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Lung adenocarcinoma (LUAD) is the leading cause of cancer-related death worldwide. Cancer-associated fibroblasts (CAFs) are a special type of fibroblasts, which play an important role in the development and immune escape of tumors. Weighted gene co-expression network analysis (WGCNA) was used to construct the co-expression module. In combination with univariate Cox regression and analysis of least absolute shrinkage operator (LASSO), characteristics associated with CAFs were developed for a prognostic model. The migration and proliferation of lung cancer cells were evaluated in vitro. Finally, the expression levels of proteins were analyzed by Western blot. LASSO Cox regression algorithm was then performed to select hub genes. Finally, a total of 2 Genes (COL5A2, COL6A2) were obtained. We then divided LUAD patients into high- and low-risk groups based on CAFs risk scores. Survival analysis, CAFs score correlation analysis and tumor mutation load analysis showed that COL5A2 and COL6A2 were high-risk genes for LUAD. Human Protein Atlas (HPA), western blot and PCR results showed that COL5A2 and COL6A2 were up-regulated in LUAD tissues. When COL5A2 and COL6A2 were knocked down, the proliferation, invasion and migration of lung cancer cells were significantly decreased. Finally, COL5A2 can affect LUAD progression through the Wnt/β-Catenin and TGF-β signaling pathways. Our CAFs risk score model offers a new approach for predicting the prognosis of LUAD patients. Furthermore, the identification of high-risk genes COL5A2 and COL6A2 and drug sensitivity analysis can provide valuable candidate clues for clinical treatment of LUAD.

Hepatic ischemia-reperfusion injury (IRI) is a common complication of hepatectomy and liver transplantation. As far as we know, mild hypothermia (MH) is an effective measure to alleviate liver IRI. However, the precise mechanisms have not been fully elucidated. This study investigated the regulatory role of FoxO1/PPARα-mediated energy metabolism in MH-alleviated IRI. Results showed a significant reduction in PPARα expression during liver IRI. Moreover, high PPARα level in post-IR liver specimens correlated with improved liver transplantation outcomes. MH increased blood glucose, elevated gluconeogenesis, and promoted fatty acid oxidation (FAO), indicating a high metabolic state, and also enhanced PPARα expression. Additionally, PPARα promoted FAO and gluconeogenesis, thereby enhancing MH’s protective effects on hepatocytes. Mechanistically, MH promoted FoxO1-PPARα interaction, enhancing PCK1 and CPT1a transcription and boosting hepatic metabolism. Selective FoxO1 inhibition by AS1842856 worsened IRI and apoptosis by reducing gluconeogenesis and FAO, MH partially mitigated this damage and promoted energy metabolism. Additionally, through the FoxO1/PPARα pathway, MH inhibits BAX/Cytochrome C/Caspase-3 cascade-initiated apoptosis. Our findings suggest that MH alleviates liver IRI by activating FoxO1/PPARα-mediated energy metabolism and inhibiting the mitochondria-dependent apoptosis pathway, potentially providing a basis for broader MH application.

Ischemia-reperfusion injury (IRI) is an inevitable and serious clinical problem in donations after heart death (DCD) liver transplantation. Excessive sterile inflammation plays a fateful role in liver IRI. Hypothermic oxygenated perfusion (HOPE), as an emerging organ preservation technology, has a better preservation effect than cold storage (CS) for reducing liver IRI, in which regulating inflammation is one of the main mechanisms. HECTD3, a new E3 ubiquitin ligase, and TRAF3 have an essential role in inflammation. However, little is known about HECTD3 and TRAF3 in HOPE-regulated liver IRI. Here, we aimed to investigate the effects of HOPE on liver IRI in a DCD rat model and explore the roles of HECTD3 and TRAF3 in its pathogenesis. We found that HOPE significantly improved liver damage, including hepatocyte and liver sinusoidal endothelial cell injury, and reduced DCD liver inflammation. Mechanistically, both the DOC and HECT domains of HECTD3 directly interacted with TRAF3, and the catalytic Cys (C832) in the HECT domain promoted the K63-linked polyubiquitination of TRAF3 at Lys138. Further, the ubiquitinated TRAF3 at Lys138 increased oxidative stress and activated the NF-κB inflammation pathway to induce liver IRI in BRL-3A cells under hypoxia/reoxygenation conditions. Finally, we confirmed that the expression of HECTD3 and TRAF3 was obviously increased in human DCD liver transplantation specimens. Overall, these findings demonstrated that HOPE can protect against DCD liver transplantation-induced-liver IRI by reducing inflammation via HECTD3-mediated TRAF3 K63-linked polyubiquitination. Therefore, HOPE regulating the HECTD3/TRAF3 pathway is a novel target for improving IRI in DCD liver transplantation.

The use of fatty livers in liver transplantation has emerged as a crucial strategy to expand the pool of donor livers; however, fatty livers are more sensitive to ischemia‒reperfusion injury (IRI). Excessive congenital inflammatory responses are crucial in IRI. Hypothermic oxygenated perfusion (HOPE) is a novel organ preservation technique that may improve marginal donor liver quality by reducing the inflammatory response. Tissue factor pathway inhibitor-2 (TFPI2) and CAP-Gly domain-containing linker protein 1 (CLIP1) exhibit modulatory effects on the inflammatory response. However, the underlying mechanisms of HOPE in fatty liver and the effects of TFPI2 and CLIP1 in fatty liver IRI remain unclear. Here, we aimed to explore the impact of HOPE on the inflammatory response in a rat model of fatty liver IRI and the mechanisms of action of TFPI2 and CLIP1. HOPE significantly reduces liver injury, especially the inflammatory response, and alleviates damage to hepatocytes and endothelial cells. Mechanistically, HOPE exerts its effects by inhibiting TFPI2, and CLIP1 can rescue the damaging effects of TFPI2. Moreover, HOPE promoted the ubiquitination and subsequent degradation of Toll/interleukin-1 receptor domain-containing adapter protein (TIRAP) by regulating the binding of R24 of the KD1 domain of TFPI2 with CLIP1, thereby negatively regulating the TLR4/NF-κB-mediated inflammatory response and reducing IRI. Furthermore, TFPI2 expression increased and CLIP1 expression decreased following cold ischemia in human fatty livers. Overall, our results suggest that targeting the inflammatory response by modulating the TFPI2/CLIP1/TIRAP signaling pathway via HOPE represents a potential therapeutic approach to ameliorate IRI during fatty liver transplantation. Targeting Inflammation Enhances Fatty Liver Transplant Outcomes Liver transplantation is the only effective treatment for end-stage liver disease, but donor organ shortages limit its progress. Researchers found that fatty livers, which make up 15-30% of donations, are more prone to damage during transplantation. In this study, the researchers used a rat model to explore how hypothermic oxygenated perfusion (HOPE) affects fatty liver transplants. HOPE is a technique where the liver is preserved at low temperatures with oxygenated fluid. They divided rats into three groups: sham, cold storage (CS), and HOPE. Results showed that HOPE significantly reduces liver injury, especially the inflammatory response, and alleviates oxidative stress to improve liver function. The researchers concluded that HOPE can protect fatty livers during transplantation by inhibiting inflammation. Future studies could explore HOPE’s potential in human liver transplants. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

Tobacco is a significant industrial crop, serving as a model for plant science and a promising specie for the production of proteins and small molecules. However, system biology studies of tobacco under natural field cultivation conditions remain scarce. Here, we construct a genome-scale metabolic regulatory network through integration of dynamic transcriptomic and metabolomic profiles from field-grown tobacco leaves across two ecologically distinct regions. We map 25,984 genes and 633 metabolites into 3.17 million regulatory pairs using multi-algorithm integration. This network reveals three pivotal transcriptional hubs, including NtMYB28 (promoting hydroxycinnamic acids synthesis by modifying Nt4CL2 and NtPAL2 expression), NtERF167 (amplifying lipid synthesis via NtLACS2 activation) and NtCYC (driving aroma production through NtLOX2 induction). These transcriptional hubs achieve substantial yield improvements of target metabolites by rewiring metabolic flux. The present work provides a systems-level atlas of tobacco metabolic regulation and may help to guide metabolic engineering. Tobacco is not only an important industrial crop but also severs as a model for plant science research and chassis for plant metabolic engineering. Here, the authors report genome-scale metabolic regulatory network and reveal key transcriptional hubs for different metabolite biosynthesis.

Background Hepatic ischemia–reperfusion injury (IRI) in donation after cardiac death (DCD) donors is a major determinant of transplantation success. Endoplasmic reticulum (ER) stress plays a key role in hepatic IRI, with potential involvement of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway and the antiapoptotic protein hematopoietic-lineage substrate-1-associated protein X-1 (HAX1). In this study, we aimed to investigate the effects of hypothermic oxygenated perfusion (HOPE), an organ preservation modality, on ER stress and apoptosis during hepatic IRI in a DCD rat model. Methods To investigate whether HOPE could improve IRI in DCD livers, levels of different related proteins were examined by western blotting and quantitative real-time polymerase chain reaction. Further expression analyses, immunohistochemical analyses, immunofluorescence staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and transmission electron microscopy were conducted to analyze the effects of HOPE on ER stress and apoptosis. To clarify the role of the JAK2/STAT3 pathway and HAX1 in this process, AG490 inhibitor, JAX1 plasmid transfection, co-immunoprecipitation (CO-IP), and flow cytometry analyses were conducted. Results HOPE reduced liver injury and inflammation while alleviating ER stress and apoptosis in the DCD rat model. Mechanistically, HOPE inhibited unfolded protein responses by activating the JAK2/STAT3 pathway, thus reducing ER stress and apoptosis. Moreover, the activated JAK2/STAT3 pathway upregulated HAX1, promoting the interaction between HAX1 and SERCA2b to maintain ER calcium homeostasis. Upregulated HAX1 also modulated ER stress and apoptosis by inhibiting the inositol-requiring enzyme 1 (IRE1) pathway. Conclusions JAK2/STAT3-mediated upregulation of HAX1 during HOPE alleviates hepatic ER stress and apoptosis, indicating the JAK2/STAT3/HAX1 pathway as a potential target for IRI management during DCD liver transplantation. Graphical Abstract

In order to study the mechanical properties of the disc cutter penetrating the particle system, a composite particle system model of the monodisperse particle system and soft and hard interlayered composite particle system was established based on the discrete element method, in which the monodisperse particle system was divided into hard particle system and soft particle system, combined with the complex network theory, and the crack propagation phenomenon and force chain were analyzed from the perspective of mesomechanics, and the distribution and evolution of the second invariant of stress and stress deviation were revealed. The results show that the composite particle system is prone to form long cracks. The force chain under the hob cutter is asymmetrically distributed, and the force chain transmission is generated inside the particle system. With the increase of depth, the average stress F in the monodisperse particle system conforms to the polynomial distribution, and the average stress F in the composite particle system increases first and then decreases with the increase of penetration depth. The clustering coefficient and the shortest path of the force-chain network of the composite particle system are sensitive to the penetration process. At the same distance and depth, the J2max of the hard layer particle system is significantly larger than that of the composite particle system.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related morbidity and mortality globally. Despite the remarkable improvements in comprehensive HCC treatment, the underlying mechanistic details of HCC remain elusive. We screened HCC patients for differentially expressed genes (DEGs) using the Gene Expression Omnibus (GSE113850) and The Cancer Genome Atlas (TCGA) datasets. LINC01554 expression in 40 paired samples was determined by quantitative reverse transcription polymerase chain reaction (RT-qPCR), and its clinical significance was assessed. LINC01554 was found to have a gain-of-function role in HCC in vitro. Additionally, the bioinformatics analysis of the genes co-expressed with LINC01554 was performed using the Co-LncRNA website, and potential molecular mechanisms were investigated using the Gene Ontology and Kyoto Encyclopaedia of Genes and Genomes resources and validated by in vitro experiments. A total of 229 DEGs were identified from the GSE113850 dataset. Among the identified DEGs, three long non-coding RNAs (lncRNAs) (DIO3OS, LINC01554, and LINC01093) with |logFC| ≥2 and P<0.05 were screened. A total of 148 lncRNAs with |logFC| ≥1 and P<0.05 were identified from TCGA dataset. Low LINC01554 expression levels were significantly correlated with overall survival, pathological stage, hepatitis B infection, tumour size, portal vein tumour thrombus, and TNM stage. Using gain-of-function assays, we further showed that LINC01554 inhibited the proliferation, migration, and invasion of the HCCLM9 and SK-Hep1 cells and promoted G0/G1 arrest, but it did not significantly affect apoptosis. Western blotting revealed that LINC01554 overexpression resulted in increased ZO-1 and E-cadherin expression levels, but decreased N-cadherin and vimentin expression levels. Moreover, LINC01554 overexpression inhibited Akt, p-Akt, β-catenin, and p-Gsk3β expression. Our results showed that LINC01554 repressed HCC cell invasiveness and epithelial-to-mesenchymal transition partly by inhibiting Wnt and PI3K-Akt signalling in vitro. Taken together, our findings provide new insights into the molecular mechanisms underlying HCC tumourigenesis and implicate LINC01554 as a potential target for HCC therapy.

Hepatic ischemia–reperfusion (IR) injury is a clinical issue that can result in poor outcome and lacks effective therapies at present. Mild hypothermia (32–35°C) is a physiotherapy that has been reported to significantly alleviate IR injury, while its protective effects are attributed to multiple mechanisms, one of which may be the regulation of fatty acid β-oxidation (FAO). The aim of the present study was to investigate the role and underlying mechanisms of FAO in the protective effects of mild hypothermia. We used male mice to establish the experimental models as previously described. In brief, before exposure to in situ ischemia for 1 h and reperfusion for 6 h, mice received pretreatment with mild hypothermia for 2 h and etomoxir (inhibitor of FAO) or leptin (activator of FAO) for 1 h, respectively. Then, tissue and blood samples were collected to evaluate the liver injury, oxidative stress, and changes in hepatic FAO. We found that mild hypothermia significantly reduced the hepatic enzyme levels and the score of hepatic pathological injury, hepatocyte apoptosis, oxidative stress, and mitochondrial injury. In addition, the expression of the rate-limiting enzyme (CPT1a) of hepatic FAO was downregulated almost twofold by IR, while this inhibition could be significantly reversed by mild hypothermia. Experiments with leptin and etomoxir confirmed that activation of FAO could also reduce the hepatic enzyme levels and the score of hepatic pathological injury, hepatocyte apoptosis, oxidative stress, and mitochondrial injury induced by IR, which had the similar effects to mild hypothermia, while inhibition of FAO had negative effects. Furthermore, mild hypothermia and leptin could promote the phosphorylation of JAK2/STAT3 and upregulate the ratio of BCL-2/BAX to suppress hepatocyte apoptosis. Thus, we concluded that FAO played an important role in hepatic IR injury and mild hypothermia attenuated hepatic IR injury mainly via the regulation of JAK2/STAT3-CPT1a-dependent FAO.