. Results The 17 patients diagnosed with PACNS via brain biopsy included one child and 16 adults.The subtyping results showed that 10,2,3,2,1,and 1 patients had tumorous,spinal cord-involved,angiography-positive,rapidly progressive,hemorrhagic,and amyloid ß-related PACNS,respectively.Eleven (64.7%) of the patients were complicated with secondary epilepsy.All the patients exhibited abnormal manifestations in head MRI,with 94.1% showing lesions with uneven enhancement around the lesions or in the leptomeninges. Magnetic resonance angiography revealed large vessel abnormalities in 3 patients,and spinal cord involvement was observed in 2 patients.Histopathological typing revealed 7 (43.7%) patients with lymphocytic vasculitis and 5 (31.2%) patients with necrotizing vasculitis.Eleven patients were treated with glucocorticoids and cyclophosphamide,which resulted in partial lesion disappearance and symptom amelioration in 6 patients upon reevaluation with head MRI after 3 months of maintenance therapy.Two,1,and 3 patients experienced rapid disease progression,death,and recurrence within 1 year,respectively.Three patients showed insensitivity to hormonotherapy and residual disabilities.Two patients received rituximab after relapse and remained clinically stable during a follow-up period of 0.5-1 year. Conclusion Tumorous PACNS was more prone to epilepsy,mainly occurring in males.The most common histopathological type was necrotizing vasculitis,which responded to hormonotherapy and had favorable outcomes.Therefore,for the young patients with epilepsy and intracranial tumorous lesions,the possibility of PACNS should be considered.Spinal cord involvement in PACNS was often located in the thoracic and cervical cords,suggesting a poorer prognosis.Electromyography commonly revealed neural conduction abnormalities in the anterior horn or roots,providing clues for differential diagnosis.For suspected spinal cord involvement,comprehensive electromyography is recommended.Rapidly progressive PACNS often presented infratentorial lesions,such as lesions in the pons and medulla,with a higher mortality rate.Hemorrhagic PACNS was rare,and a multifocal hemorrhagic lesion with enhancement in the intracranial region,particularly in young patients,should raise suspicion.For the patients with recurrent or progressive disease,rituximab is a recommended therapeutic option.
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Encéfalo , Vasculite do Sistema Nervoso Central , Humanos , Vasculite do Sistema Nervoso Central/diagnóstico , Vasculite do Sistema Nervoso Central/patologia , Vasculite do Sistema Nervoso Central/tratamento farmacológico , Adulto , Biópsia , Encéfalo/patologia , Encéfalo/diagnóstico por imagem , Prognóstico , Masculino , Criança , Feminino , Imageamento por Ressonância Magnética , AdolescenteRESUMO
This article investigates the resilient noncooperative game strategy design problem for the continuous-time system subjected to the Wiener type disturbance. To reflect the reality, the fading measurement and gain perturbation phenomena are simultaneously taken into consideration. Due to the considered complexities, there is little chance of obtaining the accurate cost function. For the sake of quantifying the controller performance, we resort to a certain upper bound of cost function (UBoCF) as an alternative. Then, the so-called noncooperative game strategy is designed which is capable of minimizing the derived UBoCF in a parallel manner. The designed noncooperative game strategy is the solution to a bunch of coupled differential Riccati-like equations (DREs). In addition, the theory analysis is generalized to the infinite-horizon with hope to describe the steady-state behavior. Specifically, the restraint conditions are provided to guarantee the stability of the system. Finally, a numerical example on the load frequency control (LFC) system is shown to verify the effectiveness of the proposed methodology.
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BACKGROUND: Regenerative endodontic procedures (REPs) is effective for treating young permanent teeth with pulp necrosis. However, its efficacy on delayed replanted avulsed teeth is unclear. AIM: This retrospective study aimed to assess the efficacy of REPs in treating delayed replanted immature permanent teeth with apical periodontitis. DESIGN: Avulsed teeth receiving REPs were systematically screened based on predetermined criteria. This study assessed the REP outcomes, postoperative periodontal healing, and overall treatment efficacy. Samples were grouped by REP outcomes and root development stage, with Fisher's exact tests used to compare outcomes among different groups. RESULTS: Among the included 17 teeth, 47.1% exhibited successful REPs and periodontal healing. Another 47.1%, due to replacement resorption or REP failure, were categorized as tooth survival. Healing of periapical lesions was observed in 88.2% of the cases, but only 41.2% demonstrated continued root development. Although differences were not significant (p = 0.05), teeth with continued root development had a higher rate of functional healing (85.7%) compared to those without (30%). CONCLUSION: Within the limitations of this study, REPs presented reliable outcomes for treating delayed replanted immature permanent teeth with apical periodontitis mainly in periapical lesion healing. Teeth with continued root development after REPs exhibited a higher rate of functional healing. Further investigation is required to explore potential synergies between REP outcomes and periodontal healing.
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The kidney maintains homeostasis through an array of parallel nephrons, which all originate in development as isolated epithelial structures that later fuse through their distal poles to a system of collecting ducts (CD). This connection is required to generate functional nephrons by providing a pathway for excretion of metabolic waste and byproducts. Currently, methods for differentiating human pluripotent stem cells into kidney organoids generate nephrons that lack CDs and instead terminate as blind-ended tubules. Here we describe a developmentally inspired system that addresses this deficiency through assembly of induced nephrogenic mesenchyme with ureteric bud (UB) tissues, the embryonic building blocks of the kidney's collecting system. The UB progenitors grow and develop into a network of CDs within the organoid, and importantly, they functionally integrate with the nephrons through recapitulating fusion between the distal tubule and CD to create a continuous epithelial lumen. We further showed that proximal-distal nephron specification, fusion frequency, and maturation of the CD can be augmented through temporal manipulation of developmental signaling pathways. This work provides a platform for interrogating the principles and mechanisms underlying nephron-UB fusion and a framework for engineering unobstructed nephrons with patterned collecting systems, an important step toward the de novo generation of functional kidney tissue.
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Although the combination of immunotherapy and radiotherapy (RT) for the treatment of malignant tumors has shown rapid development, the insight of how RT remodels the tumor microenvironment to prime antitumor immunity involves a complex interplay of cell types and signaling pathways, much of which remains to be elucidated. Four tumor samples were collected from the same abdominal wall metastasis site of the patient with gastric cancer at baseline and during fractionated RT for single-cell RNA and T-cell receptor sequencing. The Seurat analysis pipeline and immune receptor analysis were used to characterize the gastric cancer metastasis ecosystem and investigated its dynamic changes of cell proportion, cell functional profiles and cell-to-cell communication during RT. Immunohistochemical and immunofluorescent staining and bulk RNA sequencing were applied to validate the key results. We found tumor cells upregulated immune checkpoint genes in response to RT. The infiltration and clonal expansion of T lymphocytes declined within tumors undergoing irradiation. Moreover, RT led to the accumulation of proinflammatory macrophages and natural killer T cells with enhanced cytotoxic gene expression signature. In addition, subclusters of dendritic cells and endothelial cells showed decrease in the expression of antigen present features in post-RT samples. More ECM component secreted by myofibroblasts during RT. These findings indicate that RT induced the dynamics of the immune response that should be taken into consideration when designing and clinically implementing innovative multimodal cancer treatment regimens of different RT and immunotherapy approaches.
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Probiotics are potential treatments for ulcerative colitis (UC), but their efficacy is frequently compromised by gastrointestinal conditions that limit adhesion and activity. Here, we use machine learning and bioinformatics to confirm that patients with UC have decreased prevalence of Lactobacillus genus and increased oxidative stress, which correlate with inflammation severity. Accordingly, we developed a probiotic-based therapeutic that synergistically restores intestinal redox and microbiota homeostasis. Lactobacillus casei (Lac) were induced to form a pericellular film, providing a polysaccharide network for spatially confined crystallization of ultrasmall but highly active selenium dots (Se-Lac). Upon oral administration, the selenium dot-embedded pericellular film efficiently enhanced gastric acid resistance and intestinal mucoadhesion of Lac cells. At the lesion site, the selenium dots scavenged reactive oxygen species, while Lac modulated the gut microbiota. In multiple mouse models and non-human primates, this therapeutic effectively relieved inflammation and reduced colonic damage, thus showing promise as a UC treatment.