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BACKGROUND: Neoadjuvant immunotherapy using immune checkpoint inhibitors (ICIs) has revolutionized the treatment of early stage non-small cell lung cancer (NSCLC). However, little is known about which patients are likely to benefit most from neoadjuvant immunotherapy. In this study, we performed a multiplatform analysis on samples from resectable NSCLC treated with neoadjuvant immunotherapy to explore molecular characteristics related to immune responses. PATIENTS AND METHODS: A total of 17 patients with resectable stage IB-IIIA NSCLC treated with neoadjuvant immunotherapy were included. A multiplex cytokine assay, bulk TCR sequencing in peripheral blood, and multiplexed immunohistochemistry were performed. RESULTS: Low levels of stromal cell-derived factor (SDF)-1alpha at baseline were associated with unfavorable disease-free survival (DFS). Patients with major pathologic response (MPR) showed a decrease in HGF after one cycle of neoadjuvant immunotherapy. An increase in IDO and IP-10 was observed in patients who developed immune-related adverse events (irAEs) after neoadjuvant immunotherapy. There were no correlations between irAEs and MPR or DFS. The MPR group presented a significant decrease in white blood cells and neutrophil count after neoadjuvant immunotherapy. The high peripheral baseline TCR convergence was correlated with MPR and favorable DFS in lung squamous cell carcinoma (LUSC) receiving neoadjuvant immunotherapy. Neoadjuvant immunotherapy led to a significant increase in CD4+, CD8+, and CD8+CD39+ T-cell infiltration in tumor areas. CONCLUSIONS: This study suggests the potential roles of cytokines and TCR convergence for predicting ICIs response in resectable NSCLC and LUSC. CD8+CD39+T cells and CD4+ T cells could be involved in the action of neoadjuvant immunotherapy.
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Arisaema cum bile (known as Dan Nanxing in Chinese, DNX) is a herbal medicine used for treating febrile seizure (FS), which commonly prepared by using Arisaematis Rhizoma and animal bile. This study was designed to explore the optimal processing time of DNX and its potential mechanism on the anti-FS effect. A total of 17 volatile organic compounds (VOCs) were the characteristic ones to distinguish different fermentation stages of DNX by using gas chromatography-ion mobility spectrometry (GC-IMS), such as 2-heptanone monomer, and heptanal monomer. DNX with fermentation for 3 months had an obvious pattern of VOCs with others, which could be regarded as the optimal fermentation time. The Enterococcus and Staphylococcus might be the core bacteria on the production of VOCs. Additionally, DNX (2.8 g/kg, p.o.) reversed hot water bath-induced FSs of rats, as indicated by increased seizure latency and decreased seizure duration time. It also prevented hippocampal neuronal loss, increased GABAAR, and decreased GRIA1 expression. At the genus level, relative abundance of Enterococcus and Akkermansia were enriched after DNX treatment. These findings suggested that fermentation for 3 months might be the optimal process time for DNX, and DNX possess an anti-FS effect through regulating neurotransmitter disorder and gut microbiota.
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Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that certain of the western blotting data shown in Fig. 4B and C on p. 1952, and the Transwell invasion assay data in Fig. 2F and 4I, had already appeared in previously published articles written by different authors at different research institutes (a number of which have been retracted). Owing to the fact that the contentious data in the above article had already been published prior to its submission to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 42: 19461956, 2019; DOI: 10.3892/or.2019.7302].
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BACKGROUND: Currently approved targeted treatment for ROS1-rearranged non-small-cell lung cancer (NSCLC) has either inadequate intracranial activity or CNS-related toxicities. We evaluated the efficacy and safety of foritinib, a novel ALK and ROS1 inhibitor, in patients with advanced ROS1-rearranged NSCLC. METHODS: This two-part (phase 2a and 2b), multicentre, single-arm, open-label, phase 2 study was done in 29 centres in China. Eligible participants were adults (aged ≥18 years) with histologically or cytologically confirmed ROS1-rearranged, locally advanced or metastatic stage IIIB-IV NSCLC, with an Eastern Cooperative Oncology Group performance status of 2 or less. Patients who had previously received no or one ROS1 inhibitor were enrolled into phase 2a, and patients who were naive to ROS1 inhibitor therapy were enrolled into phase 2b cohort 1. Participants in phase 2a received 80, 120, 160, or 210 mg foritinib succinate (foritinib) orally once daily over 21-day cycles; patients in phase 2b received the recommended phase 2 dose of 160 mg. The primary endpoint was objective response rate, assessed by the independent review committee in the full analysis set (ie, all participants who received at least one dose of study treatment). The safety analysis set included all participants who received at least one dose of study treatment and had available safety assessments. This study is ongoing and is registered with ClinicalTrials.gov, NCT04237805. FINDINGS: Between March 26, 2020, and Dec 29, 2022, 104 patients were enrolled and treated. Six patients who had previously received more than one ROS1 inhibitor were enrolled in phase 2a before a protocol amendment stating that patients in this phase should have received no more than one ROS1 inhibitor; these patients were included in the safety analysis but excluded from the efficacy analysis of the ROS1-inhibitor-pretreated cohort. Therefore, the efficacy analysis set (n=98) included 42 patients from phase 2a (17 who were ROS1 inhibitor naive and 25 who had previously received ROS1 inhibitor) and 56 patients from phase 2b cohort 1. In phase 2a, the objective response rate was 94% (95% CI 71-100; 16 of 17 patients) in patients who were ROS1 inhibitor naive and 40% (21-61; ten of 25) in patients who had previously received ROS1 inhibitor. In phase 2b cohort 1, the objective response rate was 88% (95% CI 76-95; 49 of 56 patients). In a prespecified exploratory analysis in 41 patients with CNS metastases at baseline, the objective response rate was 100% (95% CI 48-100; five of five patients) in patients in phase 2a who were ROS1 inhibitor naive, 40% (16-68; six of 15) in patients in phase 2a who had previously received ROS1 inhibitor, and 90% (70-99; 19 of 21) in patients in phase 2b cohort 1. Grade 3-4 treatment-related adverse events occurred in 33 (32%) of 104 patients; the most common were hyperglycaemia (12 [12%] patients) and electrocardiogram prolonged QT interval (six [6%]). Serious treatment-related adverse events occurred in 11 (11%) patients, with hyperglycaemia (six [6%]) being most common. No treatment-related adverse events led to death. INTERPRETATION: Foritinib showed systemic and intracranial antitumour activity and good tolerability in ROS1-inhibitor-naive patients with ROS1-rearranged NSCLC. Foritinib represents a promising treatment for these patients, especially in those with CNS metastases. FUNDING: Fosun Pharma, Wanbang Biopharmaceuticals, and Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer.
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2D functional porous frameworks offer a platform for studying the structure-activity relationships during electrocatalytic CO2 reduction reaction (CO2RR). Yet challenges still exist to breakthrough key limitations on site configuration (typical M-O4 or M-N4 units) and product selectivity (common CO2-to-CO conversion). Herein, a novel 2D metal-organic framework (MOF) with planar asymmetric N/O mixed coordinated Cu-N1O3 unit is constructed, labeled as BIT-119. When applied to CO2RR, BIT-119 could reach a CO2-to-C2 conversion with C2 partial current density ranging from 36.9 to 165.0 mA cm-2 in flow cell. Compared to the typical symmetric Cu-O4 units, asymmetric Cu-N1O3 units lead to the re-distribution of local electron structure, regulating the adsorption strength of several key adsorbates and the following catalytic selectivity. From experimental and theoretical analyses, Cu-N1O3 sites could simultaneously couple the atop-type (on Cu site) and bridge-type (on Cu-N site) adsorption of *C1 species to reach the CO2-to-C2 conversion. This work broadens the feasible C-C coupling mechanism on 2D functional porous frameworks.
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Ulcerative colitis (UC) is a chronic non-sp ecific inflammatory disease of the colorectal mucosa. Researchers have associated UC onset with familial genetics, lifestyle behavior, inflammatory immune factors, intestinal microbiota, and the integrity of the intestinal mucosal barrier. The primary therapeutic interventions for UC consist of pharmacological management to control inflammation and promote mucosal healing and surgical interventions. The available drugs effectively control and decelerate the progression of UC in most patients; nonetheless, their long-term administration can exert adverse effects and influence the therapeutic effect. Plant essential oils (EOs) refer to a group of hydrophobic aromatic volatile substances. EOs have garnered considerable attention in both domestic and international research because of their anti-inflammatory, antibacterial, and antioxidant properties. They include peppermint, peppercorns, rosemary, and lavender, among others. Researchers have investigated the role of EOs in medicine and have elucidated their potential to mitigate the detrimental effects of UC through their anti-inflammatory, antioxidant, antidepressant, and anti-insomnia properties as well as their ability to regulate the intestinal flora. Furthermore, EOs exert minimal toxic adverse effects, further enhancing their appeal for therapeutic applications. However, these speculations are based on theoretical experiments, thereby warranting more clinical studies to confirm their effectiveness and safety. In this article, we aim to provide an overview of the advancements in utilizing natural medicine EOs for UC prevention and treatment. We will explore the potential pathogenesis of UC and examine the role of EOs therapy in basic research, quality stability, and management specification of inadequate EOs for UC treatment. We intend to offer novel insights into the use of EOs in UC prevention and management.
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The need for tumor postoperative treatments aimed at recurrence prevention and tissue regeneration have raised wide considerations in the context of the design and functionalization of implants. Herein, an injectable hydrogel system encapsulated with anti-tumor, anti-oxidant dual functional nanoparticles has been developed in order to prevent tumor relapse after surgery and promote wound repair. The utilization of biocompatible gelatin methacryloyl (GelMA) was geared towards localized therapeutic intervention. Zeolitic imidazolate framework-8@ceric oxide (ZIF-8@CeO2, ZC) nanoparticles (NPs) were purposefully devised for their proficiency as reactive oxygen species (ROS) scavengers. Furthermore, injectable GelMA hydrogels loaded with ZC NPs carrying doxorubicin (ZC-DOX@GEL) were tailored as multifunctional postoperative implants, ensuring the efficacious eradication of residual tumor cells and alleviation of oxidative stress. In vitro and in vivo experiments were conducted to substantiate the efficacy in cancer cell elimination and the prevention of tumor recurrence through the synergistic chemotherapy approach employed with ZC-DOX@GEL. The acceleration of tissue regeneration and in vitro ROS scavenging attributes of ZC@GEL were corroborated using rat models of wound healing. The results underscore the potential of the multifaceted hydrogels presented herein for their promising application in tumor postoperative treatments.
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Doxorrubicina , Hidrogeles , Estructuras Metalorgánicas , Metacrilatos , Nanopartículas , Cicatrización de Heridas , Animales , Doxorrubicina/farmacología , Doxorrubicina/administración & dosificación , Doxorrubicina/química , Cicatrización de Heridas/efectos de los fármacos , Nanopartículas/química , Hidrogeles/química , Ratas , Humanos , Especies Reactivas de Oxígeno/metabolismo , Gelatina/química , Cerio/química , Cerio/farmacología , Zeolitas/química , Zeolitas/farmacología , Línea Celular Tumoral , Masculino , Imidazoles/química , Imidazoles/administración & dosificación , Imidazoles/farmacología , Ratas Sprague-DawleyRESUMEN
Sepsis remains a significant cause of mortality and morbidity worldwide, with limited effective treatment options. The T-cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3) has emerged as a potential therapeutic target in various immune-related disorders. This narrative review aims to explore the role of TIM-3 in sepsis and evaluate its potential as a promising target for immunotherapy. We discuss the dynamic expression patterns of TIM-3 during sepsis and its involvement in regulating immune responses. Furthermore, we examine the preclinical studies investigating the regulation of TIM-3 signaling pathways in septic models, highlighting the potential therapeutic benefits and challenges associated with targeting TIM-3. Overall, this review emphasizes the importance of TIM-3 in sepsis pathogenesis and underscores the promising prospects of TIM-3-based immunotherapy as a potential strategy to combat this life-threatening condition.
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Receptor 2 Celular del Virus de la Hepatitis A , Sepsis , Humanos , Receptor 2 Celular del Virus de la Hepatitis A/metabolismo , Inmunoterapia , Sepsis/terapia , Transducción de SeñalRESUMEN
Orbital hybridization to regulate the electronic structures and surface chemisorption properties of transition metals is of great importance for boosting the oxygen reduction reaction (ORR) in proton-exchange membrane fuel cells (PEMFCs). Herein, we developed a core-shell rambutan-like nanocarbon catalyst (FeAl-RNC) with atomically dispersed Fe-Al atom pairs from metal-organic framework (MOF) material. Experimental and theoretical results demonstrate that the strong p-d orbital hybridization between Al and Fe results in an asymmetric electron distribution with moderate adsorption strength of oxygen intermediates, rendering enhanced intrinsic ORR activity. Additionally, the core-shell rambutan-like structure of FeAl-RNC with abundant micropores and macropores can enhance the density of active sites, stability, and transport pathways in PEMFC. The FeAl-RNC-based PEMFC achieves excellent activity (68.4 mA cm-2 at 0.9 V), high peak power (1.05 W cm-2), and good stability with only 7% current loss after 100 h at 0.7 V under H2-O2 condition.
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Neuroblastoma (NB) is one of the highly vascularized childhood solid tumors, and understanding the molecular mechanisms underlying angiogenesis in NB is crucial for developing effective therapeutic strategies. B-cell receptor-associated protein 31 (BAP31) has been implicated in tumor progression, but its role in angiogenesis remains unexplored. This study investigated BAP31 modulation of pro-angiogenic factors in SH-SY5Y NB cells. Through protein overexpression, knockdown, antibody blocking, and quantification experiments, we demonstrated that overexpression of BAP31 led to increased levels of vascular endothelial growth factor A (VEGFA) and Galectin-3 (GAL-3), which are known to promote angiogenesis. Conditioned medium derived from BAP31-overexpressing neuroblastoma cells stimulated migration and tube formation in endothelial cells, indicating its pro-angiogenic properties. Also, we demonstrated that BAP31 enhances capillary tube formation by regulating hypoxia-inducible factor 1 alpha (HIF-1α) and its downstream target, GAL-3. Furthermore, GAL-3 downstream proteins, Jagged 1 and VEGF receptor 2 (VEGFR2), were up-regulated, and blocking GAL-3 partially inhibited the BAP31-induced tube formation. These findings suggest that BAP31 promotes angiogenesis in NB by modulating GAL-3 and VEGF signaling, thereby shaping the tumor microenvironment. This study provides novel insights into the pro-angiogenic role of BAP31 in NB.
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Neuroblastoma , Factor A de Crecimiento Endotelial Vascular , Niño , Humanos , Angiogénesis , Línea Celular Tumoral , Células Endoteliales/metabolismo , Galectina 3/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Neovascularización Patológica/patología , Neuroblastoma/metabolismo , Microambiente Tumoral , Regulación hacia Arriba , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Chemotherapy resistance is an insurmountable problem in clinical anticancer therapy. Although Oxaliplatin is an effective chemotherapeutic agent for the treatment of colorectal cancer (CRC), it still suffers from serious toxicities as well as drug resistance. In this work, three Oxaliplatin tetravalent platinum prodrugs(O1-O3) and three novel mixed ammine/amine analogs(C1-C3) were constructed, introducing cannabidiol with anti-tumor activity in their axial position. All Pt(IV) prodrugs exhibited potent antitumor effects in a variety of tumor cell lines, especially in HCT-116 cells, where complex O3 showed strong inhibitory effects with the half maximal inhibitory concentrations (IC50) value of 6.02 ± 0.69 µM and about 2.6 times higher than that of Oxaliplatin. Further studies revealed that complex O3 decreased cellular mitochondrial membrane potential in a concentration-dependent manner and enhanced reactive oxygen species (ROS) accumulation by decreasing the expression of catalase, superoxide dismutase 2 (SOD2) and superoxide dismutase 3 (SOD3). Complex O3 induces mitochondrial dysfunction and upregulates the pro-apoptotic protein Noxa, ultimately leading to severe DNA damage. The upregulation of Phosphorylated histone protein H2AX (γ-H2AX) expression is clear evidence. In addition, O3 inhibits the expression of RAD51 protein and prevents DNA damage repair, thus overcoming drug resistance. This strategy of combining bioactive molecules cannabidiol with platinum drugs to improve therapeutic efficacy and overcome drug resistance has been proven to be very effective and deserves further investigation.
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Antineoplásicos , Cannabidiol , Enfermedades Mitocondriales , Profármacos , Humanos , Oxaliplatino/farmacología , Antineoplásicos/farmacología , Platino (Metal)/farmacología , Cannabidiol/farmacología , Línea Celular Tumoral , Profármacos/farmacología , Apoptosis , Cisplatino/farmacologíaRESUMEN
Single atomic catalysts (SACs) offer a superior platform for studying the structure-activity relationships during electrocatalytic CO2 reduction reaction (CO2RR). Yet challenges still exist to obtain well-defined and novel site configuration owing to the uncertainty of functional framework-derived SACs through calcination. Herein, a novel Bi-N2O2 site supported on the (1 1 0) plane of hydrogen-bonded organic framework (HOF) is reported directly for CO2RR. In flow cell, the target catalyst Bi1-HOF maintains a faradaic efficiency (FE) HCOOH of over 90 % at a wide potential window of 1.4â V. The corresponding partial current density ranges from 113.3 to 747.0â mA cm-2. And, Bi1-HOF exhibits a long-term stability of over 30â h under a successive potential-step test with a current density of 100-400â mA cm-2. Density function theory (DFT) calculations illustrate that the novel Bi-N2O2 site supported on the (1 1 0) plane of HOF effectively induces the oriented electron transfer from Bi center to CO2 molecule, reaching an enhanced CO2 activation and reduction. Besides, this study offers a versatile method to reach series of M-N2O2 sites with regulable metal centers via the same intercalation mechanism, broadening the platform for studying the structure-activity relationships during CO2RR.
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Importance: Adjuvant and neoadjuvant immunotherapy have improved clinical outcomes for patients with early-stage non-small cell lung cancer (NSCLC). However, the optimal combination of checkpoint inhibition with chemotherapy remains unknown. Objective: To determine whether toripalimab in combination with platinum-based chemotherapy will improve event-free survival and major pathological response in patients with stage II or III resectable NSCLC compared with chemotherapy alone. Design, Setting, and Participants: This randomized clinical trial enrolled patients with stage II or III resectable NSCLC (without EGFR or ALK alterations for nonsquamous NSCLC) from March 12, 2020, to June 19, 2023, at 50 participating hospitals in China. The data cutoff date for this interim analysis was November 30, 2022. Interventions: Patients were randomized in a 1:1 ratio to receive 240 mg of toripalimab or placebo once every 3 weeks combined with platinum-based chemotherapy for 3 cycles before surgery and 1 cycle after surgery, followed by toripalimab only (240 mg) or placebo once every 3 weeks for up to 13 cycles. Main Outcomes and Measures: The primary outcomes were event-free survival (assessed by the investigators) and the major pathological response rate (assessed by blinded, independent pathological review). The secondary outcomes included the pathological complete response rate (assessed by blinded, independent pathological review) and adverse events. Results: Of the 501 patients randomized, 404 had stage III NSCLC (202 in the toripalimab + chemotherapy group and 202 in the placebo + chemotherapy group) and 97 had stage II NSCLC and were excluded from this interim analysis. The median age was 62 years (IQR, 56-65 years), 92% of patients were male, and the median follow-up was 18.3 months (IQR, 12.7-22.5 months). For the primary outcome of event-free survival, the median length was not estimable (95% CI, 24.4 months-not estimable) in the toripalimab group compared with 15.1 months (95% CI, 10.6-21.9 months) in the placebo group (hazard ratio, 0.40 [95% CI, 0.28-0.57], P < .001). The major pathological response rate (another primary outcome) was 48.5% (95% CI, 41.4%-55.6%) in the toripalimab group compared with 8.4% (95% CI, 5.0%-13.1%) in the placebo group (between-group difference, 40.2% [95% CI, 32.2%-48.1%], P < .001). The pathological complete response rate (secondary outcome) was 24.8% (95% CI, 19.0%-31.3%) in the toripalimab group compared with 1.0% (95% CI, 0.1%-3.5%) in the placebo group (between-group difference, 23.7% [95% CI, 17.6%-29.8%]). The incidence of immune-related adverse events occurred more frequently in the toripalimab group. No unexpected treatment-related toxic effects were identified. The incidence of grade 3 or higher adverse events, fatal adverse events, and adverse events leading to discontinuation of treatment were comparable between the groups. Conclusions and Relevance: The addition of toripalimab to perioperative chemotherapy led to a significant improvement in event-free survival for patients with resectable stage III NSCLC and this treatment strategy had a manageable safety profile. Trial Registration: ClinicalTrials.gov Identifier: NCT04158440.
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Anticuerpos Monoclonales Humanizados , Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Compuestos de Platino , Femenino , Humanos , Masculino , Persona de Mediana Edad , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/cirugía , Respuesta Patológica Completa , Antineoplásicos/uso terapéutico , Terapia Combinada , Compuestos de Platino/administración & dosificación , Compuestos de Platino/uso terapéutico , AncianoRESUMEN
PURPOSE: Frankincense has been shown in studies to have healing benefits for people with ulcerative colitis (UC). However, its underlying mechanisms have not been fully investigated. The objective of this study was to explore the potential molecular mechanisms of Frankincense essential oil (FREO) in improving dextran sodium sulfate (DSS)-induced UC from multiple perspectives. METHODS: The FREO components were analyzed by GC-MS, and the interactions between the key active components and the mechanism of FREO were determined based on RNA-seq, "quantity-effect" weighting coefficient network pharmacology, WGCNA and pharmacodynamic experiments. The protection of FREO against DSS-induced UC mice was assessed by behavioral and pathological changes through mice. The expression of pro-inflammatory cytokines was measured using enzyme-linked immunosorbent assay. The expression of MAPK and NF-κB-related proteins by the Western Blotting and immunohistochemistry method. RESULTS: Treatment with FREO significantly improved the symptoms of weight loss, diarrhea, stool blood, and colon shortening in UC mice. Reduced intestinal mucosal damage and the degree of inflammatory cell infiltration in the colon. Decreased TNF-α and IL-6 levels in mice's serum and inhibited phosphorylation of ERK, p65 in MAPK and NF-κB signaling. CONCLUSION: FREO may decrease the inflammatory response to reduce the symptoms of UC by modulating the MAPK/ NF-κB pathway. This may be due to the synergistic interaction of the effective ingredient Hepten-2-yl tiglate, 6-methyl-5-, Isoneocembrene A and P-Cymene. This study provides a promising drug candidate and a new concept for the treatment of UC.
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Colitis Ulcerosa , Colitis , Olíbano , Aceites Volátiles , Sulfatos , Humanos , Animales , Ratones , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/patología , FN-kappa B/metabolismo , Dextranos/metabolismo , Dextranos/farmacología , Dextranos/uso terapéutico , Olíbano/metabolismo , Olíbano/farmacología , Olíbano/uso terapéutico , Aceites Volátiles/farmacología , RNA-Seq , Modelos Animales de Enfermedad , Estructura Molecular , Sulfato de Dextran/efectos adversos , Sulfato de Dextran/metabolismo , Colon/metabolismo , Colon/patología , Ratones Endogámicos C57BL , Colitis/tratamiento farmacológicoRESUMEN
INTRODUCTION: Saposhnikovia divaricata (Turcz.) Schischk is one of the most widely used Chinese herbs worldwide. It has anti-inflammatory and analgesic properties and hence has a high clinical value. As the moisture level in S. divaricata is high after harvest, it requires drying. OBJECTIVE: We aimed to find a scientific drying method and optimize the drying conditions of the best drying method of S. divaricata using response surface methodology (RSM). METHODOLOGY: The effects of 4 different drying methods on the contents of prim-O-glucosylcimifugin, cimifugin, 5-O-methylvisamminol, and sec-O-glucosylhamaudol were determined using high-performance liquid chromatography. Chroma, the rehydration ratio, and active component content were used as indices, and slice thickness, drying temperature, and drying time were used as independent variables to optimize the drying conditions of the optimal drying method of S. divaricata using RSM combined with the Box-Behnken design. RESULTS: The results showed that the optimal drying conditions were as follows: slice thickness, 4.00 mm; drying temperature, 60°C; and drying time, 15 h. CONCLUSION: Under optimal drying conditions, the measured values were extremely close to the predicted values. The results of variance analysis showed that the model had a high degree of fit and the drying conditions of S. divaricata were optimized successfully.
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Apiaceae , Medicamentos Herbarios Chinos , Medicamentos Herbarios Chinos/análisis , Temperatura , Apiaceae/química , Cromatografía Líquida de Alta Presión/métodosRESUMEN
Dysregulated B cell receptor-associated protein 31 (BAP31) plays a crucial role in tumor progression. This study aimed to investigate the functions and molecular mechanism of BAP31 on the miR-206/133b cluster in colorectal cancer (CRC). qPCR was conducted to detect miRNA and mRNA levels in tissues and cells. Western blot assays were used to assess the levels of biomarkers and targets, as well as the levels of BAP31 and HOXD10. Wound healing, coculture and transwell assays were conducted to assess the transendothelial migration abilities of CRC cells. A luciferase assay was employed to assess miRNA binding effects on targets, as well as the initiating transcription effect of genomic fragments. Tumor growth and lung metastatic models were established through an in vivo animal study. BAP31 overexpression in CRC cells led to a reduction in the expression of the miR-206/133b cluster. The expression of the miR-206/133b cluster was correlated with the transendothelial migration capability of CRC cells. The miR-206/133b cluster was found to directly regulate cell division cycle 42 (CDC42) and actin-related protein 2/3 complex subunit 5 (ARPC5) in the tight junction pathway (hsa04530). Moreover, a potential transcription regulator of the miR-206/133b cluster was also found to be Homeobox D10 (HOXD10). We further elucidated the molecular mechanisms and functional mechanisms of BAP31's regulatory role in the expression levels of the miR-206/133b cluster by inhibiting HOXD10 translocation from the cytoplasm to the nucleus. In conclusion, this study provides valuable insights into how BAP31 regulates the transcription of the miR-206/133b cluster and how BAP31-related lung metastases arise in CRC.
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Neoplasias Colorrectales , Neoplasias Pulmonares , MicroARNs , Animales , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Neoplasias Colorrectales/patología , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , MicroARNs/genética , MicroARNs/metabolismo , Migración Transendotelial y TransepitelialRESUMEN
Ethnopharmacological relevance: Pinellia ternata (Thunb.) Breit. is a well-known perennial herb that is used in traditional medicine in China, Japan and Korea. It's drawing worldwide interests in medicinal applications owing such as anti-diarrhea, lipid-lowering, anti-tumor, anti-cough, expectorant, anti-gastric ulcer, etc. Aim of the study: This review aims to provide useful information on the botany, traditional uses, phytochemistry, pharmacology, toxicity and quality control of Pinellia ternata to help increase its efficiency. In addition, this review will discuss the future research trends and development prospects of this plant. Materials and methods: Data was obtained through a systematic search of published literature and online databases such as Google Scholar, Web of Science, PubMed, Science Direct, and Sci-Finder. The botanical names were confirmed using the World Flora Online and chemical structures were drawn using the ChemBio Draw Ultra Version 19.0 Software. Results: Pinellia ternata is distributed in regions of China and other areas. Pinellia ternata and its compound preparations can be used for cough, vomiting, gastric ulcer and other diseases. Approximately 212 chemical constituents have been isolated from Pinellia ternata, including alkaloids, volatile oils, amino acids, organic acids, flavonoids, cerebrosides, phenylpropanoids and other compounds. Considerable pharmacological experiments in vitro and in vivo have demonstrated that Pinellia ternata possessed antitumor effect, antitussive effects, antiasthmatic effects, increasing resistance to gastric ulcer, and antidiarrheal effect. However, these extracts can also lead to various toxicities such as irritant toxicity, cardiotoxicity, hepatotoxicity and embryonic toxicity. Considerable experiments have demonstrated that different processing methods and suitable compatibility with other herbs can effectively reduce the toxicities and increase the efficiency of Pinellia ternata. Conclusions: Pinellia ternata is an ancient herbal medicine with a broad spectrum of pharmacological activities that has been used for thousands of years in China. Future studies should perform an in-depth analyses of the pharmacokinetics and mechanisms of toxicity of Pinellia ternata. Quality standards should be developed to correspond to the various application methods to ensure the efficacy of drugs in actual treatment.
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OBJECTIVE: The purpose of this study was to investigate the mechanism through which rosemary essential oil treats atopic dermatitis. METHODS: A dinitrochlorobenzene (DNCB)-induced atopic dermatitis mouse model was established and treated with low (1%), medium (2%), and high (4%) doses of Rosmarinus officinalis essential oil (EORO). Serum levels of interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-α) in each group were determined using enzyme-linked immunosorbent assay (ELISA). Skin tissues were stained with hematoxylin-eosin and toluidine blue. We used network pharmacology and molecular docking techniques to verify the biological activity of essential proteins and their corresponding compounds in the pathway. Gas chromatography-mass spectrometry (GC-MS) was used for metabolomics analysis and multivariate statistical analysis of mouse serum to screen differential metabolites and metabolic pathway analysis. Protein expression of p-JAK1, CD4+ cells, and IL-4 in the skin tissue was detected by immunohistochemistry analysis. Protein levels of STAT3, p-STAT3, P65, and p-P65 in damaged skin tissues were detected using western blotting. RESULT: The skin of mice in the model group showed different degrees of erythema, dryness, scratches, epidermal erosion and shedding, and crusting. After treatment, the serum levels of IL-6 and TNF-α in EORO group were significantly decreased, and the expression of p-JAK1,CD4 + cells, IL-4, p-P65 / P65 and p-STAT3 / STAT3 proteins in skin tissues were decreased. CONCLUSION: EORO can effectively improve DNCB-induced AD-like skin lesions in mice by regulating the JAK/STAT/NF-κB signaling pathway, thereby reducing the production of downstream arachidonic acid metabolites, inhibiting skin inflammation, and restoring epidermal barrier function.
Asunto(s)
Dermatitis Atópica , Aceites Volátiles , Rosmarinus , Animales , Ratones , Citocinas/metabolismo , Dermatitis Atópica/tratamiento farmacológico , Dinitroclorobenceno/farmacología , Interleucina-4/metabolismo , Interleucina-6/metabolismo , Ratones Endogámicos BALB C , Simulación del Acoplamiento Molecular , FN-kappa B/metabolismo , Aceites Volátiles/farmacología , Aceites Volátiles/uso terapéutico , Transducción de Señal , Piel/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The epithelial cell-adhesion molecule (EpCAM) is hyperglycosylated in carcinoma tissue and the oncogenic function of EpCAM primarily depends on the degree of glycosylation. Inhibiting EpCAM glycosylation is expected to have an inhibitory effect on cancer. We analyzed the relationship of BAP31 with 84 kinds of tumor-associated antigens and found that BAP31 is positively correlated with the protein level of EpCAM. Triple mutations of EpCAM N76/111/198A, which are no longer modified by glycosylation, were constructed to determine whether BAP31 has an effect on the glycosylation of EpCAM. Plasmids containing different C-termini of BAP31 were constructed to identify the regions of BAP31 that affects EpCAM glycosylation. Antibodies against BAP31 (165-205) were screened from a human phage single-domain antibody library and the effect of the antibody (VH-F12) on EpCAM glycosylation and anticancer was investigated. BAP31 increases protein levels of EpCAM by promoting its glycosylation. The amino acid region from 165 to 205 in BAP31 plays an important role in regulating the glycosylation of EpCAM. The antibody VH-F12 significantly inhibited glycosylation of EpCAM which, subsequently, reduced the adhesion of gastric cancer cells, inducing cytotoxic autophagy, inhibiting the AKT-PI3K-mTOR signaling pathway, and, finally, resulting in proliferation inhibition both in vitro and in vivo. Finally, we clarified that BAP31 plays a key role in promoting N-glycosylation of EpCAM by affecting the Sec61 translocation channels. Altogether, these data implied that BAP31 regulates the N-glycosylation of EpCAM and may represent a potential therapeutic target for cancer therapy.