课程文献中心 更多>>

关键词： IL-25   Intestine   Cholesterol absorption   Obesity  

摘要： The intestine is essential for digestion and nutrient absorption, and its altered function contributes to metabolic dysregulation and obesity-induced intestinal inflammation. Intestinal immune responses have been associated with the regulation of metabolic dysfunction during obesity. Given that the epithelial cell-derived cytokine IL-25 has been demonstrated to regulate metabolic disorders, we sought to examine the role of intestinal IL-25 in modulating a high-fat diet (HFD)-induced obesity. We found that mice on a high-fat diet exhibited decreased IL-25 expression in the small intestine. Intestinal IL-25 mRNA levels displayed an inverse association with plasma triglycerides, total cholesterol, glucose levels, and the expression of the cholesterol transporter Npc1l1 in the intestine. In HFD-induced obesity, transgenic mice overexpressing IL-25 in the intestinal epithelial cells demonstrated diminished mRNA expression of intestinal genes related to glucose, cholesterol, and fat absorption, along with chylomicron production, while also systemically decreasing plasma glucose, total cholesterol, and triglyceride levels, fat accumulation, and weight gain. In vitro, IL-25 treatment of human intestinal Caco-2 cells directly decreased cholesterol uptake and downregulated the expression of NPC1L1 and its transcriptional regulator, SREBP2. These findings highlight IL-25 as a potential modulator in the intestine that regulates intestinal cholesterol absorption and systemic metabolism in obesity.

关键词： Geometric morphometrics   Inflammation   Rheumatoid arthritis   Transgenic mouse   Temporomandibular joints   Tumor necrosis factor-alpha, ribosomal s6 kinase 2  

摘要： ObjectivesThis study aims to investigate the impact of the pro-osteoblastogenic ERK-activated ribosomal S6 kinase (Rsk2) on Tumor necrosis factor (TNF)alpha-induced bone loss in the craniofacial system, focusing on its role in rheumatoid arthritis (RA). The objective is to understand whether Rsk2, previously shown to have protective effects in long bones against TNF alpha-induced bone resorption, exhibits similar effects in the craniofacial ***, and *** study compares mice with TNF alpha overexpression, Rsk2 knockout mice, and a combination of TNF alpha, and Rsk2 knockout mice using detailed micro-computed tomography coupled with landmark based morphometric analysis, and classical histology. The overall skull morphology, mandible shape, and the temporomandibular joint were examined. Additionally, histological sections were utilized to examine the synovial ***, and *** study compares mice with TNF alpha overexpression, Rsk2 knockout mice, and a combination of TNF alpha, and Rsk2 knockout mice using detailed micro-computed tomography coupled with landmark based morphometric analysis, and classical histology. The overall skull morphology, mandible shape, and the temporomandibular joint were examined. Additionally, histological sections were utilized to examine the synovial *** TNF alpha, and Rsk2 deficiency does not further alter overall skull shape compared to TNF alpha alone. TNF alpha overexpression shortens the mandibular ramus, exacerbated by Rsk2 absence. Micro-computed tomography (mu CT) reveals significant temporomandibular joint damage from TNF alpha, independent of Rsk2. However, histological sections show increased synovial membrane thickness with TNF alpha, heightened in the absence of ***2 mitigates TNF alpha-induced effects on mandibular ramus length in the craniofacial system but has limited impact on the temporomandibular joint, except for synovial membrane thickness. Over

关键词： Qingjie Fuzheng Granules   Colitis associated colorectal cancer   Macrophage polarization   TLR4   IL-4R  

摘要： Ethnopharmacological relevance: Qingjie Fuzheng Granules (QFG), a herbal formula, has been employed as an adjuvant therapy for colitis-associated colorectal cancer (CAC), yet the underlying mechanisms by which QFG operates remain unclear. Aims of the study: The aim of this study is to investigate whether the potential mechanism of QFG against CAC is associated with macrophage polarization. Materials and methods: Non-targeted metabolomics and molecular docking assessed potential compounds of QFG to interact with targets associated with macrophage polarization. A model of AOM/DSS-induced CAC mice was established to analyze the effects of QFG on macrophage polarization using flow cytometry and immunohistochemical staining. In vitro experiments involved models of Ana-1 macrophages, either induced by varying QFG concentrations or with MD2 knockdown, to analyze M1-like phenotype. Meanwhile, M2-like macrophages models induced by IL-4 or culture supernatant of CT26 cells were utilized to assess the effects of QFG on M2-like macrophages. Finally, the mRNA expression of M1-like phenotype related to TLR4 pathways and the protein expression in IL-4R-mediated pathways were analyzed using RT-qPCR and Western blot, respectively. Results: Molecular docking confirmed the presence of binding sites between the ingredients of QFG and IL-4R or TLR4/MD2 receptor complex. QFG could induce a shift in macrophages towards an M1-like phenotype while inhibiting an M2-like phenotype in the colon with CAC mice and Ana-1 macrophages. QFG resulted in the upregulation of iNOS, IL-6, IL-1 beta, and TNF-alpha mRNA expression, which could be counteracted by TAK242, SR11302, INH14, PDTC, and LY294002, or by the knockdown of MD2. Meanwhile, QFG inhibited IL-4R-induced phosphorylation of STAT 6 and Akt. Conclusion: Various monomer components within QFG can bind to MD2 or IL-4R, respectively, thereby inducing macrophages towards an M1-like phenotype through TLR4-mediated NF-kappa B, MAPK, and PI3K/Akt pat

关键词： 早孕因子   单克隆抗体   宫颈癌  

摘要： 通过研究早孕因子单克隆抗体EPF-B6对宫颈癌HeLa细胞的增殖、迁移、克隆及凋亡的影响，来探讨EPF单抗对宫颈癌细胞生物学行为的抑制作用。利用RT-PCR及Western Blot检测等6种常见肿瘤细胞中EPF基因及细胞培养液中EPF蛋白表达。CCK8、细胞划痕、平板克隆分别检测不同浓度的EPF-B6单抗对HeLa细胞增殖、迁移与群体依赖性的影响，流式细胞术检测HeLa细胞凋亡与周期。结果表明，常见肿瘤细胞中均存在EPF基因，宫颈癌HeLa细胞、乳腺癌MCF-7细胞与人卵巢癌A2780细胞培养液中有EPF蛋白的表达；以宫颈癌HeLa细胞为重点研究对象，EPF-B6单抗能显著抑制HeLa细胞的增殖、迁移、克隆形成能力，呈现浓度依赖性（P<0.05）；促进HeLa细胞凋亡（P<0.05）；细胞周期结果显示，EPF-B6单抗将HeLa细胞的DNA复制进程阻滞在G2/M期。

关键词： Ovarian cancer   ASCT2   Overexpression   Natural killer cells   IL-17 signaling pathway   c-JUN/ PTGS2  

摘要： Ovarian cancer (OC) is a deadly gynecologic cancer associated with metastasis, recurrence, and treatment resistance. The expression of the alanine-serine-cysteine transporter 2 (ASCT2) has been linked to poor prognosis and immune cell infiltration in OC tumors, but the underlying mechanisms are unclear. Lentiviral constructs were used to manipulate ASCT2 expression in OC cells (SKOV-3). The effects of ASCT2 on SKOV-3 behaviors including proliferation, invasion, migration, apoptosis, and cell cycle were assessed using various assays. The correlation between ASCT2 expression and immune infiltration in OC was analyzed using the Cancer Genome Atlas (TCGA) database. Co-culture experiments were conducted to evaluate the impact of ASCT2 overexpression in SKOV-3 on NK cells, followed by transcriptomics and cytokine analysis. ASCT2 expression and cytokine levels were characterized using qPCR and western blotting. ASCT2 overexpression significantly promoted cell proliferation, invasion, migration, and the percentage of G1-phase cells, while inhibiting apoptosis. ASCT2 silencing had the opposite effect. The expression of ASCT2 was negatively associated with NK cells in OC. ASCT2 overexpression in SKOV-3 cells led to excessive IL-17A/F production and inhibited the antitumor activity of NK cells, possibly through activating the IL-17 signaling pathway. The core regulatory genes c-JUN/PTGS2 in this pathway were upregulated, and antitumor cytokines were decreased in co-cultured NK cells, resulting in decreased antitumor activity and immune infiltration within the tumor. Our results suggest that overexpression of ASCT2 may play a predominant role in OC and NK cell immune infiltration within the tumor.

关键词： Sepsis   Continuous renal replacement therapy (CRRT)   Cytosorb   Interleukin-6 (IL-6)   Pediatric leukemia  

摘要： BackgroundSepsis is a critical condition characterized by a dysregulated immune response to infection, often resulting in organ dysfunction. Interleukin-6 (IL-6) is a key proinflammatory cytokine associated with sepsis and its complications. This case study explored the use of Continuous Renal Replacement Therapy (CRRT) combined with Cytosorb in managing pediatric patients with leukemia, severe thrombocytopenia, and elevated IL-6 *** presentationA 10-year-old boy with Fanconi anemia presented with pancytopenia, fever, and necrotic lesions, indicative of mucormycosis. Following the diagnosis of acute myeloid leukemia (AML), the patient experienced severe complications, including septic shock. Despite appropriate treatment, inflammatory markers, such as C-reactive protein (CRP), procalcitonin (PCT), and IL-6, were significantly elevated. CRRT with Cytosorb was initiated to manage hypercytokinemia and improve the patient's clinical *** CRRT procedure utilizes citrate as an anticoagulant because of severe thrombocytopenia. The treatment lasted for 20 h, during which the inflammatory biomarkers were monitored. The post-treatment results indicated a significant reduction in IL-6 levels within 24 h and a decrease in PCT levels at 8 h. CRP levels gradually declined over 40 *** patient exhibited marked clinical improvement, with significant healing of cutaneous lesions and stabilization of inflammatory markers, allowing transfer to the ward for continued *** case suggests that CRRT combined with cytosorb may be a valuable adjunctive therapy for managing complex cases of septic shock. The observed reduction in inflammatory markers, particularly IL-6, warrants further investigation. Concurrent antimicrobial, antifungal, and dexamethasone treatments for IRIS may have influenced the observed outcomes in this single case. Controlled studies are needed to evaluate the specific contribution of Cytosorb-CRRT and assess its

关键词： HLA-G   WNT signaling   TEAD1   TEAD3   pregnancy  

摘要： Maternal-fetal immune tolerance guarantees a successful pregnancy throughout gestation. HLA-G, a nonclassical human leukocyte antigen (HLA) molecule exclusively expressed in extravillous trophoblasts (EVT), is a crucial factor in establishing maternal-fetal immune tolerance by interacting with inhibitory receptors on various maternal immune cells residing in the uterus. While trophoblast-specific cis-regulatory elements impacting HLA-G transcription have been described, the identity of trans-acting factors controlling HLA-G expression in EVT remains poorly understood. Utilizing a genome-wide CRISPR-Cas9 knockout screen, we find that the WNT signaling pathway negatively regulates HLA-G expression in EVT. In addition, we identified two trophoblast-specific transcription factors, TEAD1 and TEAD3, required for HLA-G transcription in EVT in aYes-associated protein-independent manner. Altogether, we systematically elucidated essential genes and pathways underlying HLA-G expression in EVT, shedding light on the mechanisms of maternal-fetal tolerance and potentially providing insights into controlling HLA-G expression beyond EVT to protect allogeneic cells from immune rejection.

关键词： drug delivery   autophagy regulation   MHC-I   immunogenic cell death   photoimmunotherapy  

摘要： Breast cancer cells are characterized by heightened autophagy, which impairs tumor-associated antigen presentation and represents a significant barrier to the antitumor immunity. In this study, a PD-L1-targeting autophagy modulator (PFC@CQ) is fabricated to activate the photoimmunotherapy against breast cancer. Specifically, the hydrophobic photosensitizer protoporphyrin IX (PpIX) is covalently linked to the hydrophobic peptide FFVLK and a PD-L1-targeting peptide sequence CLQKTPKQC, resulting in the formation of an amphiphilic photosensitizer-peptide conjugate (PpIX-FFVLK-CLQKTPKQC, called PFC), which is capable of encapsulating the autophagy inhibitor chloroquine (CQ). PFC@CQ can not only facilitate the targeted drug codelivery to PD-L1-overexpressing breast cancer cells, but also effectively disrupt their immune evasion by blocking PD-1/PD-L1 pathway. Upon light irradiation, the photodynamic therapy (PDT) of PFC@CQ induces tumor cell destruction and immunogenic cell death (ICD), causing the release of damage-associated molecular patterns (DAMPs). Simultaneously, PFC@CQ can inhibit autophagy pathway to mediate the upregulation of MHC-I, thereby enhancing antigen presentation. This cascade immunomodulation promotes the dendritic cell maturation and CD8+ T cell activation, leading to a synergistic suppression of both primary and metastatic tumors. This work introduces an innovative autophagy modulation strategy with potent immunomodulatory capability, demonstrating a potential to trigger systemic antitumor immune responses through local treatment.

关键词： Leishmania   Multi-epitope vaccine   Immunoinformatics   Wolbachia surface protein   Adjuvant  

摘要： BackgroundVisceral leishmaniasis (VL) is the most lethal form of leishmaniasis. In terms of anti-leishmanial vaccines, favorable immune responses are Th1 responses that primarily produce interferon gamma (IFN-gamma) and activate macrophages for leishmanicidal effects. The selection of IFN-gamma-inducing epitopes in silico may reduce the steps of pre-clinical evaluation and increase the certainty of the better-designed vaccine. Wolbachia surface protein (WSP) derived from Wolbachia bacteria that have been reported to reside in sandflies can trigger TLR2 and TLR4 activation to favor Th1 immune responses, which may serve as a potential adjuvant candidate for the Leishmania vaccine. Therefore, in this study, helper T lymphocyte epitopes that may induce favorable immune responses were identified, and WSP was served as an adjuvant to design a novel multi-epitope vaccine *** hemoglobin receptor (HbR), kinetoplastid membrane protein-11 (KMP-11), glycoprotein of 63 kDa (Gp63), thiol-specific antioxidant antigen (TSA), and sterol 24-c-methyltransferase (SMT) were analyzed by immunoinformatics to screen helper T lymphocyte and cytotoxic T lymphocyte epitopes. The antigenicity, toxicity, allergenicity, and IFN-gamma-inducing epitope potential of T epitopes were predicted. The immune simulation was performed to calculate IFN-gamma/interleukin (IL)-10 ratios to predict the immune responses induced by the helper T lymphocyte epitopes. Molecular docking and molecular dynamics simulations were carried out to analyze the interactions and stability of the docked complexes. The immune simulation of a multi-epitope vaccine candidate was carried out to predict its *** helper T lymphocyte epitopes that were predicted with the potential of inducing Th1 responses and cytotoxic T lymphocyte epitopes were selected to develop a novel multi-epitope vaccine candidate with WSP as an adjuvant. It was found in molecular docking and interaction analysis