Irreversible and extensive pulmonary fibrosis caused by paraquat (PQ) poisoning is the main cause of death induced by PQ poisoning in developing countries. Studies have confirmed that epithelial-mesenchymal transition (EMT) contributes to the process of pulmonary interstitial fibrosis caused by PQ poisoning. Many studies have proved that a variety of miRNAs are involved in the occurrence and development of EMT. Through animal and cell experiments, we established the model of EMT on mouse lung and MLE-12 cell. We found that the expression of Regulator of G-protein signaling 2 (RGS2) was decreased in mice lung tissue and MLE-12 induced by PQ, and over-expressed/inhibited miR-9-8974-5p can decrease/increase the level of RGS2. We found that pirfenidone (PFD) can relieve PQ-induced EMT in mice lung tissue and MLE-12 cells. Meanwhile, we found that it had high expression of RGS2 in PFD group. Mimic/inhibited miR-9-8974-5p can aggravate or relieve the EMT with decreasing /increasing the level of RGS2. In conclusion, miR-9-8974-5p can mediate the pulmonary EMT induced by PQ by regulating RGS2. PFD exerts a potential therapeutic effect on PQ-induced pulmonary EMT by regulating miR-9-8974-5p/RGS2 expression.

Colitis-associated colorectal cancer (CAC) is a major contributor to cancer-related mortality worldwide. Titanium dioxide (TiO2, E171), a widely used food additive, has been insufficiently studied regarding its effects on macrophages within colon tumors during CAC development. In this study, CAC mouse models were used to investigate the biological impact of dietary E171 on macrophages in vivo, while lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cell lines were employed to elucidate the underlying mechanisms in vitro. We found that dietary E171 intake accelerated CAC development, exacerbated inflammatory responses and oxidative stress, and upregulated CAC-associated genes, including S100a8, S100a9, Lcn2, S100a11, Cxcl2, and interleukin-1α (Il-1α). E171 also increased the expression of S100A8, S100A9, NOD-like receptor family pyrin domain-containing 3 (NLRP3), and gasdermin-D N-terminal (GSDMD-N) in macrophages within colon tumors. In inflammatory macrophages, E171 exposure enhanced cell viability, increased reactive oxygen species (ROS) levels, and elevated the expression and secretion of S100A8 and S100A9, consistent with in vivo histological observations. Furthermore, E171-induced secretion of S100A8 and S100A9 in macrophages was suppressed by specific inhibitors, including N-acetylcysteine (NAC, ROS inhibitor), MCC950 (NLRP3 inhibitor), Z-YVAD-FMK (caspase 1 inhibitor), disulfiram (GSDMD inhibitor), and transfection of NLRP3 small interfering ribonucleic acid (siRNA). These results indicate that dietary E171 promotes CAC development by activating macrophages, with S100A8 and S100A9 serving as key mediators, and the NLRP3/caspase 1/GSDMD pathway acting as a critical mechanism.

The hydrophobic sonosensitizer IR780 iodide (IR780) was loaded into liposomes to form Liposome@IR780 nanoparticles (NPs) for triple-negative breast cancer (TNBC) to enhance SDT via low-intensity ultrasound (LIU) irradiation. The NPs were characterized using various physicochemical methods including size distribution, zeta potential, and morphology. In vitro experiments show that the Liposome@IR780 NPs can generate more reactive oxygen species (ROS) upon LIU irradiation. The apoptosis experiment results further demonstrate that Liposome@IR780 NPs show better apoptosis rate against 4T1 cells. Our results indicate that Liposome@IR780 NPs will provide a promising approach for TNBC upon SDT treatment.

Antiangiogenic therapies, such as bevacizumab, are among the causes of cancer-related death in patients with colorectal cancer (CRC) with liver metastasis. Delivering siRNAs via primary cell originating from primary cells is a promising method for targeting CRC liver metastasis and drug resistance. Here, it is found that the expression of CCL24 is significantly upregulated in tumor tissues at the CRC liver metastasis site. In addition, CCL24 is significantly upregulated in tumor tissues from bevacizumab-resistant patients. CCL24 promotes the formation of inflammatory tumor-associated fibroblast subsets in the CRC liver metastasis microenvironment and induces resistance to bevacizumab therapy. Based on these results, a primary cell-derived extracellular vehicle delivery system is designed for the simultaneous delivery of siRNAs targeting CCL24 in the tumor microenvironment (TME). Downregulation of CCL24 in the TME by delivering bioengineered extracellular vehicles significantly increased sensitivity to antiangiogenic therapy in a CRC mouse model. A novel therapeutic target is identified for patients with CRC with liver metastasis and suggested a possible therapeutic alternative for patients with CRC with resistance to antiangiogenic therapy and distant metastasis.

Disulfidptosis is a unique type of programmed cell death that is distinct from previously known forms of cell death, such as pyroptosis, apoptosis, and necroptosis. Researchers have studied the significance of many forms of cell death in various diseases, particularly malignant tumors, in great detail in recent years. Therefore, how disulfidptosis affects colon cancer and how it functions in the immune system are unknown. Disulfidptosis-related gene (DRG) expression information was obtained from the TCGA-COAD cohort. Patients were categorized into two DRG groups using consensus cluster analysis, and the disulfidptosis-related differentially expressed genes (DRDEGs) were subsequently identified by differential analysis of the two clusters. Univariate Cox regression analysis of the DRDEGs was used to identify prognosis-related DEGs (PRDEGs). The screened PRDEGs were then subjected to LASSO-Cox regression analysis to determine the prognostic model on the basis of ten genes. Immunohistochemistry was used to verify the expression and prognostic value of marker genes. In the two DRG clusters, the characteristics of the tumor microenvironment (TME) significantly differed by the TME scores and infiltration levels of 23 human immune cell subpopulations. Prognostically meaningful risk scores were found, with a greater chance of mortality (p = 4.4e−7) for patients in the high-risk category. Furthermore, notable differences in TME scores, immune cell infiltration, and immune checkpoint expression were detected among the risk categories. The ROC curves revealed that the nomogram’s 1-, 2-, and 3-year AUCs were 0.75, 0.76, and 0.77, respectively, demonstrating the superior predictive capacity of the nomogram. Immunohistochemistry revealed that patients with high FABP4 and low ADAM8 and FSTL3 expressions had a better prognosis. The prognostic features based on 10 PRDEGs performed well in predicting survival, TME status, and response to immunity in COAD patients, helping provide personalized immunotherapy strategies for patients.

Introduction:Nicotinamide plays a critical role in the prevention and treatment of tumors, and its metabolism is closely associated with tumor progression. The aim of this study was to understand the prognostic and immunological significance of nicotinamide metabolism-related genes in pan-cancer. Methods:We downloaded The Cancer Genome Atlas and Genotype Tissue Expression pan-cancer datasets for NMNAT1 from the UCSC database. We analyzed the differential expression, prognosis, genetic alterations, DNA methylation, immune infiltration, and co-expression with RNA modification-related genes and immune checkpoint-related genes. Genes with expression patterns similar to NMNAT1 were identified using the GEPIA library. The GSCA database was used to investigate the correlation between gene expression and drug sensitivity, as assessed by GDSC and CTRP. The CancerSEA database was employed to examine the association of NMNAT1 expression at the single-cell level across different tumors and its relation to 14 functional states. Immunohistochemistry was performed to assess the clinical significance of NMNAT1 expression. Results:NMNAT1 exhibited differential expression across 25 tumor types, including colorectal cancer (CRC), and its expression was significantly associated with the prognosis of 11 tumors. Furthermore, NMNAT1 expression correlated significantly with clinicopathological features. NMNAT1 was strongly associated with immune cells, RNA modification-related genes, and immune checkpoint-related genes in most tumors, affecting immune responses. The expression of NMNAT1 also correlated with sensitivity and resistance to several drugs. Single-cell analysis revealed that NMNAT1 is involved in the progression of retinoblastoma, uveal melanoma, and CRC. Immunohistochemical analysis confirmed that NMNAT1 expression is an independent prognostic factor in patients with CRC. Conclusion:NMNAT1 is a crucial prognostic and immune marker gene for nicotinamide metabolism, particularly in CRC. It has potential as a clinical biomarker and a therapeutic target for cancer treatment.

Age significantly affects the prognosis of patients with rectal cancer after radical excision (RE), and local excision (LE) is an alternative surgical procedure to RE. To compare the survival prognosis in different age groups of LE versus RE for rectal cancer. Patients diagnosed with rectal adenocarcinoma treated by LE or RE from 2010 to 2017 were obtained from the SEER database. The primary outcomes are 5-year OS and CSS. A total of 11,170 patients were eventually included, and there were 490 patients in LE and RE groups, respectively, after 1:1 propensity score matching. The 5-year OS and CSS after LE were significantly better in < 50 years and 50-66 years groups than in > 66 years group (5-year OS: 95.70% vs 88.40% vs 67.00%, P < 0.001; 5-year CSS: 95.70% vs 96.30% vs 82.60%, P < 0.001). No statistical significance was found for the differences in 5-year OS and CSS between LE and RE in < 50, 50-66, and > 66 years group (P > 0.05). Multivariate analysis showed age > 66 years, poorly differentiated or undifferentiated (Grade III/IV), and tumor size 3 to 5 cm was independent risk factors for 5-year OS after LE; age > 66 years, perineural invasion, and tumor size 3 to 5 cm were the 5-year CSS independent risk factors for after LE. We found that the survival prognosis of younger rectal cancer patients treated with LE was significantly better than older (> 66 years) patients, and the survival prognosis of rectal cancer patients in the three age groups was similar between LE and RE.

Biofilm and bone tissue defect induced by the bacterial infection severely impede chronic osteomyelitis treatment. It is critical to break though the densely and obstinate biofilm so that the target drugs can deliver to the infected bone more effectively. Herein, an acoustically responsive multifunctional hydrogel microsphere-bomb (EMgel) was designed and prepared by microfluidic technology, which could be injected to the focus of bone infection, and blasted into the nidus deeply to destroy the bacterial biofilm matrix barrier under penetrating ultrasound, so the encapsulated natural polyphenolic EGCG and bioactive MoS2 released to repair the damaged bone. The results proved the hydrogel microsphere-bomb exhibited controlling drug release, favorable antibacterial (as high as 99 %), high biofilm resistance, fascinating antioxidation, good cytocompatibility, and osteogenic differentiation. The acoustically responsive microsphere-bomb further proved their fantastic ability to eradicate biofilm and promote bone regeneration in the Methicillin-resistant Staphylococcus aureus (MRSA) infected chronic osteomyelitis model due to the synergy effects of EGCG and bioactive MoS2. Especially, immunohistochemical staining showed lower inflammatory reaction and higher expression of OCN in EMgel group treated with ultrasound wave. This study presents a new design of hydrogel microsphere-based intelligence drug delivery for osteomyelitis treatment, which exhibit great promising potential for dealing with chronic orthopedic infections, drug delivery system and tissue engineering.

The clinical potential applications of platelet-rich plasma (PRP) in wound healing have been extensively studied. However, the rapid release of its active components limits its clinical application and therapeutic effectiveness. In this study, a polyacrylamide hydrogel incorporating activated-PRP (PAM-PRP) through a one-pot method was prepared to achieve sustained-release effect with low-intensity ultrasound (LIU). The resulting PAM-PRP hydrogel demonstrates its ability to enhance release of PRP using LIU, the tunable mechanical properties, and the porous network. The cytocompatibility experiments demonstrate the favorable biocompatibility in vitro of PAM-PRP hydrogel. Notably, in vivo experiments further show the PAM-PRP-1 (acrylamide solution/activated-PRP solution, v/v, 1:1) hydrogel, when combined with LIU, facilitates complete wound healing without scarring in the SD rat full-thickness skin defect model. Additionally, the efficacy of the PAM-PRP-1 hydrogel in promoting formation of granulation tissues, collagen deposition, reducing inflammation and angiogenesis is confirmed by histologic and immunohistochemistry analysis. This study presents a promising approach to enhance effectiveness of PRP clinical therapy.

As a potential treatment strategy for low immunogenic triple negative breast cancer (TNBC), photodynamic therapy (PDT) induced antitumor immunotherapy is greatly limited by the immunosuppressive tumor microenvironment (ITM), especially the M2 phenotype tumor-associated macrophages (TAMs). The balance of arginine metabolism plays an important role in TAMs polarization. Herein, a multifunctional nanoplatform (defined as HN-HFPA) was employed to burst the anti-tumor immunity of TNBC post PDT by reeducating TAMs through interfering the TAMs-associated arginine metabolism. The L-arginine (L-Arg) was loaded in the hollow cavity of HN-HFPA, which could not only generate nitric oxide (NO) for tumor therapy, but also serve as a substrate of arginine metabolism pathway. As an inhibitor of arginases-1 (Arg-1) of M2 TAMs, L-norvaline (L-Nor) was modified to the hyaluronic acid (HA), and coated in the surface of HFPA. After degradation of HA by hyaluronidase in tumor tissue and GSH-mediated disintegration, HN-HFPA depleted intracellular GSH, produced remarkable reactive oxygen species (ROS) under light irradiation and released L-Arg to generate NO, which induced tumor immunogenic cell death (ICD). Real-time ultrasound imaging of tumor was realized taking advantage of the gas feature of NO. The L-Nor suppressed the Arg-1 overexpressed in M2, which skewed the balance of arginine metabolism and reversed the ITM with increased ratios of M1 and CD8+ T cells, finally resulted in amplified antitumor immune response and apparent tumor metastasis inhibition. This study remodeled ITM to strengthen immune response post PDT, which provided a promising treatment strategy for TNBC.

Abstract Background Hepatic inflammation is a common initiator of liver diseases and considered as the primary driver of hepatocellular carcinoma (HCC). However, the precise mechanism of inflammation-induced HCC development and immune evasion remains elusive and requires extensive investigation. This study sought to identify the new target that is involved in inflammation-related liver tumorigenesis. Methods RNA-sequencing (RNA-seq) analysis was performed to identify the differential gene expression signature in primary human hepatocytes treated with or without inflammatory stimulus. A giant E3 ubiquitin protein ligase, HECT domain and RCC1-like domain 2 (HERC2), was identified in the analysis. Prognostic performance in the TCGA validation dataset was illustrated by Kaplan–Meier plot. The functional role of HERC2 in HCC progression was determined by knocking out and over-expressing HERC2 in various HCC cells. The precise molecular mechanism and signaling pathway networks associated with HERC2 in HCC stemness and immune evasion were determined by quantitative real-time PCR, immunofluorescence, western blot, and transcriptomic profiling analyses. To investigate the role of HERC2 in the etiology of HCC in vivo, we applied the chemical carcinogen diethylnitrosamine (DEN) to hepatocyte-specific HERC2-knockout mice. Additionally, the orthotopic transplantation mouse model of HCC was established to determine the effect of HERC2 during HCC development. Results We found that increased HERC2 expression was correlated with poor prognosis in HCC patients. HERC2 enhanced the stemness and PD-L1-mediated immune evasion of HCC cells, which is associated with the activation of signal transducer and activator of transcription 3 (STAT3) pathway during the inflammation-cancer transition. Mechanically, HERC2 coupled with the endoplasmic reticulum (ER)-resident protein tyrosine phosphatase 1B (PTP1B) and limited PTP1B translocation from ER to ER-plasma membrane junction, which ameliorated the inhibitory role of PTP1B in Janus kinase 2 (JAK2) phosphorylation. Furthermore, HERC2 knockout in hepatocytes limited hepatic PD-L1 expression and ameliorated HCC progression in DEN-induced mouse liver carcinogenesis. In contrast, HERC2 overexpression promoted tumor development and progression in the orthotopic transplantation HCC model. Conclusion Our data identified HERC2 functions as a previously unknown modulator of the JAK2/STAT3 pathway, thereby promoting inflammation-induced stemness and immune evasion in HCC.

In the present study, we investigated the role of salt-induced kinase 1 (SIK1), a serine/threonine kinase protein, in colorectal cancer (CRC). Despite the reported association of SIK1 with tumor malignancy suppression in various cancers, limited research has been conducted on its function in CRC. Our findings revealed that SIK1 expression was low in CRC cells. The results of a KEGG pathway analysis showed a strong association between SIK1 and the TGF-β signaling pathway. In addition, a coimmunoprecipitation assay validated the interaction between SIK1 and Smad7. Our data indicate that SIK1 inhibited the phosphorylation of Smad2, a critical molecule in the Smad-related TGF-β pathway, and downstream target genes of the TGF-β pathway. Furthermore, SIK1 was found to inhibit indicators of epithelial-mesenchymal transition (EMT) and reverse oxaliplatin resistance in CRC. Additionally, SIK1 reduced cell migration and invasion. Our results suggest that the inhibitory effect of SIK1 on the TGF-β pathway contributes to the suppression of metastasis and oxaliplatin chemoresistance in CRC. However, this effect was reversed by galunisertib (LY2157299). In conclusion, our findings provide novel insights into the role of SIK1 in the regulation of the TGF-β pathway in CRC, suggesting its potential as a therapeutic target for the treatment of CRC. Further studies are required to fully characterize the mechanism underlying these observations and to validate these findings in animal models.

Scavenger receptor A (SRA) is preferentially expressed in macrophages and implicated as a multifunctional pattern recognition receptor for innate immunity. Hepatic macrophages play a primary role in the pathogenesis of alcoholic liver disease. Herein, we observed that SRA expression was significantly increased in the liver tissues of mice with alcohol-related liver injury. SRA-deficient (SRA-/-) mice developed more severe alcohol-induced liver disease than wild-type mice. Enhanced liver inflammation existed in alcohol-challenged SRA-/- mice and was associated with increased Notch activation in hepatic macrophages compared with wild-type control animals. Mechanistically, SRA directly bound with Notch1 and suppressed its S-glutathionylation, thereby inhibiting Notch pathway activation. Further, we determined that the SRA interacted with thioredoxin-1 (Trx-1), a redox-active protein. SRA inhibited Trx-1 dimerization and facilitated the interaction of Trx-1 with Notch1. Application of a Trx-1-specific inhibitory agent during macrophage stimulation abolished SRA-mediated regulation of the Notch pathway and its downstream targets. In summary, our study revealed that SRA plays a critical role in macrophage inflammatory response by targeting Notch1 for its glutathionylation. SRA-mediated negative regulation of Notch activation might serve as a novel therapeutic strategy for alcohol-induced liver injury. Our study revealed that SRA plays a critical role in macrophage inflammatory response by targeting Notch1 for its glutathionylation, and SRA-mediated negative regulation of Notch activation might serve as a novel therapeutic strategy for alcohol-induced liver injury.

Esophageal squamous cell carcinoma (ESCC), one of the most commonly diagnosed and lethal malignant diseases, has a complex tumor ecosystem. An obvious requirement for T-cell-mediated tumor control is the infiltration of tumor-reactive T cells into the tumor. Here, we obtained detailed T-cell compositions in both ESCC tumors and matched peripheral blood mononuclear cells (PBMCs) at single-cell resolution. We demonstrated that T cells in tumors and PBMCs had different compositions and functional states. ESCC tumors were rich in Treg and exhausted T cells but poor in cytotoxic and naïve T cells compared with PBMCs. The exhausted T cells showed higher exhausted signature in tumors than in PBMCs, while the cytotoxic T cells exhibited higher cytotoxic signature in PBMCs than in tumors. Our data indicated an immunosuppressive status and a defect at the level of T-cell priming in the tumor microenvironment. Leukocyte-associated Ig-like receptor-2 (LAIR2), a soluble collagen receptor that prevents the binding of human leukocyte-associated Ig-like receptor-1 (LAIR1) to collagens, was predominantly expressed in proliferating CD8+ T and Treg cells in tumors but in cytotoxic cells in PBMCs. LAIR2 could inhibit tumor metastasis, invasion, and collagen deposition via suppressing transforming growth factor-β signaling. These findings revealed differential T-cell populations in tumors and PBMCs and provided convincing evidence that LAIR2 acted as a tumor suppressor.

骨骼肌是机体调节血糖的重要主体之一,胰岛素介导的微血管灌注受损将减少其葡萄糖摄取.超声造影(CEUS)可通过静脉输注造影剂并观察其信号强度随时间的变化而评估骨骼肌微循环灌注情况.本文就骨骼肌CEUS成像原理及其评估2型糖尿病患者骨骼肌微循环灌注研究进展进行综述.

目的 探讨血小板、凝血功能以及生殖激素监测对早孕期绒毛膜下血肿孕妇病情评估的临床价值.方法 选取2019年1月至2020年10月于广州市番禺区妇幼保健院B超确诊的236例宫内早孕并绒毛膜下血肿患者作为观察组.按妊娠结局将观察组患者分为A组(104例正常分娩者)和B组(132例流产者).选取同期健康的正常分娩孕妇206例作为对照组.检测凝血酶原时间(PT)、凝血酶时间(TT)、活化部分凝血活酶时间(APTT)、纤维蛋白原(Fib)、人绒毛膜促性腺激素(hCG)和血小板水平.首先比较观察组与对照组上述指标的差异,再比较A组和B组上述指标的差异.结果 观察组和对照组血小板水平比较,差异无统计学意义(P>0.05);观察组PT、APTT、TT较对照组长,Fib、hCG水平较对照组低(P<0.05).A组和B组血小板、PT、APTT水平比较,差异无统计学意义(P>0.05);与A组比较,B组TT较长,Fib、hCG水平较低(P<0.05).结论 检测PT、APTT、TT、Fib和hCG可为早孕期绒毛膜下血肿患者病情监测提供重要的参考依据.hCG、TT、Fib可被作为预测早孕绒毛膜下血肿孕妇妊娠结局的指标.

Atopic dermatitis (AD) is a severe inflammatory skin disease caused by a combination of genetic, immune, and environmental factors. Intestinal microbiome disorders and changes in the immune microenvironment are associated with AD. We observed that gut bacterial metabolite enterolactone (ENL) was significantly reduced in AD model mice. Notably, patients with early childhood-onset AD exhibited decreased sera ENL level compared to the healthy controls, and the ENL level was negatively correlated with the SCORAD index. Secoisolariciresinol-diglycoside (SDG) is a natural dietary lignan of flaxseeds that can be converted by intestinal bacteria to ENL. Repeated applications of 2,4-dinitrochlorobenzene (DNCB) were performed on the ear and dorsal skin of mice to induce AD-like symptoms and skin lesions. Oral administration of SDG significantly decreased serum IgE levels and limited skin inflammation in the DNCB-induced AD mice. In addition, SDG treatment strongly limited the Th2 responses in AD mice. Moreover, we demonstrated that the IL-4 production was significantly suppressed by ENL under Th2 polarization conditions via the JAK-STAT6 signaling pathway in a concentration-dependent manner. We concluded that SDG and its derived metabolite ENL ameliorated AD development by reducing the Th2 immune response. These results suggested that SDG and ENL might be exploited as potential therapeutic candidates for AD treatment.

跟腱是人体最粗大的肌腱,在下肢运动中有重要作用.跟腱疾病包括跟腱断裂和跟腱病.随着超声新技术的不断发展,超声在跟腱检查中广泛应用,为跟腱疾病的诊断、治疗及随访提供重要参考信息.本文就弹性成像、介入超声、超微血管成像、超声造影、三维成像等技术在跟腱疾病诊疗中的应用进展进行综述.

Endothelial lipase (LIPG/EL) performs fundamental and vital roles in the human body, including cell composition, cytokine expression, and energy provision. Since LIPG predominantly functions as a phospholipase as well as presents low levels of triglyceride lipase activity, it plays an essential role in lipoprotein metabolism, and involves in the metabolic syndromes such as inflammatory response and atherosclerosis. Cytokines significantly affect LIPG expression in endothelial cells in many diseases. Recently, it is suggested that LIPG contributes to cancer initiation and progression, and LIPG attached increasing importance to its potential for future targeted therapy.

Feature pyramids have become an essential component in most modern object detectors, such as Mask RCNN, YOLOv3, RetinaNet. In these detectors, the pyramidal feature representations are commonly used which represent an image with multi-scale feature layers. However, the detectors can’t be used in many real world applications which require real time performance under a computationally limited circumstance. In the paper, we study network architecture in YOLOv3 and modify the classical backbone--darknet53 of YOLOv3 by using a group of convolutions and dilated convolutions (DC). Then, a novel one-stage object detection network framework called DC-YOLOv3 is proposed. A lot of experiments on the Pascal 2017 benchmark prove the effectiveness of our framework. The results illustrate that DC-YOLOv3 achieves comparable results with YOLOv3 while being about 1.32× faster in training time and 1.38× faster in inference time.