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关键词： Zearalenone   TNF   Ovary   Gut microbes   Inflammation  

摘要： As a widely encountered foodborne mycotoxin, Zearalenone (ZEN) has the potential to accumulate along the food chain, posing threats to public health and safety. However, the precise mechanisms by which ZEN causes tissue damage remain incompletely understood. Here, we established in vivo (40 mu g/kg) and in vitro (30 mu M) models to elucidate the underlying processes of ZEN-induced damage to the ovary and intestine. Our results demonstrated that, following ZEN exposure, pro-inflammatory signaling factors, including NLR family pyrin domain containing 3 (NLRP3) and Interleukin 6 (IL6), were significantly elevated in both ovarian and intestines. Metagenomic analysis revealed dysbiosis of the gut microbiota, which was closely associated with tumor necrosis factor (TNF)-alpha signaling pathway. Transcriptomic results further indicated that inflammatory response are intricately linked to TNF signaling pathway. Additionally, the Tnf-alpha knockout mouse model showed a marked resistance to ZEN-induced ovarian and intestinal injuries. In vitro, RNA interference targeting TNF-alpha attenuated the inflammatory response in IPEC-J2 cells. Moreover, dysregulated expression of the hormone synthesis genes, including KISS-1 metastasis suppressor (Kiss1) and gonadotropin releasing hormone 1 (Gnrh1), was observed, suggesting that ZEN-induced microbial dysbiosis and ovary damage may be interconnected through hormonal disruption. In summary, our results emphasize the role of TNF-alpha in causing ovarian and intestinal damage after ZEN exposure.

关键词： Schizophrenia   Interleukin-33   Aggression   Cytokine   Alarmin  

摘要： Aggression in schizophrenia (SCZ) poses a serious risk to others and complicates treatment. Inflammation has been confirmed to be associated with aggression in SCZ, but specific biomarkers remain unidentified. This study aimed to measure plasma interleukin-33 (IL-33) levels and explore their association with aggression in SCZ for the first time. The enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of IL-33 in SCZ with aggression (SCZ-Ag, n = 31) and non-aggression (NSCZ-Ag, n = 32), and healthy controls (HCs, n = 26). Aggression was measured using the Modified Overt Aggression Scale (MOAS), and clinical symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS). The results showed that the plasma IL-33 levels were elevated in SCZ-Ag compared with NSCZ-Ag and HCs, with no significant difference between NSCZ-Ag and HCs. In the patient group, partial correlation analysis indicated a positive correlation between IL-33 levels and PANSS total scores, positive symptom subscores, and MOAS total scores. Regression analysis showed that a higher likelihood of aggression in SCZ was associated with elevated plasma IL-33 levels (OR = 1.075, 95 % CI: 1.023-1.129). ROC curve analysis showed that IL-33 (AUC = 0.713, 95 % CI: 0.582-0.844) demonstrated moderate performance in distinguishing SCZ-Ag from NSCZ-Ag. These findings suggest that elevated plasma IL-33 levels are a potential risk factor for aggression in patients with SCZ and are implicated in the clinical symptoms of patients. Increased plasma IL-33 levels may serve as a potential marker for aggression in SCZ. These findings require further validation in future studies.

关键词： Colorectal Cancer   Immunotherapy   MHC class I-related chain A   T cell  

摘要： Background Distant metastasis and immune evasion are the major obstacles for successful colorectal cancer (CRC) treatment. The link between metastasis and immune evasion, as well as their therapeutic significance, remains *** Long non-coding RNAs from six paired CRC and normal tissues were screened by RNA sequencing (RNA-seq). LncRNA-CTD (CTD-2568A17.8) expression levels were determined using in situ hybridization and quantitative PCR analysis. In vitro and in vivo assays were performed to confirm the function of lncRNA-CTD. Flow cytometry was used to analyze the impact of lncRNA-CTD on immune cell infiltration and T-cell function. RNA-seq combined with RNA pull-down and RNA immunoprecipitation assay was used to identify the changes in downstream molecules induced by lncRNA-CTD. The therapeutic value of the combination of lncRNA-CTD and immune checkpoint inhibitors has been *** In this study, we identified a novel long non-coding RNA, lncRNA-CTD, which is downregulated in CRC and correlates with both metastasis and immunotherapy response. Mechanistically, the interaction of lncRNA and smad2 prevented the phosphorylation and nuclear translocation of smad2, which inhibited the expression of snail1, thereby inhibiting the metastasis of CRC. LncRNA-CTD enhances major histocompatibility complex class I (MHC-I) expression on the cancer cell membrane by interacting with STUB1 to disrupt the interaction of STUB1 with the MHC-I activator NLRC5 and subsequent NLRC5 ubiquitination-mediated degradation, increasing the susceptibility of CRC cells to being killed by CD8+ T cells. TFAP4 overexpression in CRC cells caused lncRNA-CTD downregulation. Moreover, the combination of lncRNA-CTD gene delivery therapy with immune checkpoint inhibitors exerted an additive effect on tumor growth *** Collectively, our study reveals the role and mechanism of lncRNA-CTD in CRC metastasis and immune evasion. Overexpression of lncRNA-CTD suppresses CRC

关键词： Malaria   Medical risk factors   Anemia   Iron deficiency anemia   Ghana   Malarial parasites   Alleles   Polymerase chain reaction  

摘要： Background of the study Malaria is a paramount health concern mostly among infants and young children. The World Health Organization recommends iron fortification for children with iron deficiency anaemia living in malaria-endemic regions like Ghana. However, the intricate interplay between genetic polymorphisms and nutritional interventions in malaria susceptibility and severity remains unclear. The Human Leukocyte Antigen-G (HLA-G) locus within the Major Histocompatibility Complex (MHC) genes has surfaced as a critical player in regulating immune responses and influencing disease outcomes. Therefore, we aimed to evaluate the effect of HLA-G 14 bp polymorphism and its associated risk of malaria severity among Ghanaian infants and young children on iron *** This secondary double-blinded cluster randomized controlled trial involved 432 archival samples from the Tain District and Wenchi Municipal in the Bono Region. Participants aged between 6 and 36 months and consuming semi-solid foods were recruited in the study while children with malaria infection or other known medical conditions were excluded. Capillary blood samples were taken for anaemia determination using a haematology autoanalyzer, malaria infection status, and parasitaemia were assessed via microscopy, and HLA-G 14 bp polymorphism using PCR. Hardy-Weinberg equilibrium and multivariate regression models were used to analyze the data *** The research findings indicate that among the iron-fortified children with HLA-G, 14 bp + /- and 14 bp-/- variants are likely to develop severe malaria. Also, the HLA-G 14 bp + /- variant was linked to a higher risk of anaemia development among participants who received iron *** The study results indicated that iron-fortified individuals carrying the HLA-G 14 bp insertion/deletion polymorphism have an elevated risk of developing severe malaria, which in turn predisposes them to anaemia.

关键词： Interleukin-6   Molecularly imprinted polymer   Electrochemical sensor   Lipopolysaccharide   Point-of-care  

摘要： Interleukin-6 (IL-6) is a multifunctional cytokine that plays a key role in driving proinflammatory responses in a wide range of acute, chronic, and infectious diseases. Therefore, it is of practical importance to monitor the IL-6 level of individuals in disease diagnosis and healthcare. Currently, there is an urgent need for developing rapid, cost-effective diagnostic and prognostic sensing systems. Herein, we developed a molecularly imprinted polymer (MIP)-based electrochemical sensor for IL-6 detection. The results showed that the MIP sensor demonstrated high sensitivity in the trace of IL-6 concentration, with a limit of detection of 31.3 fM and a wide dynamic range of 100 fg/mL to 1 mu g/mL. Moreover, the MIP sensors are highly selective for IL-6, compared to other inflammatory cytokines (Interleukin-1 beta, transforming growth factor-beta 3, and tumor necrosis factor-alpha) and various interfering biomolecules (glucose, human serum albumin, fibrinogen, and lactic acid). We also confirmed that the MIP sensors maintained robust stability over three weeks without appreciable deterioration. The performance of the MIP sensors was validated using a lipopolysaccharide-induced cellular senescence model, emphasizing its potential as a point-of-care tool for IL-6 monitoring. The results suggest that our MIP-based IL-6 sensor could serve as an effective point-of-care tool in quantifying age-related physiological changes and monitoring low-grade systemic inflammation.

关键词： Chronic stress intensity   Depression severity   Behavior   Cortisol   Inflammatory factors  

摘要： Backgrounds: The etiology of depression involves chronic stress, a recognized determinant of onset and severity. This study adopts a translational approach, utilizing a mouse model and a clinical cohort to explore the relationship between chronic stress, molecular changes, and depression severity. Methods: In the mouse model, mice were exposed to varying frequencies of chronic stressors over several weeks, followed by behavioral assessments to confirm depressive-like behaviors and measurement of serum indicators to analyze their relationship with stress intensity. In the clinical cohort, we recruited 239 participants, including 137 patients with diagnosed depression and 102 healthy controls, and analyzed their plasma profiles for cortisol and inflammatory cytokines. The clinical cohort revealed distinctive plasma profiles, identifying cortisol and IL17 as potential markers. Machine learning models were developed using these markers to distinguish depression severity. Results: The study revealed subtle behavioral-molecular changes in mice subjected to varying chronic stress intensities, confirming dose-response relationships. It identified cortisol and IL-17 as potential biomarkers for distinguishing depression severity and developed machine learning models demonstrating robust diagnostic capabilities. Limitations: There is a substantial disparity in the number of individuals among different groups in the clinical participants. Conclusion: The study establishes a correlation between cortisol, IL-17, and chronic stress intensity, suggesting the latter accelerates depression progression. Cortisol and IL-17 exhibit diagnostic potential, providing insights into depression progression and guiding targeted interventions. This research advances our understanding of stress-induced molecular changes in depression, contributing to the comprehension of the intricate relationship between chronic stress, molecular alterations, and depression severity.

关键词： IL-2   IL-2 receptor alpha   IL-2 receptor beta &   gamma   Inclusion body   Refolding   Assay validation  

摘要： IL-2 is a potent cytokine that promotes multiple immune cells proliferation and activation. Accordingly, IL-2 based immunotherapies are emerging to treat cancers or AIDS by enhancing T cell growth and function. Besides, IL-2 is indispensable in in vitro cultivation of immune cells which is a critical step of CAR-T or CAR-NK immunotherapies. In bulk manufacturing of recombinant IL-2, E. coli expression system has several advantages such as low cost and rapid growth. However, high level protein expression in prokaryotic organisms often results in inactive insoluble aggregates, also known as inclusion bodies. It is crucial and most challenging work to solubilize and refold the protein of interest from inclusion bodies to generate its bioactive form. While multiple spectrum method had been applied to monitor the refolding process, the question of how to measure the refolding efficiency from the perspective of its biological function remained unaddressed. Here we present a receptor-based sandwich ELISA method to evaluate the bioactive product in samples and provide a guidance for manufacturing bioactive rhIL-2 (recombinant human IL-2) with prokaryotic expression system. Compared to traditional antibody-based ELISA method, this novel approach truly measures the presence of functional rhIL-2 and also potentially allows the detection of rhIL-2 variants with modifications like PEGylation as it doesn't rely on the exact amino acid sequence.

关键词： 侵袭性肺曲霉病   临床特征   预后不良   危险因素   淋巴细胞   重症医学科  

摘要： 目的 分析侵袭性肺曲霉病(IPA)患者的病原菌特点及临床特征,归纳影响预后不良的危险因素。方法 通过电子病例系统查询东南大学附属中大医院2022年8月-2024年7月通过痰或肺泡灌洗液培养微生物鉴定为曲霉菌,且结合诊断标准诊断为IPA患者的89例临床资料,回顾性分析IPA患者曲霉菌病原菌分布及患者临床特征,归纳影响患者预后不良的危险因素。结果 89例病例共检出107株曲霉,其中烟曲霉55株(51.40%)、黄曲霉30株(28.04%)、黑曲霉10株(9.34%)。男性63例(70.79%),不良预后34例。外周血基础淋巴细胞计数(<0.645×10～9)(OR=6.653,95%CI:2.013～21.990,P=0.002)及入住ICU(OR=8.303,95%CI:1.283～53.741,P=0.026)是IPA患者预后不良的危险因素。受试者工作特征曲线分析结果显示,IPA患者预后的外周血基础淋巴细胞计数折点为0.645×10～9/L,敏感度为85.22%,特异度为69.67%。结论 外周血基础淋巴细胞计数、入住ICU是IPA患者预后不良的危险因素,外周血基础淋巴细胞计数警戒值为0.645×10～9/L,对预后不良的发生有较好预测价值。

关键词： Immunotherapy   Cytokine   co-stimulatory molecules   Tumor infiltrating lymphocyte - TIL  

摘要： Background The strong regulatory T cell (Treg) inhibitory activity and dysfunctional cytotoxic T lymphocytes (CTLs) represent major barriers to effective antitumor immunity, particularly in late-stage cancer. Multiple anti-OX40 (aOX40) agonistic antibodies have been developed but exhibit limited antitumor efficacy. Interleukin-2 (IL-2) effectivity expands CTLs but has severe side *** We construct an aOX40-mIL2-Fc bispecific antibody through Fab physical blocking and attenuated IL-2 with R beta reducing N88D mutation. We also produced aOX40-Fc and IL-2/aOX40-Fc as a comparison using the 293F expression system. Single-cell and flow cytometry were used to analyze the change of T-cell subsets in the tumor microenvironment (TME). Mouse tumor models were used to assess the antitumor efficacy of aOX40-mIL2-Fc by tumor growth and survival, and toxicity by body weight loss, inflammatory cytokine production, and natural killer (NK) cell proliferation in the blood. The tumor-bearing mice were randomly assigned, and the average size was similar among various *** aOX40-mIL2-Fc bispecific antibody-cytokine exhibited a synergistic therapeutic effect with limited toxicity, outperforming IL-2-Fc or aOX40 alone treatment, and conferring resistance to tumor rechallenge. On cellular mechanisms, aOX40-mIL2-Fc treatment showed great Treg depletion and increased both stem-like and effector functional terminal CD8+ T cells in the TME, while avoiding NK cells expansion in the periphery. Furthermore, this bispecific antibody remarkably improved the anti-programmed death-ligand 1 (PD-L1) therapeutic *** Our study unveils a novel approach to IL-2 design that addresses several critical shortcomings of existing strategies and elucidates the cellular mechanisms underlying aOX40-mIL2-Fc therapy. Meanwhile, combining aOX40-mIL2-Fc with PD-L1 blockade represents a strategic approach to enhance tumor control and overcome resistance to immune checkpoint blockade t

关键词： Cytokine   Inflammation   Neurotoxicity   Oxidative stress   Sodium/glucose cotransporter 2 inhibitor  

摘要： Background: Neuroinflammation drives neuronal degeneration and cognitive decline through various mechanisms. Interleukin (IL)-17A, secreted by Th17 cells, activates glycogen synthase kinase 3 beta (GSK3 beta), worsening neuroinflammation via the nuclear factor kappa B (NF-kappa B) pathway. Dapagliflozin (DPG), a sodium/ glucose cotransporter 2 inhibitor with neuroprotective effects, reduces oxidative stress, apoptosis, and inflammation. This study examines DPG's molecular impact on neuroinflammation in an LPS-induced rat model. Methods: The experiment was designed with four groups as control, lipopolysaccharide (LPS) (5 mg/kg, intraperitoneal), LPS + DPG (10 mg/kg via oral gavage), and DPG, with a total of thirty-two female Wistar Albino rats. After five days of treatment, the rats were euthanized. Brain and cerebellum tissues were gathered for biochemical analysis to examine oxidative stress parameters spectrophotometrically;histological and immunostaining analysis focusing on caspase-9 (Cas-9), NF-kappa B, and IL-10 immunoexpressions, and genetic analysis as IL-17A, GSK3 beta, IL-6, and cyclooxygenase 2 gene expressions by qRT-PCR. Results: Histopathological evaluation revealed hyperemia, edema, mild degeneration, neuronal death, and modest gliosis in the LPS group. Increment of Cas-9 and NF-kappa B immunoexpressions, oxidative stress parameters, and the mRNA expressions of all four genes, in addition to the decrement of IL-10 and total antioxidant status, have been observed. DPG treatment significantly reversed all these findings and protected the neuronal tissues against LPS-induced substantial neuronal damage. Conclusion: In conclusion, DPG may exert neuroprotective effects through the involvement of the IL-17A/GSK3 beta pathway and reduction of oxidative stress;however, further studies are needed to clarify causal mechanisms and broader anti-inflammatory actions.