Immune mediated support of metastasis: Implication for bone invasion.

Bone is a common organ affected by metastasis in various advanced cancers, including lung, breast, prostate, colorectal, and melanoma. Once a patient is diagnosed with bone metastasis, the patient's quality of life and overall survival are significantly reduced owing to a wide range of morbidities and the increasing difficulty of treatment. Many studies have shown that bone metastasis is closely related to bone microenvironment, especially bone immune microenvironment. However, the effects of various immune cells in the bone microenvironment on bone metastasis remain unclear. Here, we described the changes in various immune cells during bone metastasis and discussed their related mechanisms. Osteoblasts, adipocytes, and other non-immune cells closely related to bone metastasis were also included. This review also summarized the existing treatment methods and potential therapeutic targets, and provided insights for future studies of cancer bone metastasis.

Role of acupuncture in improving the outcome of sepsis-induced lung injury.

OBJECTIVE: The purpose of this study was to investigate the effect of serum exosomes of mice after acupuncture (acu-exo) on acute lung injury (ALI) in sepsis in vitro and in vivo. METHODS: Serum exosomes (acu-exo) of normal mice were prepared after acupuncture. Lipopolysaccharide (LPS) was used to establish the model of ALI in vivo and in vitro. Immunohistochemistry, western blot, and immunofluorescence were used to evaluate the mechanism of acu-exo on ALI. P2X7 knockout mice and P2X7 siRNA were used to verify the mechanism. RESULTS: Compared with normal mice, serum exosomes were significantly increased in normal mice after acupuncture. The results showed that P2X7 was increased in the lung of septic mice as compared with the WT group. It was also found that the increase in NLRP3 and NF-κB was accompanied by the activation of P2X7. Increased P2X7 led to activation of the P2X7 receptor causing mitochondrial dysfunctions in lung tissue of septic mice. Knockout of P2X7 or silenced P2X7 markedly decreased NLRP3 and NF-κB and led to mitochondrial function recovery in lung tissue of sepsis. At the same time, acu-exo significantly restored the above changes in the lung tissue of septic mice. CONCLUSIONS: Inhibition of P2X7 led to mitochondrial function recovery of lung tissue by inhibiting NLRP3 and NF-κB. At the same time, acu-exo could improve ALI by decreasing NLRP3 and NF-κB activation.

Predictive value of MRI-based deep learning model for lymphovascular invasion status in node-negative invasive breast cancer.

To retrospectively assess the effectiveness of deep learning (DL) model, based on breast magnetic resonance imaging (MRI), in predicting preoperative lymphovascular invasion (LVI) status in patients diagnosed with invasive breast cancer who have negative axillary lymph nodes (LNs). Data was gathered from 280 patients, including 148 with LVI-positive and 141 with LVI-negative lesions. These patients had undergone preoperative breast MRI and were histopathologically confirmed to have invasive breast cancer without axillary LN metastasis. The cohort was randomly split into training and validation groups in a 7:3 ratio. Radiomics features for each lesion were extracted from the first post-contrast dynamic contrast-enhanced (DCE)-MRI. The Least Absolute Shrinkage and Selection Operator (LASSO) regression method and logistic regression analyses were employed to identify significant radiomic features and clinicoradiological variables. These models were established using four machine learning (ML) algorithms and one DL algorithm. The predictive performance of the models (radiomics, clinicoradiological, and combination) was assessed through discrimination and compared using the DeLong test. Four clinicoradiological parameters and 10 radiomic features were selected by LASSO for model development. The Multilayer Perceptron (MLP) model, constructed using both radiomic and clinicoradiological features, demonstrated excellent performance in predicting LVI, achieving a high area under the curve (AUC) of 0.835 for validation. The DL model (MLP-radiomic) achieved the highest accuracy (AUC = 0.896), followed by DL model (MLP-combination) with an AUC of 0.835. Both DL models were significantly superior to the ML model (RF-clinical) with an AUC of 0.720. The DL model (MLP), which integrates radiomic features with clinicoradiological information, effectively aids in the preoperative determination of LVI status in patients with invasive breast cancer and negative axillary LNs. This is beneficial for making informed clinical decisions.

Evaluating the role of DNA methyltransferases in trophoblast fusion and preeclampsia development: Insights from methylation-regulated genes.

The etiology of preeclampsia (PE), a complex and multifactorial condition, remains incompletely understood. DNA methylation, which is primarily regulated by three DNA methyltransferases (DNMTs), DNMT1, DNMT3A, and DNMT3B, plays a vital role in early embryonic development and trophectoderm differentiation. Yet, how DNMTs modulate trophoblast fusion and PE development remains unclear. In this study, we found that the DNMTs expression was downregulated during trophoblast cells fusion. Downregulation of DNMTs was observed during the reconstruction of the denuded syncytiotrophoblast (STB) layer of placental explants. Additionally, overexpression of DNMTs inhibited trophoblast fusion. Conversely, treatment with the DNA methylation inhibitor 5-aza-CdR decreased the expression of DNMTs and promoted trophoblast fusion. A combined analysis of DNA methylation data and gene transcriptome data obtained from the primary cytotrophoblasts (CTBs) fusion process identified 104 potential methylation-regulated differentially expressed genes (MeDEGs) with upregulated expression due to DNA demethylation, including CD59, TNFAIP3, SDC1, and CDK6. The transcription regulation region (TRR) of TNFAIP3 showed a hypomethylation with induction of 5-aza-CdR, which facilitated CREB recruitment and thereby participated in regulating trophoblast fusion. More importantly, clinical correlation analysis of PE showed that the abnormal increase in DNMTs may be involved in the development of PE. This study identified placental DNA methylation-regulated genes that may contribute to PE, offering a novel perspective on the role of epigenetics in trophoblast fusion and its implication in PE development.

Nitrogenous fertilizer plays a more important role than cultivars in shaping sorghum-associated microbiomes.

The plant microbiome plays a crucial role in facilitating plant growth through enhancing nutrient cycling, acquisition and transport, as well as alleviating stresses induced by nutrient limitations. Despite its significance, the relative importance of common agronomic practices, such as nitrogenous fertilizer, in shaping the plant microbiome across different cultivars remains unclear. This study investigated the dynamics of bacterial and fungal communities in leaf, root, rhizosphere, and bulk soil in response to nitrogenous fertilizer across ten sorghum varieties, using 16S rRNA and ITS gene amplicon sequencing, respectively. Our results revealed that nitrogen addition had a greater impact on sorghum-associated microbial communities compared to cultivar. Nitrogen addition significantly reduced bacterial diversity in all compartments except for the root endophytes. However, N addition significantly increased fungal diversity in both rhizosphere and bulk soils, while significantly reducing fungal diversity in the root endophytes. Furthermore, N addition significantly altered the community composition of bacteria and fungi in all four compartments, while cultivars only affected the community composition of root endosphere bacteria and fungi. Network analysis revealed that fertilization significantly reduced microbial network complexity and increased fungal-related network complexity. Collectively, this study provides empirical evidence that sorghum-associated microbiomes are predominantly shaped by nitrogenous fertilizer rather than by cultivars, suggesting that consistent application of nitrogenous fertilizer will ultimately alter plant-associated microbiomes regardless of cultivar selection.

Radiomics analysis using magnetic resonance imaging of bone marrow edema for diagnosing knee osteoarthritis.

This study aimed to develop and validate a bone marrow edema model using a magnetic resonance imaging-based radiomics nomogram for the diagnosis of osteoarthritis. Clinical and magnetic resonance imaging (MRI) data of 302 patients with and without osteoarthritis were retrospectively collected from April 2022 to October 2023 at Longhua Hospital affiliated with the Shanghai University of Traditional Chinese Medicine. The participants were randomly divided into two groups (a training group, n = 211 and a testing group, n = 91). We used logistic regression to analyze clinical characteristics and established a clinical model. Radiomics signatures were developed by extracting radiomic features from the bone marrow edema area using MRI. A nomogram was developed based on the rad-score and clinical characteristics. The diagnostic performance of the three models was compared using the receiver operating characteristic curve and Delong's test. The accuracy and clinical application value of the nomogram were evaluated using calibration curve and decision curve analysis. Clinical characteristics such as age, radiographic grading, Western Ontario and McMaster Universities Arthritis Index score, and radiological features were significantly correlated with the diagnosis of osteoarthritis. The Rad score was constructed from 11 radiological features. A clinical model was developed to diagnose osteoarthritis (training group: area under the curve [AUC], 0.819; testing group: AUC, 0.815). Radiomics models were used to effectively diagnose osteoarthritis (training group,: AUC, 0.901; testing group: AUC, 0.841). The nomogram model composed of Rad score and clinical characteristics had better diagnostic performance than a simple clinical model (training group: AUC, 0.906; testing group: AUC, 0.845; p < 0.01). Based on DCA, the nomogram model can provide better diagnostic performance in most cases. In conclusion, the MRI-bone marrow edema-based radiomics-clinical nomogram model showed good performance in diagnosing early osteoarthritis.

The Clinical Impact of Refined Nursing Intervention on Severe Neonatal Pneumonia Accompanied by Respiratory Failure.

Background: Neonatal pneumonia is a common respiratory disease in the neonatal period, often accompanied by respiratory failure. In addition to timely treatment, effective nursing is essential. Objective: We attempted to determine the clinical effect of refined nursing applied to the nursing of patients with severe neonatal pneumonia accompanied by respiratory failure. Design: This was a randomized controlled study. Setting: This study was performed in the Neonatal Department, The First Hospital of China Medical University. Participants: A total of 60 newborns with severe pneumonia and respiratory failure diagnosed and treated in the neonatal intensive care unit of our hospital between January 2022 and December 2022 were selected and assigned to either the control group (CG) or the experimental group (EG) based on the random number table method, with 30 patients in each group. Interventions: The CG received conventional nursing intervention and the EG received refined nursing intervention. Primary Outcome Measures: (1) Symptom improvement time; (2) blood gas indicators; (3) vital signs; (4) complication occurrence rate and (5) nursing satisfaction. Results: The improvement time of cough, shortness of breath and wheezing in the EG was decreased compared with the CG (P < .05). After nursing, the EG exhibited higher partial arterial oxygen pressure and blood oxygen saturation levels and lower partial arterial carbon dioxide pressure relative to the control group (P < .05). After nursing, the heart and respiratory rates in both groups were decreased compared with before nursing, and in the EG group were decreased in comparison with the CG (P < .05). The incidence of adverse events in the EG was lower in comparison with the CG (P < .05). Nursing satisfaction in the EG was higher compared with the CG. Conclusion: The application of refined nursing in the clinical nursing of patients with neonatal pneumonia accompanied by respiratory failure can facilitate improvement in their condition, improve blood gas indicators and vital signs and prevent adverse events.

Identification and Validation of Tumor Microenvironment-Associated Signature in Clear-Cell Renal Cell Carcinoma through Integration of DNA Methylation and Gene Expression.

The tumor microenvironment (TME) is crucial in tumor development, metastasis, and response to immunotherapy. DNA methylation can regulate the TME without altering the DNA sequence. However, research on the methylation-driven TME in clear-cell renal cell carcinoma (ccRCC) is still lacking. In this study, integrated DNA methylation and RNA-seq data were used to explore methylation-driven genes (MDGs). Immune scores were calculated using the ESTIMATE, which was employed to identify TME-related genes. A new signature connected with methylation-regulated TME using univariate, multivariate Cox regression and LASSO regression analyses was developed. This signature consists of four TME-MDGs, including AJAP1, HOXB9, MYH14, and SLC6A19, which exhibit high methylation and low expression in tumors. Validation was performed using qRT-PCR which confirmed their downregulation in ccRCC clinical samples. Additionally, the signature demonstrated stable predictive performance in different subtypes of ccRCC. Risk scores are positively correlated with TMN stages, immune cell infiltration, tumor mutation burden, and adverse outcomes of immunotherapy. Interestingly, the expression of four TME-MDGs are highly correlated with the sensitivity of first-line drugs in ccRCC treatment, especially pazopanib. Molecular docking indicates a high affinity binding between the proteins and pazopanib. In summary, our study elucidates the comprehensive role of methylation-driven TME in ccRCC, aiding in identifying patients sensitive to immunotherapy and targeted therapy, and providing new therapeutic targets for ccRCC treatment.

Perfluorooctane sulfonate promotes the migration of colorectal cancer cells by inducing epithelial-mesenchymal transition.

The potential association between colorectal cancer (CRC) and environmental pollutants is worrisome. Previous studies have found that some perfluoroalkyl acids, including perfluorooctane sulfonate (PFOS), induced colorectal tumors in experimental animals and promoted the migration of and invasion by CRC cells in vitro, but the underlying mechanism is unclear. Here, we investigated the effects of PFOS on the proliferation and migration of CRC cells and the potential mechanisms involving activating the PI3K/Akt-NF-κB signal pathway and epithelial-mesenchymal transition (EMT). It was found that PFOS promoted the growth and migration of HCT116 cells at non-cytotoxic concentrations and increased the mRNA expression of the migration-related angiogenic cytokines vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8). In a mechanistic investigation, the up-stream signal pathway PI3K/Akt-NF-κB was activated by PFOS, and the process was suppressed by LY294002 (PI3K/Akt inhibitor) and BAY11-7082 (NF-κB inhibitor) respectively, leading to less proliferation of HCT116 cells. Furthermore, matrix metalloproteinases (MMP) and EMT-related markers were up-regulated after PFOS exposure, and were also suppressed respectively by LY294002 and BAY11-7082. Moreover, the up-regulation of EMT markers was suppressed by a MMP inhibitor GM6001. Taken together, our results indicated that PFOS promotes colorectal cancer cell migration and proliferation by activating the PI3K/Akt-NF-κB signal pathway and epithelial-mesenchymal transition. This could be a potential toxicological mechanism of PFOS-induced malignant development of colorectal cancer.

Gypenoside L inhibits hepatocellular carcinoma by targeting the SREBP2-HMGCS1 axis and enhancing immune response.

Hepatocellular carcinoma (HCC) is a malignant tumor that occurs in the liver, with a high degree of malignancy and relatively poor prognosis. Gypenoside L has inhibitory effects on liver cancer cells. However, its mechanism of action is still unclear. This study aims to investigate the inhibitory effects of gypenoside L on HCC in vitro and in vivo, and explore its potential mechanisms. The results showed that gypenoside L reduced the cholesterol and triglyceride content in HepG2 and Huh-7 cells, inhibited cell proliferation, invasion and metastasis, arrested cell cycle at G0/G1 phase, promoted cell apoptosis. Mechanistically, it targeted the transcription factor SREPB2 to inhibit the expression of HMGCS1 protein and inhibited the downstream proteins HMGCR and MVK, thereby regulating the mevalonate (MVA) pathway. Overexpression HMGCS1 led to significant alterations in the cholesterol metabolism pathway of HCC, which mediated HCC cell proliferation and conferred resistance to the therapeutic effect of gypenoside L. In vivo, gypenoside L effectively suppressed HCC growth in tumor-bearing mice by reducing cholesterol production, exhibiting favorable safety profiles and minimal toxic side effects. Gypenoside L modulated cholesterol homeostasis, enhanced expression of inflammatory factors by regulating MHC I pathway-related proteins to augment anticancer immune responses. Clinical samples from HCC patients also exhibited high expression levels of MVA pathway-related genes in tumor tissues. These findings highlight gypenoside L as a promising agent for targeting cholesterol metabolism in HCC while emphasizing the effectiveness of regulating the SREBP2-HMGCS1 axis as a therapeutic strategy.

Palmitic acid impairs human and mouse placental function by inhibiting trophoblast autophagy through induction of acyl-coenzyme A-binding protein (ACBP) upregulation.

STUDY QUESTION: Can exposure to palmitic acid (PA), a common saturated fatty acid, modulate autophagy in both human and mouse trophoblast cells through the regulation of acyl-coenzyme A-binding protein (ACBP)? SUMMARY ANSWER: PA exposure before and during pregnancy impairs placental development through mechanisms involving placental autophagy and ACBP expression. WHAT IS KNOWN ALREADY: High-fat diets, including PA, have been implicated in adverse effects on human placental and fetal development. Despite this recognition, the precise molecular mechanisms underlying these effects are not fully understood. STUDY DESIGN, SIZE, DURATION: Extravillous trophoblast (EVT) cell line HTR-8/SVneo and human trophoblast stem cell (hTSC)-derived EVT (hTSCs-EVT) were exposed to PA or vehicle control for 24 h. Female wild-type C57BL/6 mice were divided into PA and control groups (n = 10 per group) and subjected to a 12-week dietary intervention. Afterward, they were mated with male wild-type C57BL/6 mice and euthanized on Day 14 of gestation. Female ACBPflox/flox mice were also randomly assigned to control and PA-exposed groups (each with 10 mice), undergoing the same dietary intervention and mating with ACBPflox/floxELF5-Cre male mice, followed by euthanasia on Day 14 of gestation. The study assessed the effects of PA on mouse embryonic development and placental autophagy. Additionally, the role of ACBP in the pathogenesis of PA-induced placental toxicity was investigated. PARTICIPANTS/MATERIALS, SETTING, METHODS: The findings were validated using real-time PCR, Western blot, immunofluorescence, transmission electron microscopy, and shRNA knockdown approaches. MAIN RESULTS AND THE ROLE OF CHANCE: Exposure to PA-upregulated ACBP expression in both human HTR-8/SVneo cells and hTSCs-EVT, as well as in mouse placenta. PA exposure also induced autophagic dysfunction in HTR-8/SVneo cells, hTSCs-EVT, and mouse placenta. Through studies on ACBP placental conditional knockout mice and ACBP knockdown human trophoblast cells, it was revealed that reduced ACBP expression led to trophoblast malfunction and affected the expression of autophagy-related proteins LC3B-II and P62, thereby impacting embryonic development. Conversely, ACBP knockdown partially mitigated PA-induced impairment of placental trophoblast autophagy, observed both in vitro in human trophoblast cells and in vivo in mice. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Primary EVT cells from early pregnancy are fragile, limiting research use. Maintaining their viability is tough, affecting data reliability. The study lacks depth to explore PA diet cessation effects after 12 weeks. Without follow-up, understanding postdiet impacts on pregnancy stages is incomplete. Placental abnormalities linked to elevated PA diet in embryos lack confirmation due to absence of control groups. Clarifying if issues stem solely from PA exposure is difficult without proper controls. WIDER IMPLICATIONS OF THE FINDINGS: Consuming a high-fat diet before and during pregnancy may result in complications or challenges in successfully carrying the pregnancy to term. It suggests that such dietary habits can have detrimental effects on the health of both the mother and the developing fetus. STUDY FUNDING/COMPETING INTEREST(S): This work was supported in part by the National Natural Science Foundation of China (82171664, 82301909) and the Natural Science Foundation of Chongqing Municipality of China (CSTB2022NS·CQ-LZX0062, cstc2019jcyj-msxmX0749, and cstc2021jcyj-msxmX0236). The authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Imaging Rovibrational Excitation of Scattered YO Molecules in Inelastic Collisions with Kr and Ne.

Energy transfer between atoms and molecules is fundamental to many physical and chemical processes, and understanding the mechanisms and outcomes of energy transfer is crucial for various applications in physics and chemistry. Here, the rovibrational excitation of YO(X 2Σ+) molecules with the collision of Kr and Ne has been studied in the laser-ablation crossed beam and time-sliced ion velocity map imaging setup in combination with the resonance enhanced multiphoton ionization scheme. Significant changes in the angular distribution for different rovibrational excitations of YO molecules are observed with the collision of Kr. The sharp forward distribution for low rovibrational excitation of YO(v' = 0, 1) molecules suggest that the weak attractive potential between Kr and YO is dominant at large impact parameters. Comparatively, the strong sideway distribution for highly rovibrationally excited YO(v' = 1, 2, 3, and 5) is due to rainbow scattering from the stronger attractive potential of Kr···YO at relatively small impact parameters. The more isotropic angular distribution in the highly rovibrationally excited YO(v' = 11) indicates the formation of a short-lived complex. A change in the angular distribution of scattered YO with different rovibrational excitations was also observed in the collisions of Ne. For YO as a heteronuclear diatomic molecule, collisions of the Y- and the O-end of YO with rare gases would affect the contribution of inelastic processes at different impact parameters.

Polyacrylonitrile as an Efficient Transfer Medium for Wafer-Scale Transfer of Graphene.

The disparity between growth substrates and application-specific substrates can be mediated by reliable graphene transfer, the lack of which currently strongly hinders the graphene applications. Conventionally, the removal of soft polymers, that support the graphene during the transfer, would contaminate graphene surface, produce cracks, and leave unprotected graphene surface sensitive to airborne contaminations. In this work, it is found that polyacrylonitrile (PAN) can function as polymer medium for transferring wafer-size graphene, and encapsulating layer to deliver high-performance graphene devices. Therefore, PAN, that is compatible with device fabrication, does not need to be removed for subsequent applications. The crack-free transfer of 4 in. graphene onto SiO2/Si wafers, and the wafer-scale fabrication of graphene-based field-effect transistor arrays with no observed clear doping, uniformly high carrier mobility (≈11 000 cm2 V-1 s-1), and long-term stability at room temperature, are achieved. This work presents new concept for designing the transfer process of 2D materials, in which multifunctional polymer can be retained, and offers a reliable method for fabricating wafer-scale devices of 2D materials with outstanding performance.

Subacute exposure to DEHP leads to impairing decidualization process and exacerbating the risk of early pregnancy miscar-riage in mice. / 孕早期增塑剂DEHPäºšæ€¥æ€§æš´éœ²å½±å“èœ•è†œååº”å¹¶å¢žåŠ æµäº§é£Žé™©.

OBJECTIVES: To investigate the effect of subacute exposure of Di (2-ethylhexyl) phthalate (DEHP) on endometrial decidualization in mice. METHODS: CD1 mice were orally administrated with 300 mg·kg－1·d－1 (low-dose group), 1000 mg·kg－1·d－1 (medium-dose group), or 3000 mg·kg－1·d－1 DEHP (1/10 LD50, high-dose group) for 28 days, respectively. The early natural pregnancy model and artificially induced decidualization model were established, and the uterine tissues were collected on D7 of natural pregnancy and D8 of artificially induced decidualization, respectively. The effects of subacute exposure to DEHP on the decidualization of mice were detected by HE staining, Masson staining, TUNEL staining, and Western blotting, respectively. A model of spontaneous abortion was constructed in mice after subacute exposure to 300 mg·kg-1·d-1 DEHP, and the effect of impaired decidualization on pregnancy was investigated by observing the pregnancy outcome on the 10th day of gestation. RESULTS: Compared with the control group, the conception rate was significantly lower in the high-dose DEHP subacute exposure group. HE staining showed that, compared with the control group, the decidual stromal cells in the low- and medium-dose exposure groups were disorganized, the nuclei of the cells were irregular, the cytoplasmic staining was uneven, and the number of polymorphonuclear cells was significantly reduced. Masson staining showed that compared with the control group, the collagen fibers in the decidua region of the DEHP low-dose group and the medium-dose group were more distributed, more abundant and more disorderly. TUNEL staining showed increased apoptosis in the decidua area compared to the control group. Western blotting showed that the expression of BMP2, a marker molecule for endometrial decidualization, was significantly reduced. The abortion rate and embryo resorption rate were significantly higher, and the number of embryos, uterine wet weight, uterine area and placenta wet weight were significantly lower in mice exposed to 300 mg·kg－1·d－1 DEHP than in control mice stimulated by mifepristone abortifacient drug. CONCLUSIONS: Subacute exposure to DEHP leads to impaired endometrial decidualization during early pregnancy and exacerbates the risk of adverse pregnant outcomes in mice.

The 6-kilodalton peptide 1 in plant viruses of the family Potyviridae is a viroporin.

Potyviridae, the largest family of plant RNA viruses, includes many important pathogens that significantly reduce the yields of many crops worldwide. In this study, we report that the 6-kilodalton peptide 1 (6K1), one of the least characterized potyviral proteins, is an endoplasmic reticulum-localized protein. AI-assisted structure modeling and biochemical assays suggest that 6K1 forms pentamers with a central hydrophobic tunnel, can increase the cell membrane permeability of Escherichia coli and Nicotiana benthamiana, and can conduct potassium in Saccharomyces cerevisiae. An infectivity assay showed that viral proliferation is inhibited by mutations that affect 6K1 multimerization. Moreover, the 6K1 or its homologous 7K proteins from other viruses of the Potyviridae family also have the ability to increase cell membrane permeability and transmembrane potassium conductance. Taken together, these data reveal that 6K1 and its homologous 7K proteins function as viroporins in viral infected cells.

Dimethyl fumarate alleviates allergic asthma by strengthening the Nrf2 signaling pathway in regulatory T cells.

Allergic asthma is a widely prevalent inflammatory condition affecting people across the globe. T cells and their secretory cytokines are central to the pathogenesis of allergic asthma. Here, we have evaluated the anti-inflammatory impact of dimethyl fumarate (DMF) in allergic asthma with more focus on determining its effect on T cell responses in allergic asthma. By utilizing the ovalbumin (OVA)-induced allergic asthma model, we observed that DMF administration reduced the allergic asthma symptoms and IgE levels in the OVA-induced mice model. Histopathological analysis showed that DMF treatment in an OVA-induced animal model eased the inflammation in the nasal and bronchial tissues, with a particular decrease in the infiltration of immune cells. Additionally, RT-qPCR analysis exhibited that treatment of DMF in an OVA-induced model reduced the expression of inflammatory cytokine (IL4, IL13, and IL17) while augmenting anti-inflammatory IL10 and Foxp3 (forkhead box protein 3). Mechanistically, we found that DMF increased the expression of Foxp3 by exacerbating the expression of nuclear factor E2-related factor 2 (Nrf2), and the in-vitro activation of Foxp3+ Tregs leads to an escalated expression of Nrf2. Notably, CD4-specific Nrf2 deletion intensified the allergic asthma symptoms and reduced the in-vitro iTreg differentiation. Meanwhile, DMF failed to exert protective effects on OVA-induced allergic asthma in CD4-specific Nrf2 knock-out mice. Overall, our study illustrates that DMF enhances Nrf2 signaling in T cells to assist the differentiation of Tregs, which could improve the anti-inflammatory immune response in allergic asthma.

Structural and functional insights into transcription activation of the essential LysR-type transcriptional regulators.

The enormous LysR-type transcriptional regulators (LTTRs), which are diversely distributed amongst prokaryotes, play crucial roles in transcription regulation of genes involved in basic metabolic pathways, virulence and stress resistance. However, the precise transcription activation mechanism of these genes by LTTRs remains to be explored. Here, we determine the cryo-EM structure of a LTTR-dependent transcription activation complex comprising of Escherichia coli RNA polymerase (RNAP), an essential LTTR protein GcvA and its cognate promoter DNA. Structural analysis shows two N-terminal DNA binding domains of GcvA (GcvA_DBD) dimerize and engage the GcvA activation binding sites, presenting the -35 element for specific recognition with the conserved σ70R4. In particular, the versatile C-terminal domain of α subunit of RNAP directly interconnects with GcvA_DBD, σ70R4 and promoter DNA, providing more interfaces for stabilizing the complex. Moreover, molecular docking supports glycine as one potential inducer of GcvA, and single molecule photobleaching experiments kinetically visualize the occurrence of tetrameric GcvA-engaged transcription activation complex as suggested for the other LTTR homologs. Thus, a general model for tetrameric LTTR-dependent transcription activation is proposed. These findings will provide new structural and functional insights into transcription activation of the essential LTTRs.

[Role of COX-2/PGE2/EP4 Axis-induced Macrophage Functional Activation 
in NSCLC Development].

BACKGROUND: Tumor microenvironment (TME) is one of the important factors in tumorigenesis and progression, in which tumor-associated macrophages (TAMs) play an important role in non-small cell lung cancer (NSCLC) progression. However, the mechanism of TAMs in NSCLC progression remains unclear, so this study aimed to investigate the role of TAMs in NSCLC progression and to find potential therapeutic targets. METHODS: Gene Expression Profiling Interactive Analysis (GEPIA) database was used to analyze the expression of prostaglandin E2 receptor 4 (EP4) mRNA in NSCLC and normal lung tissues; the protein expression levels of cyclooxygenase-2 (COX-2), EP4, cluster of differentiation 86 (CD86), CD163 and CD31 were detected by immunohistochemistry (IHC) in 120 NSCLC tissues and 24 paracancerous tissues specimens. The nude mouse lung adenocarcinoma cell A549 and macrophage RAW264.7 co-transplanted tumor model was established. And the samples were collected by gavage with EP4 inhibitor E7046, and then stained with hematoxylin-eosin (HE), IHC, and immunofluorescence (IF), and then detected by Western blot for the epithelial mesenchymal transformation (EMT) of the tumor tissues of the nude mice in each group. Western blot was used to detect the expressions of EMT related protiens in each group of nude mice; full-length transcriptome sequencing was used to screen the key genes causing liver metastasis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was performed. RESULTS: EP4 mRNA expression level in NSCLC tissues was generally lower than that in normal lung tissues (P<0.05); COX-2, EP4, CD163, CD31 proteins were differentially expressed in NSCLC tissues and adjacent tissues, and differences were observed in many clinicopathological parameters of NSCLC patients; RAW264.7 shortened the latency period of tumorigenesis of A549 and promoted the proliferation of tumors and liver metastasis of tumors, and E7046 could reduce tumor cell proliferation activity, tumor tissue vascular density and M2-type macrophage infiltration in nude mice; IF staining showed that macrophages were mainly distributed around the metastatic foci of tumors; Western blot results showed that compared with A549 alone transplantation group, the relative expression of E-cadherin protein in tumor tissues of mice in A549 and RAW264.7 co-transplantation group was significantly decreased, and the difference was statistically significant (P<0.05), while the relative expression of N-cadherin protein was up-regulated, but the difference was not statistically significant (P>0.05); the main pathways enriched in the differential genes of the full-length transcriptome were the PI3K-AKT and MAPK signaling pathways. CONCLUSIONS: During NSCLC development, the COX-2/PGE2/EP4 axis may promote tumor progression by inducing macrophage functional activation, and EP4 may be a potential new target for tumor immunotherapy. This study provides new perspectives and ideas for in-depth exploration of the mechanisms of NSCLC development, as well as a theoretical basis for the development of new therapeutic strategies for NSCLC.

Degradation mechanisms and toxicity determination of bisphenol A by FeOx-activated peroxydisulfate under ultraviolet light.

Ultraviolet light (UV)-assisted advanced oxidation processes (AOPs) are commonly used to degrade organic contaminants. However, this reaction system's extensive comprehension of the degradation mechanisms and toxicity assessment remains inadequate. This study focuses on investigating the degradation mechanisms and pathways of bisphenol A (BPA), generation of reactive oxygen species (ROS), and toxicity of degradation intermediates in UV/PDS/ferrous composites (FeOx) systems. The degradation rate of BPA gradually increased from the initial 11.92% to 100% within 120 min. Sulfate radicals (SO4.-), hydroxyl radicals (.OH), superoxide anions (O2.-), and singlet oxygen (1O2) were the primary factors in the photocatalytic degradation of BPA in the UV/PDS/FeOx systems. The main reactions of BPA in this system were deduced to be ß-bond cleavage, hydroxyl substitution reaction, hydrogen bond cleavage, and oxidation reaction. A trend of decreasing toxicity for the degradation intermediates of BPA was observed according to the toxicity investigations. The efficient degradation of BPA in UV/PDS/FeOx systems provided theoretical data for AOPs, which will improve the understanding of organic contaminants by FeOx in natural industry wastewater.