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ETHNOPHARMACOLOGICAL RELEVANCE: Zhubi Decoction (ZBD) is a modified formulation derived from the classic traditional Chinese medicine prescription "Er-Xian Decoction" documented in the esteemed "Clinical Manual of Chinese Medical Prescription". While the utilization of ZBD has exhibited promising clinical outcomes in treating rheumatoid arthritis (RA), the precise bioactive chemical constituents and the underlying mechanisms involved in its therapeutic efficacy remain to be comprehensively determined. AIM OF THE STUDY: This study aims to systematically examine ZBD's pharmacological effects and molecular mechanisms for RA alleviation. MATERIALS AND METHODS: Utilizing the collagen-induced arthritis (CIA) rat model, we comprehensively evaluated the anti-rheumatoid arthritis effects of ZBD in vivo through various indices, such as paw edema, arthritis index, ankle diameter, inflammatory cytokine levels, pathological conditions, and micro-CT analysis. The UPLC-MS/MS technique was utilized to analyze the compounds of ZBD. The potential therapeutic targets and signaling pathways of ZBD in the management of RA were predicted using network pharmacology. To analyze comprehensive metabolic profiles and identify underlying metabolic pathways, we conducted a serum-based widely targeted metabolomics analysis utilizing LC-MS technology. Key targets and predicted pathways were further validated using immunofluorescent staining, which integrated findings from serum metabolomics and network pharmacology analysis. Additionally, we analyzed the gut microbiota composition in rats employing 16 S rDNA sequencing and investigated the effects of ZBD on the microbiota of CIA rats through bioinformatics and statistical methods. RESULTS: ZBD exhibited remarkable efficacy in alleviating RA symptoms in CIA rats without notable side effects. This included reduced paw redness and swelling, minimized joint damage, improved the histopathology of cartilage and synovium, mitigated the inflammatory state, and lowered serum concentrations of cytokines TNF-α, IL-1ß and IL-6. Notably, the effectiveness of ZBD was comparable to MTX. Network pharmacology analysis revealed inflammation and immunity-related signaling pathways, such as PI3K/AKT, MAPK, IL-17, and TNF signaling pathways, as vital mediators in the effectual mechanisms of ZBD. Immunofluorescence analysis validated ZBD's ability to inhibit PI3K/AKT pathway proteins. Serum metabolomics studies revealed that ZBD modulates 170 differential metabolites, partially restored disrupted metabolic profiles in CIA rats. With a notable impact on amino acids and their metabolites, and lipids and lipid-like molecules. Integrated analysis of metabolomics and network pharmacology identified 6 pivotal metabolite pathways and 3 crucial targets: PTGS2, GSTP1, and ALDH2. Additionally, 16 S rDNA sequencing illuminated that ZBD mitigated gut microbiota dysbiosis in the CIA group, highlighting key genera such as Ligilactobacillus, Prevotella_9, unclassified_Bacilli, and unclassified_rumen_bacterium_JW32. Correlation analysis disclosed a significant link between 47 distinct metabolites and specific bacterial species. CONCLUSION: ZBD is a safe and efficacious TCM formulation, demonstrates efficacy in treating RA through its multi-component, multi-target, and multi-pathway mechanisms. The regulation of inflammation and immunity-related signaling pathways constitutes a crucial mechanism of ZBD's efficacy. Furthermore, ZBD modulates host metabolism and intestinal flora. The integrated analysis presents experimental evidence of ZBD for the management of RA.

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Artritis Experimental , Artritis Reumatoide , Medicamentos Herbarios Chinos , Microbioma Gastrointestinal , Metabolómica , Farmacología en Red , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Artritis Experimental/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Masculino , Ratas , Antirreumáticos/farmacología , Antirreumáticos/uso terapéutico , Citocinas/sangre , Citocinas/metabolismo , Transducción de Señal/efectos de los fármacos

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BACKGROUND Cardiac calcified amorphous tumor (CCAT), a peculiar and uncommon non-neoplastic cardiac lesion, was initially characterized by Reynolds and colleagues in the medical literature in 1997. This distinctive entity is hallmarked by its unique feature of pedunculated and diffused calcifications, primarily infiltrating the cardiac structures, with a predilection for the mitral valve annulus initially, followed in sequence by the right atrium, right ventricle, left atrium, left ventricle, and tricuspid valve annulus. The nature of CCATs, despite being benign, poses diagnostic dilemmas, as they frequently masquerade as malignant tumors due to their clinical presentations, which resemble those caused by potential complications such as obstructive masses and thromboembolic events. CASE REPORT A 50-year-old man presented to our hospital with shortness of breath. He had been short of breath for more than 5 years after repeated activities. Transthoracic echocardiography showed a mobile high echogenic mass from the middle of the right ventricular wall and pericardial effusion and right heart insufficiency. The electrocardiogram (ECG) results demonstrated a sinus rhythm, complete right bundle branch block, and T-wave alterations. Additionally, the chest computed tomography (CT) scan revealed a slightly enlarged heart with a lack of density and calcification in the right ventricle. He had an uneventful postoperative recovery after the resection of the cardiac tumor. The mass had not continued to grow when we compared it with preoperative cardiac color doppler echocardiography, after 3 months follow-up. CONCLUSIONS CCAT is a rare non-neoplastic cardiac entity. Diagnosis of CCAT poses a challenge due to the absence of distinct clinical features and its frequent misidentification as a malignant tumor mimic. Surgical resection serves as the sole treatment for symptom relief.

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Calcinosis , Neoplasias Cardíacas , Ventrículos Cardíacos , Humanos , Masculino , Persona de Mediana Edad , Calcinosis/diagnóstico por imagen , Neoplasias Cardíacas/diagnóstico , Neoplasias Cardíacas/diagnóstico por imagen , Neoplasias Cardíacas/cirugía , Diagnóstico Diferencial , Ecocardiografía , Tomografía Computarizada por Rayos X

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Background: Hepatocellular carcinoma (HCC) remains one of the most lethal cancers globally. Patients with advanced HCC tend to have poor prognoses and shortened survival. Recently, data from bulk RNA sequencing have been employed to discover prognostic markers for various cancers. However, they fall short in precisely identifying core molecular and cellular activities within tumor cells. In our present study, we combined bulk-RNA sequencing (bulk RNA-seq) data with single-cell RNA sequencing (scRNA-seq) to develop a prognostic model for HCC. The goal of our research is to uncover new biomarkers and enhance the accuracy of HCC prognosis prediction. Methods: Integrating single-cell sequencing data with transcriptomics were used to identify epithelial-mesenchymal transition (EMT)-related genes (ERGs) implicated in HCC progression and their clinical significance was elucidated. Utilizing marker genes derived from core cells and ERGs, we constructed a prognostic model using univariate Cox analysis, exploring a multitude of algorithmic combinations, and further refining it through multivariate Cox analysis. Additionally, we conducted an in-depth investigation into the disparities in clinicopathological features, immune microenvironment composition, immune checkpoint expression, and chemotherapeutic drug sensitivity profiles between high- and low-risk patient cohorts. Results: We developed a prognostic model predicated on the expression profiles of eight signature genes, namely HSP90AA1, CIRBP, CCR7, S100A9, ADAM17, ENG, PGF, and INPP4B, aiming at predicting overall survival (OS) outcomes. Notably, patients classified with high-risk scores exhibited a propensity towards diminished OS rates, heightened frequencies of stage III-IV disease, increased tumor mutational burden (TMB), augmented immune cell infiltration, and diminished responsiveness to immunotherapeutic interventions. Conclusions: This study presented a novel prognostic model for predicting the survival of HCC patients by integrating scRNA-seq and bulk RNA-seq data. The risk score emerges as a promising independent prognostic factor, showing a correlation with the immune microenvironment and clinicopathological features. It provided new clinical tools for predicting prognosis and aided future research into the pathogenesis of HCC.

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Emergent superconductivity at the LaAlO3/KTaO3 interfaces exhibits a mysterious dependence on the KTaO3 crystallographic orientations. Here by soft X-ray angle-resolved photoemission spectroscopy, we directly resolve the electronic structure of the LaAlO3/KTaO3 interfacial superconductors and the non-superconducting counterpart. We find that the mobile electrons that contribute to the interfacial superconductivity show strong k⊥ dispersion. Comparing the superconducting and non-superconducting interfaces, the quasi-three-dimensional electron gas with over 5.5 nm spatial distribution ubiquitously exists and shows similar orbital occupations. The signature of electron-phonon coupling is observed and intriguingly dependent on the interfacial orientations. Remarkably, the stronger electron-phonon coupling signature correlates with the higher superconducting transition temperature. Our observations help scrutinize the theories on the orientation-dependent superconductivity and offer a plausible and straightforward explanation. The interfacial orientation effect that can modify the electron-phonon coupling strength over several nanometers sheds light on the applications of oxide interfaces in general.

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Developing drug delivery systems capable of achieving deep tumor penetration is a challenging task, yet there is a significant demand for such systems in cancer treatment. Hitchhiking on tumor-derived extracellular vesicles (EVs) represents a promising strategy for enhancing drug penetration into tumors. However, the limited drug assembly on EVs restricts its further application. Here, we present a novel approach to efficiently attach antitumor drugs to EVs using an engineered cell membrane-based vector. This vector includes the AS1411 aptamer for tumor-specific targeting, the vesicular stomatitis virus glycoprotein (VSV-G) for tumor cell membrane fusion, and a photosensitizer as the therapeutic agent while ensuring optimal drug encapsulation and stability. Upon injection, photosensitizers are firstly transferred to the tumor cell membrane and subsequently piggybacked onto EVs with the inherent secretion process. By hitchhiking with EVs, photosensitizers can be transferred layer by layer deep into the solid tumors. The results suggest that this EVs-hitchhiking strategy enables photosensitizers to penetrate deeply into tumor tissue, thereby enhancing the efficacy of phototherapy. This study offers broad application prospects for delivering drugs deeply into tumor tissues.

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BACKGROUND: Atherosclerotic (AS) plaques require a dense necrotic core and a robust fibrous cap to maintain stability. While previous studies have indicated that the traditional Chinese medicine Huang Lian Jie Du Decoction (HLJDD) possesses the capability to stabilize AS plaques, the underlying mechanisms remain obscure. This study aims to delve deeper into the potential mechanisms by which HLJDD improves AS through an integrated research strategy. METHODS: Leveraging an AS model in ApoE-/- mice exposed to a high-fat diet (HFD), we scrutinized the therapeutic effects of HLJDD using microscopic observations, oil red O staining, HE staining and Masson staining. Employing comprehensive techniques of network pharmacology, bioinformatics, and molecular docking, we elucidated the mechanism by which HLJDD stabilizes AS plaques. In vitro experiments, utilizing ox-LDL-induced macrophages and apoptotic vascular smooth muscle cells (VSMCs), assessed the impact of HLJDD on efferocytosis and the role of SLC2A1. RESULTS: In vivo experiments showcased the efficacy of HLJDD in reducing the quantity of aortic plaques, diminishing lipid deposition, and enhancing plaque stability in AS mice. Employing network pharmacology and machine learning, we pinpointed SLC2A1 as a crucial regulatory target. Molecular docking further validated the binding of HLJDD components with SLC2A1. The experiments demonstrated a dose-dependent upregulation in SLC2A1 expression by HLJDD, amplifying efferocytosis. Importantly, this effect was reversed by the SLC2A1 inhibitor STF-31, highlighting the pivotal role of SLC2A1 as a target. CONCLUSION: The HLJDD can modulate macrophage efferocytosis by enhancing the expression levels of SLC2A1, thereby improving the stability of atherosclerotic plaques.

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Medicamentos Herbarios Chinos , Transportador de Glucosa de Tipo 1 , Macrófagos , Placa Aterosclerótica , Animales , Placa Aterosclerótica/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Ratones , Masculino , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Transportador de Glucosa de Tipo 1/metabolismo , Transportador de Glucosa de Tipo 1/genética , Dieta Alta en Grasa , Ratones Endogámicos C57BL , Fagocitosis/efectos de los fármacos , Humanos , Simulación del Acoplamiento Molecular , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Modelos Animales de Enfermedad , Apoptosis/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Lipoproteínas LDL/metabolismo , Células RAW 264.7 , Ratones Noqueados para ApoE , Eferocitosis

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Objective To investigate the effects and underlying mechanisms of tetratricopeptide repeat domain 36 (TTC36) on injury of HK2 renal tubular epithelial cell. Methods HK2 stable cell lines expressing either TTC36 and an empty vector control-CMV-Flag were generated with lentivirus . The mRNA expression level of tumor necrosis factor α (TNF-α), inducible nitric oxide synthase(iNOS), interleukin 6(IL-6), C-C motif chemokine ligand 2(CCL2), IL-1ß, inhibitor of nuclear factor κB α(IκBα) and nuclear factor κB p65(NF-κB p65) were analyzed by real time quantitative PCR (qRT-PCR). Flow cytometry was used to quantify cell apoptosis. Cell proliferation was evaluated by using cell counting kit-8(CCK-8) assay. The protein expression levels of iNOS, TNF-α, caspase-3, cleaved-caspase-3(c-caspase-3), Bcl2 associated X protein(BAX), proliferating cell nuclear antigen (PCNA), zonula occludens 1(ZO-1), IκBα, NF-κB p65, and phosphorylated NF-κB p65(p-NF-κB p65) were determined by Western blot analysis. IκBα protein expression level was further analyzed by Western blot after being treated with cycloheximide (CHX) and MG132. Results Compared with the control group, the expression of inflammatory molecules were reduced after the overexpression of TTC36 in HK2 cells. TTC36 inhibited the apoptosis of HK2 cells, and the expression of apoptosis-related proteins c-caspase-3 and BAX were significantly decreased in the TTC36 overexpression group. Upregulation of TTC36 promoted cell proliferation and strengthened the expressions of PCNA and ZO-1. Meanwhile, the expression of IκBα was significantly increased, while that of NF-κB p65 and p-NF-κB p65 was markedly downregulated. Furthermore, TTC36 overexpression substantially prolonged the half-life of IκBα in HK2 cells after being treated with CHX. MG132 could restore the changes of IκBα caused by overexpression of TTC36. Conclusion Overexpression of TTC36 inhibits the inflammatory response of HK2 cells, reduces cell apoptosis, promotes proliferation, and strengthens tight junctions. The mechanism may be to inhibit the activation of NF-κB signaling pathway by enhancing the expression of IκBα, thereby reducing the cell damage caused by inflammatory response.

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Apoptosis , Proliferación Celular , Inhibidor NF-kappaB alfa , FN-kappa B , Transducción de Señal , Humanos , Transducción de Señal/efectos de los fármacos , Inhibidor NF-kappaB alfa/metabolismo , Inhibidor NF-kappaB alfa/genética , FN-kappa B/metabolismo , FN-kappa B/genética , Apoptosis/efectos de los fármacos , Línea Celular , Proliferación Celular/efectos de los fármacos , Inflamación/genética , Inflamación/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Transcripción ReIA/metabolismo , Factor de Transcripción ReIA/genética , Células Epiteliales/metabolismo , Células Epiteliales/efectos de los fármacos , Túbulos Renales/metabolismo , Túbulos Renales/citología

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Water stress, a significant abiotic stressor, significantly hampers crop growth and yield, posing threat to food security. Despite the promising potential of nanoparticles (NPs) in enhancing plant stress tolerance, the precise mechanisms underlying the alleviation of water stress using O-Carboxymethyl chitosan nanoparticles (O-CMC-NPs) in maize remain elusive. In this study, we synthesized O-CMC-NPs and delved into their capacity to mitigate water stress (waterlogging and drought) in maize seedlings. Structural characterization revealed spherical O-CMC-NPs with a size of approximately 200 nm. These NPs accumulated near the seed embryo and root tip, resulting in a substantial increase in fresh and dry weights. The application of O-CMC-NPs to water-stressed maize seedlings remarkedly elevated the chlorophyll content and activity of various antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), and polyphenol oxidase (PPO). The malondialdehyde (MDA) content was significantly reduced compared to the untreated control. Additionally, the expression of stress-responsive genes, such as ZmSOD, ZmCAT, ZmPOD, ZmTIFY, ZmACO, ZmPYL2, ZmNF-YC12, and ZmEREB180, were significantly upregulated in the O-CMC-NPs treated seedlings. These findings unveil the novel role of O-CMC-NPs in enhancing plant stress tolerance, suggesting their potential application in safeguarding maize seedlings under water stress conditions and facilitating the recovery from oxidative damage.

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Quitosano , Nanopartículas , Plantones , Zea mays , Zea mays/efectos de los fármacos , Zea mays/metabolismo , Quitosano/análogos & derivados , Quitosano/química , Quitosano/farmacología , Nanopartículas/química , Plantones/efectos de los fármacos , Plantones/crecimiento & desarrollo , Plantones/metabolismo , Regulación de la Expresión Génica de las Plantas/efectos de los fármacos , Agua/química , Antioxidantes/metabolismo , Estrés Fisiológico/efectos de los fármacos , Deshidratación , Proteínas de Plantas/metabolismo , Clorofila/metabolismo , Malondialdehído/metabolismo

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The size of the initial primordial follicle pool in the ovary depends on primordial follicle formation, which determines the female reproductive lifespan. However, the molecular regulation of primordial follicle formation in chickens remains unclear. In this study, the left ovaries of chickens were collected at 2 d posthatch (dph), 5.5 dph, and 10.5 dph to examine the formation of primordial follicles. Single-cell mRNA sequencing (scRNA-seq) and spatial transcriptomic analysis were performed to explore the ovarian microenvironment and identify regulatory pathways involved in the formation of primordial follicles in chickens. Histomorphological analysis of chicken ovary tissues revealed the presence of germ cell cysts at 1 dph, which began to disintegrate at 2 dph. Primordial follicles appeared at 5.5 dph and continued to develop into larger-diameter follicles. scRNA-seq and spatial transcriptomic analysis revealed 24 cellular clusters involved in chicken primordial follicle formation. The metabolic pathway of steroid hormone synthesis was found in pregranulosa and pretheca cells. Histological analysis showed that chicken ovaries did not form primordial follicles after the inhibition of the steroid hormone synthesis pathway by simvastatin or tamoxifen. In addition, mRNA transcriptomic and bioinformatics analyses revealed that GREB1 was a downstream gene of the steroid hormone synthesis pathway during the formation of chicken primordial follicles. This study provides a valuable foundation for investigating primordial follicle formation in avian species and optimizing their reproductive performance.

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BACKGROUND: Atherosclerosis (AS) is the main cause of coronary heart disease, cerebral infarction, and peripheral vascular disease. QingRe HuoXue Formula (QRHXF), a common prescription of traditional Chinese medicine, has a definite effect on the clinical treatment of AS, but its mechanism remains to be further explored. PURPOSE: The current study aimed to demonstrate the effectiveness of the QRHXF in the treatment of AS and further reveal its potential pharmacological mechanisms. METHODS: Explore the potential mechanisms of QRHXF in treating AS through network pharmacology, machine learning, transcriptome analysis, and molecular docking, then validate them through animal experiments and PCR experiments. RESULTS: The results indicate that through network pharmacology and machine learning methods, 10 genes including COL1A1 and CCR7 have been identified as potential candidate genes for QRHXF treatment of atherosclerosis. Molecular docking indicates that the key active compounds of QRHXF have good binding affinity with the predicted genes. Two key genes, COL1A1 and CCR7, were identified through transcriptome sequencing analysis of the aortic tissue of APOE-/- mice in the AS model. Finally, the animal and PCR experiment found that QRHXF can effectively reduce the formation of aortic plaques in APOE-/- mice of the AS model, lower blood lipid levels in mice, and upregulate the mRNA expression level of COL1A1, promoting the formation of fibrosis within plaques. CONCLUSIONS: We revealed the inflammatory and immune pathways underlying QRHXF treatment for AS, and verified through transcriptome sequencing and experiments that QRHXF can promote the expression of COL1A1, thereby increasing the stability of AS plaques.

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Aterosclerosis , Cadena alfa 1 del Colágeno Tipo I , Biología Computacional , Medicamentos Herbarios Chinos , Aprendizaje Automático , Simulación del Acoplamiento Molecular , Animales , Medicamentos Herbarios Chinos/uso terapéutico , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/genética , Biología Computacional/métodos , Ratones , Humanos , Masculino , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Placa Aterosclerótica/tratamiento farmacológico

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Understanding the maintenance and shift in reproductive strategies is a fundamental question in evolutionary research. Although many efforts have been made to compare different reproductive strategies, the association between reproductive strategies and lineage divergence is largely unknown. To explore the impact of different reproductive strategies on lineage divergence, we investigated the evolution of clonality in Saxifraga sect. Irregulares+Heterisia. By integrating several lines of evidence, we found that the loss of clonality in Irregulares+Heterisia was associated with a progressive increase in diversification rate and intraspecific morphological diversity but with a reduction in species distribution range. Our findings provide insights into the ecological and evolutionary effects of different reproductive strategies, suggesting the necessity of integrating clonality into ecological and evolutional research.

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Hipocampo , Neuronas , Transmisión Sináptica , Neuronas/efectos de la radiación , Neuronas/fisiología , Hipocampo/efectos de la radiación , Hipocampo/citología , Animales , Transmisión Sináptica/efectos de la radiación , Radiación Terahertz , Células Cultivadas , Ratas

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Aluminum adjuvants remain the most commonly used vaccine adjuvants. Being rather effective in triggering humoral immunity, however, aluminum adjuvants usually show limited abilities in activating cellular immunities. Herein, by adding manganese ions during the preparation of aluminum adjuvant, a manganese-modified aluminum (Mn-Al) adjuvant is obtained, which can effectively stimulate both humoral and cellular immune responses. Such Mn-Al adjuvant can enhance antigen adsorption and promote antigen internalization by dendritic cells (DCs). Subsequently, the released Mn2+ can activate the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes pathway to further promote DC activation. When combines with the model antigen ovalbumin (OVA), the Mn-Al-adjuvantes vaccine can induce high levels of antigen-specific antibody titers and high proportions of antigen-specific cytotoxic T cells in vivo. Moreover, the Mn-Al-adjuvanted vaccine elicited stronger antigen-specific humoral and cellular immune responses than high-dose of the aluminum-based adjuvant. Additionally, immunization of mice with OVA in the presence of the Mn-Al adjuvant significantly inhibited the growth of B16-OVA tumors. Furthermore, when formulated with human papillomavirus antigens, Mn-Al-adjuvanted vaccines show better in vivo vaccination performance than aluminum-adjuvanted vaccines. Therefore, the manganese-modified aluminum adjuvant may thus become a new vaccine adjuvant with the potential to replace conventional aluminum adjuvants.

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BACKGROUND AND AIMS: Biopterins, including tetrahydrobiopterin (BH4), dihydrobiopterin (BH2), and biopterin (B), were crucial enzyme cofactors in vivo. Despite their recognized clinical significance, there remain notable research gaps and controversies surrounding experimental outcomes. This study aims to clarify the biopterins-related issues, including analytical art, physiological intervals, and pathophysiological implications. MATERIALS AND METHODS: A novel LC-MS/MS method was developed to comprehensively profile biopterins in plasma, utilizing chemical derivatization and cold-induced phase separation. Subsequently, apparently healthy individuals were enrolled to investigate the physiological ranges. And the relationships between biopterins and biochemical indicators were analyzed to explore the pathophysiological implications. RESULTS: The developed method was validated as reliable for detecting biopterins across the entire physiological range. Timely anti-oxidation was found to be essential for accurate assessment of biopterins. The observed overall mean ± SDs levels were 3.51 ± 0.94, 1.54 ± 0.48, 2.45 ± 0.84 and 5.05 ± 1.14 ng/mL for BH4, BH2, BH4/BH2 and total biopterins. The status of biopterins showed interesting correlations with age, gender, hyperuricemia and overweight. CONCLUSION: In conjunction with proper anti-oxidation, the newly developed method enables accurate determination of biopterins status in plasma. The observed physiological intervals and pathophysiological implications provide fundamental yet inspiring support for further clinical researches.

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Biopterinas , Espectrometría de Masas en Tándem , Humanos , Biopterinas/análogos & derivados , Biopterinas/sangre , Biopterinas/metabolismo , Femenino , Masculino , Adulto , Espectrometría de Masas en Tándem/métodos , Persona de Mediana Edad , Cromatografía Liquida/métodos , Adulto Joven , Anciano , Biomarcadores/sangre

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Drug development remains a critical focus within the global pharmaceutical industry. To date, more than 80 % of disease targets are considered difficult to target. The emergence of PROTAC technology has, to some extent, alleviated this challenge. Since introduction, PROTAC technology has evolved through the peptide E3 ligase ligand phase and the small molecule E3 ligase ligand phase. Currently, multiple PROTAC molecules are in the clinical research phase, showing promising potential for addressing drug resistance, disease recurrence, and intractable targets. Target deconvolution is a crucial step in the drug discovery and development process. Due to the exceptional targeting ability and specificity of PROTAC, it is widely used and promoted as an innovative technology for discovering new drug targets, leading to significant breakthroughs. The use of PROTAC probe requires only a catalytic dose and weak interaction with the target protein to achieve target degradation. Thus, it offers substantial advantages over traditional probes, particularly in identifying new targets that are low-abundance or difficult to target. This review provides a comprehensive overview of the advancements made by PROTAC technology in drug development and drug target discovery, while also systematically reviewing the workflow of PROTAC probe. With the ongoing development of PROTAC technology, PROTAC probe is poised to become a key research area in future drug target deconvolution.

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Desarrollo de Medicamentos , Descubrimiento de Drogas , Humanos , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/antagonistas & inhibidores , Ligandos , Estructura Molecular

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T-cell receptor (TCR) engineered T-cell therapy, unlike chimeric antigen receptor T-cell therapy, relies on the inherent ability of TCRs to detect a wider variety of antigenic epitopes, such as protein fragments found internally or externally on cells. Hence, TCR-T-cell therapy offers broader possibilities for treating solid tumors. However, because of the complicated process of identifying specific antigenic peptides, their clinical application still encounters significant challenges. Thus, we aimed to establish a novel "universal" TCR-T "artificial antigen expression" technique that involves the delivery of the antigen to tumor cells using DSPE-PEG-NY-ESO-1157-165 liposomes (NY-ESO-1 Lips) to express TCR-T-cell-specific recognition targets. In vitro as well as in vivo studies revealed that they could accumulate efficiently in the tumor area and deliver target antigens to activate the tumor-specific cytotoxic T-cell immune response. NY-ESO-1 TCR-T therapy, when used in combination, dramatically curbed tumor progression and extended the longevity of mice. Additionally, PD-1 blockage enhanced the therapeutic effect of the aforementioned therapy. In conclusion, NY-ESO-1 Lips "cursed" tumor cells by enabling antigenic target expression on their surface. This innovative technique presents a groundbreaking approach for the widespread utilization of TCR-T in solid tumor treatment.

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Background: As an autoimmune disease, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) often affects multiple organs, including the ocular system. This study aims to investigate differences in retinal thickness (RT) and retinal superficial vascular density (SVD) between patients with AAV and healthy controls (HCs) using optical coherence tomography angiography (OCTA). Currently, these differences are not clear. Methods: A total of 16 AAV individuals (32 eyes) and 16 HCs (32 eyes) were recruited to this cross-sectional study conducted in the First Affiliated Hospital of Nanchang University from June 2023 to September 2023. The study protocol conformed with the tenets of the Declaration of Helsinki (as revised in 2013). Each image observed by OCTA was divided into 9 regions using the Early Treatment Diabetic Retinopathy Study (ETDRS) subzones as a guide. Results: In the full layer, the RT of AAV patients was found to be significantly reduced in the inner superior (IS, P<0.001), outer superior (OS, P=0.003), inner temporal (IT, P=0.003), and outer temporal (OT, P<0.001) regions; inner RT was significantly lower in the IS (P=0.006), OS (P<0.001), inner nasal (IN, P=0.005), outer nasal (ON, P<0.001), and center (C, P=0.01) regions than that in HCs. Outer RT of AAV patients showed a reduction in the IS (P<0.001), as well as IT (P=0.008), and OT (P<0.001) regions. No statistically significant differences were seen in the different subregions in other different layers (P>0.05). Only the inner inferior (II) and outer inferior (OI) regions of SVD in AAV patients did not differ significantly from controls. All other regions showed a reduction in SVD. The details are as follows: IS (P<0.001), OS (P<0.001), IT (P=0.005), OT (P<0.001), IN (P<0.001), ON (P<0.001), and C (P=0.003). According to receiver operating characteristic (ROC) curve analysis, the full IS region [area under the curve (AUC): 0.8892, 95% confidence interval (CI): 0.8041-0.9742, P<0.001] had the highest diagnostic value for AAV-induced reduction in RT. The IS (AUC: 0.9121, 95% CI: 0.8322-0.9920, P<0.001) region was also the most sensitive to changes in SVD of AAV individuals. In addition, we found that SVD in the IN region (r=-0.4224, 95% CI: -0.6779 to -0.0757, P=0.02) as well as mean visual acuity (r=-0.3922, 95% CI: -0.6579 to -0.0397, P=0.03) of AAV patients were negatively correlated with disease duration. However, we did not find an association between SVD and RT in this study. Conclusions: The findings from OCTA indicated a reduction in RT and SVD among patients with AAV. OCTA allows for the evaluation of AAV-related ocular lesions and holds promise for monitoring of disease progression through regular evaluations.