课程文献中心 更多>>

关键词： Bifidobacterium longum CKD1   anti-diabetic medicines   IL-22 signaling   insulin resistance   hepatic steatosis  

摘要： The gut microbiota plays a pivotal role in metabolic disorders, notably type 2 diabetes mellitus (T2DM). In this study, we investigated the synergistic potential of combining the effects of Bifidobacterium longum NBM7-1 (CKD1) with anti-diabetic medicines, Lobeglitazone (R) (LO), Sitagliptin (R) (SI), and Metformin (R) (Met), to alleviate hyperglycemia in a diabetic mouse model. CKD1 effectively mitigated insulin resistance, hepatic steatosis, and enhanced pancreatic beta-cell function, as well as fortifying gut-tight junction integrity. In the same way, SI-CKD1 and Met- CKD1 synergistically improved insulin sensitivity and prevented hepatic steatosis, as evidenced by the modulation of key genes associated with insulin signaling, beta-oxidation, gluconeogenesis, adipogenesis, and inflammation by qRT-PCR. The comprehensive impact on modulating gut microbiota composition was observed, particularly when combined with Metformin (R). This combination induced an increase in the abundance of Rikenellaceae and Alistipes related negatively to the T2DM incidence while reducing the causative species of Cryptosporangium, Staphylococcaceae, and Muribaculaceae. These alterations intervene in gut microbiota metabolites to modulate the level of butyrate, indole-3-acetic acid, propionate, and inflammatory cytokines and to activate the IL-22 pathway. However, it is meaningful that the combination of B. longum NBM7-1(CKD1) reduced the medicines' dose to the level of the maximal inhibitory concentrations (IC50). This study advances our understanding of the intricate relationship between gut microbiota and metabolic disorders. We expect this study to contribute to developing a prospective therapeutic strategy modulating the gut microbiota.

关键词： Norepinephrine   beta 2-adrenergic receptor   Interleukin-6   M2 macrophage polarization   Breast cancer   Cancer migration  

摘要： Previous studies have demonstrated that norepinephrine (NE) released during chronic stress promotes breast cancer (BC) metastasis via adrenergic receptors (ARs). However, the effect of NE on tumor-associated macrophage polarization and the underlying mechanisms remain largely unknown. In this study, we aimed to investigate the influence of NE on M2 macrophage polarization, with a particular focus on the crosstalk between macrophages and BC cells. Our results demonstrated that, although NE alone did not directly induce the expression of M2 macrophage markers, conditioned medium from NE-treated MDA-MB-231 human BC cells (NE CM) significantly promoted M2 macrophage polarization in THP-1 macrophages. We found that NE stimulated IL-6 production in MDA-MB-231 cells via beta 2-AR/NF-kappa B pathway, which activated STAT3 in THP-1 cells to induce M2 macrophage polarization. NE failed to induce IL-6 production and NF-kappa B activation when ADRB2 was knocked down in MDA-MB-231 cells. Furthermore, ADRB2 knockdown in cancer cells suppressed NE CMinduced M2 macrophage polarization, as well as M2 macrophage-induced cancer cell migration. Taken together, our results suggest that NE stimulates M2 macrophage polarization by inducing IL-6 secretion from BC cells through a beta 2-AR-dependent mechanism, which subsequently promotes cancer cell migration. Targeting beta 2AR may represent a promising strategy to prevent chronic stress-induced BC metastasis.

关键词： AIDS   allogeneic   cell therapy   clinical trail   immune restoration  

摘要： Recurrent opportunistic infections (OIs) in patients with severely immunosuppressed AIDS remain an unresolved medical challenge despite advancements in antiretroviral therapy (ART). To address this gap, we developed an HLA-mismatched allogeneic adoptive immune therapy (AAIT) specifically targeting this patient population. The safety and efficacy of this novel therapeutic approach were preliminarily confirmed in our phase 1 trial. Subsequently, a multicenter, open-label, controlled, phase 2a trial was conducted to evaluate the efficacy of AAIT in combination with ART compared with the conventional ART-only regimen. No difference in the incidence of adverse events (AEs) was observed between the two groups at the 96-week follow-up. AAIT treatment improved CD4+ T cell recovery at weeks 72 (P = 0.048) and 96 (P = 0.024) compared to the Control Group. Additionally, stratified analysis of patients in the AAIT Group showed that donor/recipient sex mismatch was significantly associated with the likelihood of patients achieving an immunological response (OR = 8.667;95% CI, 2.010-37.377;P = 0.004). These findings suggest that AAIT serves as a promising adjunct therapy for improving the outcomes of patients with severely immunosuppressed AIDS. Further studies are needed to elucidate the immunological mechanisms underlying AAIT and identify the subpopulations that respond optimally to this therapeutic approach. This trial is registered at *** (NCT04098770).Trial registration: *** identifier: *** registration: *** identifier: NCT02651376.

关键词： Breast cancer   benign breast tumours   differential diagnosis   DNA methylation   IL21R gene   biomarker  

摘要： Some benign and malignant breast tumours are similar in pathological morphology, which are difficult to be distinguished in clinical diagnosis. In this study, we intended to explore novel biomarkers for differential diagnosis of benign and malignant breast tumours. Methylation EPIC 850K beadchip and RNA-sequencing were used to analyse 29 tissue samples from patients with early-stage breast cancer (BC) and benign breast tumours for differently methylated and expressed genes. The altered methylation of IL21R was semi-quantitatively validated in an independent study with 566 tissue samples (279 BC vs. 287 benign breast tumours) using mass spectrometry. Binary logistic regression analysis was performed to evaluate the association between IL21R methylation and BC. BC-associated IL21R hypomethylation and overexpression were identified in the discovery round. In the validation round, BC patients presented significant IL21R hypomethylation compared to women with benign breast tumours (ORs >= 1.29 per-10% methylation, p-values <= 5.69E-14), and this hypomethylation was even enhanced in BC patients with ER-negative and PR-negative tumours as well as with triple-negative tumours. The methylation of IL21R showed efficient discriminatory power to distinguish benign breast tumours from BC (area under curve (AUC) = 0.88), and especially from ER-negative BC (AUC = 0.95), PR-negative BC (AUC = 0.93) and triple-negative BC (AUC = 0.96). We disclosed significant IL21R hypomethylation in patients with BC compared to women with benign breast tumours, and revealed the somatic change of DNA methylation could be a potential biomarker for molecular pathology of BC.

关键词： Human dermal fibroblasts   Methylnissolin   Methylnissolin-3-O-β-D -glucopyranoside   Skin-aging   Tumor necrosis factor-α  

摘要： Methylnissolin-3-O-β-d-glucopyranoside (MNG) and methylnissolin (MN) are pterocarpan derivatives that are found in plants, such as Astragalus membranaceus. There are limited existing studies on the potential health benefits of MNG, and currently there is no evidence to suggest that MNG has any impact on skin-aging. Tumor necrosis factor-alpha (TNF-α) plays a significant role in skin aging by promoting chronic inflammation, damaging skin cells, and impairing the skin's natural repair mechanisms. Targeting TNF-α or its downstream signaling pathways may be a promising strategy for preventing or reversing skin-aging. We tested the effect of MNG and MN on skin-aging by inducing cell inflammation and oxidative stress with TNF-α in HDFs. MNG and MN significantly reduced the TNF-α-induced secretion of matrix metalloproteinase-1 (MMP-1). However, MNG has more beneficial compound for oral administration than MN in pharmacokinetics analysis. The mechanism underlying the anti-skin-aging effect of MNG is related to the suppression of TNF-α-induced reactive oxygen species (ROS) generation and mitogen-activated protein kinase (MAPKs) phosphorylation. Our results suggest that MNG is a potential candidate for preventing skin-aging induced by TNF-α.

关键词： Klebsiella pneumoniae   DNA vaccine   recombinant proteins   antibacterial immunity   IL-17  

摘要： Klebsiella pneumoniae is an important gram-negative bacterium that causes severe respiratory and healthcare-associated infections. Although antibiotic therapy is applied to treat severe infections caused by K. pneumoniae, drug-resistant isolates pose a huge challenge to clinical practices owing to adverse reactions and the mismanagement of antibiotics. Several studies have attempted to develop vaccines against K. pneumoniae, but there are no licensed vaccines available for the control of K. pneumoniae infection. In the current study, we constructed a novel DNA vaccine, pVAX1-YidR, which encodes a highly conserved virulence factor YidR and a recombinant expression plasmid pVAX1-IL-17 encoding Interleukin-17 (IL-17) as a molecular adjuvant. Adaptive immune responses were assessed in immunized mice to compare the immunogenicity of the different vaccine schemes. The results showed that the targeted antigen gene was expressed in HEK293T cells using an immunofluorescence assay. Mice immunized with pVAX1-YidR elicited a high level of antibodies, induced strong cellular immune responses, and protected mice from K. pneumoniae challenge. Notably, co-immunization with pVAX1-YidR and pVAX1-IL-17 significantly augmented host adaptive immune responses and provided better protection against K. pneumoniae infections in vaccinated mice. Our study demonstrates that combined DNA vaccines and molecular adjuvants is a promising strategy to develop efficacious antibacterial vaccines against K. pneumoniae infections.

关键词： GVHD   MMUD   PTCY‐based prophylaxis   allo‐HCT   overall survival   progression‐free survival  

摘要： Although post-transplant cyclophosphamide (PTCY)-based prophylaxis has become a widely adopted strategy for preventing graft-versus-host disease (GVHD) in 9 out of 10 HLA-mismatched unrelated donors (MMUDs), allogeneic hematopoietic cell transplants (allo-HCTs), data on the safety and efficacy of PTCY in this setting remain limited. This single-center study investigates the outcomes of 94 adults with hematological malignancies undergoing MMUD allo-HCT with PTCY and tacrolimus (Tac) (PTCY-Tac) between 2014 and 2023. The median age was 53 years, and 60.6% were male. Peripheral blood stem cells were infused in all cases. By Day +100, the cumulative incidence of Grades II-IV and Grades III and IV acute GVHD were 33.0% and 9.7%, with 2-year incidence of moderate-to-severe chronic GVHD at 12.6%. By Day +30, 40.8% of patients experienced bacterial bloodstream infections, and 52.4% had cytomegalovirus (CMV) reactivation before letermovir prophylaxis. With letermovir's introduction, CMV reactivation rates dropped significantly, with only one case reported. At 3 years, overall survival was 60.8%, non-relapse mortality was 23%, and the cumulative incidence of relapse was 24.5%. HLA Class I or II mismatches did not affect key outcomes or GVHD rates. These findings demonstrate that PTCY-Tac offers effective GVHD prevention and favorable outcomes in MMUD allo-HCT, supporting its application for patients without fully matched donors.

摘要： Picralima nitida possesses anti-inflammatory, antioxidant and antiulcerogenic properties, among others. The crude alkaloidal extract from the seeds of Picralima nitida (PNE) has been reported to exhibit anti-inflammatory effect in some rodent models. This study aims to investigate the intestinal anti-inflammatory effects of PNE in rats with bowel inflammation induced by trinitrobenzenesulfonic acid (TNBS) administration. Rats were treated with PNE (30, 100, and 300 mg/kg) or sulphasalazine 500 mg/kg daily for 7 days after bowel inflammation induction with TNBS and euthanized 24 h following administration of the final doses of treatments. Blood samples were collected for haematological and biochemical investigations whereas colons were excised and inspected for tissue damage, both macroscopically and microscopically. Macroscopic assessment showed that PNE reduced mucosal inflammation and ulceration. Histology showed preservation of normal mucosal architecture and goblet cells numbers, lowered inflammatory cell infiltration and decreased mucosal thickening. PNE treatment altered haematological markers and lowered serum levels of interleukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α) and p38 mitogen-activated protein kinase (p38 MAPK). Moreover, PNE treatment increased glutathione (GSH) levels, inhibited nitric oxide (NO) production, and decreased myeloperoxidase (MPO) activity and malondialdehyde (MDA) production. The results depict that PNE suppresses oxidative stress and inflammatory injuries in the intestines induced with TNBS, suggesting its potential benefits in intestinal inflammatory diseases.

摘要： Based on the success of cancer immunotherapy, personalized cancer vaccines have emerged as a leading oncology treatment. Antigen presentation on MHC class I (MHC-I) is crucial for the adaptive immune response to cancer cells, necessitating highly predictive computational methods to model this phenomenon. Here, we introduce HLApollo, a transformer-based model for peptide-MHC-I (pMHC-I) presentation prediction, leveraging the language of peptides, MHC, and source proteins. HLApollo provides end-to-end treatment of MHC-I sequences and deconvolution of multi-allelic data, using a negative-set switching strategy to mitigate misassigned negatives in unlabelled ligandome data. HLApollo shows a 12.65% increase in average precision (AP) on ligandome data and a 4.1% AP increase on immunogenicity test data compared to next-best models. Incorporating protein features from protein language models yields further gains and reduces the need for gene expression measurements. Guided by clinical use, we demonstrate pan-allelic generalization which effectively captures rare alleles in underrepresented ancestries.

关键词： 严重发热伴血小板减少综合征病毒   核蛋白   噬菌体展示   人源单克隆抗体  

摘要： 目的 筛选严重发热伴血小板减少综合征病毒(severe fever with thrombocytopenia syndrome virus, SFTSV)核蛋白人源单克隆抗体，鉴定单克隆抗体与重组核蛋白以及病毒颗粒中核蛋白结合特异性，测定其亲和力常数和结合动力学参数。 方法 运用噬菌体展示技术，从严重发热伴血小板减少综合征(severe fever with thrombocytopenia syndrome, SFTS)恢复期患者外周血中提取抗体基因，构建抗体文库。使用重组核蛋白对文库进行筛选，获得的抗体片段表达成IgG全抗。然后使用酶联免疫吸附试验(enzyme linked immunosorbent assay, ELISA)、蛋白印迹(western blot, WB)和间接免疫荧光试验(indirect immunofluorescence assay, IFA)测定单克隆抗体与重组核蛋白以及病毒粒子中核蛋白的结合特异性，利用生物膜干涉技术(biolayer interferometry, BLI)测定抗体亲和力常数。 结果 成功构建了一个库容量为7.24×10 7 的抗体文库，用核蛋白筛选获得6株抗体，命名为：NP-1、NP-10、NP-11、NP-20、NP-21、NP-27。6株抗体经间接ELISA, WB检测，均为核蛋白特异性单克隆抗体。经IFA检测，该组抗体也能特异性结合在病毒粒子中的核蛋白上。经BLI测定，6株抗体与核蛋白亲和力常数范围为0.47 nmol/L至32 nmol/L之间。 结论 从文库中获得的6株抗体为SFTSV核蛋白特异性人源单克隆抗体，且具有较高亲和力。该抗体可为SFTSV基础研究、诊断试剂开发提供候选抗体。