NFKBIZ regulates NFκB signaling pathway to mediate tumorigenesis and metastasis of hepatocellular carcinoma by direct interaction with TRIM16.

Hepatocellular carcinoma (HCC) is a malignant tumor with high incidence and mortality rates. NFKBIZ, a member of the nuclear factor kappa B inhibitory family, is closely related to tumor progression. However, the precise role of NFKBIZ in HCC remains unclear. To explore this, we conducted a series of experiments from clinic to cells. Western blot and qPCR revealed a significant downregulation of NFKBIZ in human HCC tissues. Clinical character analysis showed that the patients with lower NFKBIZ expression had poorer prognosis and higher clinical stage. By using CCK-8, wound healing, transwell invasion and migration assay, we discovered that NFKBIZ expression was reversely associated with the proliferation, invasion, and migration ability of HCC cells in vitro. Additionally, the results obtained from xenograft assay and lung metastasis models showed that NFKBIZ overexpression inhibited the growth and metastasis of HCC cells in vivo. Western blot and immunofluorescence assay further revealed that NFKBIZ mediated HCC cell growth and migration by regulating NFκB signaling transduction. Finally, flow cytometry, protein degradation assay and Co-immunoprecipitation indicated that TRIM16 can enhance NFKBIZ ubiquitination by direct interactions at its K48 site, which may thereby alleviate HCC cell apoptosis to induce the insensitivity to sorafenib. In conclusion, our study demonstrated that NFKBIZ regulated HCC tumorigenesis and metastasis by mediating NFκB signal transduction and TRIM16/NFKBIZ/NFκB axis may be the underlying mechanism of sorafenib insensitivity in HCC.

Multiomics analysis investigating the impact of a high-fat diet in female Sprague-Dawley rats: alterations in plasma, intestinal metabolism, and microbial composition.

Introduction: With improvements in living conditions, modern individuals exhibit a pronounced inclination towards a high-fat diet, largely because of its distinctive gustatory appeal. However, the association between high-fat diets and metabolic complications has largely been ignored, and metabolic diseases such as obesity and non-alcoholic fatty liver disease now constitute a major public health concern. Because high-fat diets increase the risk of metabolic diseases, a thorough investigation into the impact of high-fat diets on gut microbiota and metabolism is required. Methods: We utilize 16S rRNA sequencing and untargeted metabolomics analysis to demonstrate that SD rats fed a high-fat diet exhibited marked alterations in gut microbiota and plasma, intestinal metabolism. Results: Changes in gut microbiota included a decreased abundance at phylum level for Verrucomicrobiota, and a decreased abundance at genus level for Akkermansia, Ralstonia, Bacteroides, and Faecalibacterium. Additionally, significant changes were observed in both intestinal and plasma metabolite levels, including an upregulation of bile acid metabolism, an upregulation of glucose-lipid metabolism, and increased levels of metabolites such as norlithocholic acid, cholic acid, D-fructose, D-mannose, fructose lactate, and glycerophosphocholine. We also investigated the correlations between microbial communities and metabolites, revealing a significant negative correlation between Akkermansia bacteria and cholic acid. Discussion: Overall, our findings shed light on the relationship between symbiotic bacteria associated with high-fat diets and metabolic biomarkers, and they provide insights for identifying novel therapeutic approaches to mitigate disease risks associated with a high-fat diet.

Phosphoglycerate mutase 5 exacerbates liver ischemia-reperfusion injury by activating mitochondrial fission.

Although the death of hepatocytes is a crucial trigger of liver ischemia-reperfusion (I/R) injury, the regulation of liver I/R-induced hepatocyte death is still poorly understood. Phosphoglycerate mutase 5 (PGAM5), a mitochondrial Serine/Threonine protein phosphatase, regulates mitochondrial dynamics and is involved in the process of both apoptosis and necrotic. However, it is still unclear what role PGAM5 plays in the death of hepatocytes induced by I/R. Using a PGAM5-silence mice model, we investigated the role of PGAM5 in liver I/R injury and its relevant molecular mechanisms. Our data showed that PGAM5 was highly expressed in mice with liver I/R injury. Silence of PGAM5 could decrease I/R-induced hepatocyte death in mice. In subcellular levels, the silence of PGAM5 could restore mitochondrial membrane potential, increase mitochondrial DNA copy number and transcription levels, inhibit ROS generation, and prevent I/R-induced opening of abnormal mPTP. As for the molecular mechanisms, we indicated that the silence of PGAM5 could inhibit Drp1(S616) phosphorylation, leading to a partial reduction of mitochondrial fission. In addition, Mdivi-1 could inhibit mitochondrial fission, decrease hepatocyte death, and attenuate liver I/R injury in mice. In conclusion, our data reveal the molecular mechanism of PGAM5 in driving hepatocyte death through activating mitochondrial fission in liver I/R injury.

Influence of sex on outcomes of liver transplantation for hepatocellular carcinoma: a multicenter cohort study in China.

OBJECTIVE: Sex-specific differences are observed in various liver diseases, but the influence of sex on the outcomes of hepatocellular carcinoma (HCC) after liver transplantation (LT) remains to be determined. This study is the first Chinese nationwide investigation of the role of sex in post-LT outcomes in patients with HCC. METHODS: Data for recipients with HCC registered in the China Liver Transplant Registry between January 2015 and December 2020 were analyzed. The associations between donor, recipient, or donor-recipient transplant patterns by sex and the post-LT outcomes were studied with propensity score matching (PSM). The survival associated with different sex-based donor-recipient transplant patterns was further studied. RESULTS: Among 3,769 patients enrolled in this study, the 1-, 3-, and 5-year overall survival (OS) rates of patients with HCC after LT were 96.1%, 86.4%, and 78.5%, respectively, in female recipients, and 95.8%, 79.0%, and 70.7%, respectively, in male recipients after PSM (P = 0.009). However, the OS was comparable between recipients with female donors and male donors. Multivariate analysis indicated that male recipient sex was a risk factor for post-LT survival (HR = 1.381, P = 0.046). Among the donor-recipient transplant patterns, the male-male donor-recipient transplant pattern was associated with the poorest post-LT survival (P < 0.05). CONCLUSIONS: Our findings highlighted that the post-LT outcomes of female recipients were significantly superior to those of male recipients, and the male-male donor-recipient transplant pattern was associated with the poorest post-LT survival. Livers from male donors may provide the most benefit to female recipients. Our results indicate that sex should be considered as a critical factor in organ allocation.

Dynamic immune recovery process after liver transplantation revealed by single-cell multi-omics analysis.

Elucidating the temporal process of immune remodeling under immunosuppressive treatment after liver transplantation (LT) is critical for precise clinical management strategies. Here, we performed a single-cell multi-omics analysis of peripheral blood mononuclear cells (PBMCs) collected from LT patients (with and without acute cellular rejection [ACR]) at 13 time points. Validation was performed in two independent cohorts with additional LT patients and healthy controls. Our study revealed a four-phase recovery process after LT and delineated changes in immune cell composition, expression programs, and interactions along this process. The intensity of the immune response differs between the ACR and non-ACR patients. Notably, the newly identified inflamed NK cells, CD14+RNASE2+ monocytes, and FOS-expressing monocytes emerged as predictive indicators of ACR. This study illuminates the longitudinal evolution of the immune cell landscape under tacrolimus-based immunosuppressive treatment during LT recovery, providing a four-phase framework that aids the clinical management of LT patients.

Activation of σ-1 receptor mitigates estrogen withdrawal-induced anxiety/depressive-like behavior in mice via restoration of GABA/glutamate signaling and neuroplasticity in the hippocampus.

Postpartum depression (PPD) is a significant contributor to maternal morbidity and mortality. The Sigma-1 (σ-1) receptor has received increasing attention in recent years because of its ability to link different signaling systems and exert its function in the brain through chaperone actions, especially in neuropsychiatric disorders. YL-0919, a novel σ-1 receptor agonist developed by our institute, has shown antidepressive and anxiolytic effects in a variety of animal models, but effects on PPD have not been revealed. In the present study, excitatory/inhibitory signaling in the hippocampus was reflected by GABA and glutamate and their associated excitatory-inhibitory receptor proteins, the HPA axis hormones in the hippocampus were assessed by ELISA. Finally, immunofluorescence for markers of newborn neuron were undertaken in the dentate gyri, along with dendritic spine staining and dendritic arborization tracing. YL-0919 rapidly improves anxiety and depressive-like behavior in PPD-like mice within one week, along with normalizing the excitation/inhibition signaling as well as the HPA axis activity. YL-0919 rescued the decrease in hippocampal dendritic complexity and spine density induced by estrogen withdrawal. The study results suggest that YL-0919 elicits a therapeutic effect on PPD-like mice; therefore, the σ-1 receptor may be a novel promising target for PPD treatment in the future.

"Access to pharmacy services is difficult in China": a qualitative study from the perspective of transplant recipients to explore their expectations.

PURPOSE: To gain an in-depth and comprehensive understanding of Chinese organ transplant recipients' perceptions, expectations, and suggestions of pharmacy services to hospital pharmacists. METHODS: This qualitative study was conducted in central China, from February to December 2020. Participants were collected with a purposive and snowball sampling method. Focus group discussions were conducted with organ transplant recipients and content analysis was applied to identify themes and subthemes. RESULTS: 21 recipients participated in the qualitative study. Four themes and thirteen subthemes were identified: (1) perceptions of clinical pharmacists and pharmacy services; (2) expectations for pharmacy service content; (3) expectations for pharmacy service form; and (4) difficulties as a special group. CONCLUSION: The pharmacy services provided by Chinese healthcare institutions are inadequate to meet the needs of organ transplant recipients. However, the acceptance and expectation of pharmacy services by transplant recipients are high. Therefore, China should learn from the experience of developed countries and focus on the actual needs of patients to establish a better pharmacy service system for organ transplantation.

The segmentation and intelligent recognition of structural surfaces in borehole images based on the U2-Net network.

Structural planes decrease the strength and stability of rock masses, severely affecting their mechanical properties and deformation and failure characteristics. Therefore, investigation and analysis of structural planes are crucial tasks in mining rock mechanics. The drilling camera obtains image information of deep structural planes of rock masses through high-definition camera methods, providing important data sources for the analysis of deep structural planes of rock masses. This paper addresses the problems of high workload, low efficiency, high subjectivity, and poor accuracy brought about by manual processing based on current borehole image analysis and conducts an intelligent segmentation study of borehole image structural planes based on the U2-Net network. By collecting data from 20 different borehole images in different lithological regions, a dataset consisting of 1,013 borehole images with structural plane type, lithology, and color was established. Data augmentation methods such as image flipping, color jittering, blurring, and mixup were applied to expand the dataset to 12,421 images, meeting the requirements for deep network training data. Based on the PyTorch deep learning framework, the initial U2-Net network weights were set, the learning rate was set to 0.001, the training batch was 4, and the Adam optimizer adaptively adjusted the learning rate during the training process. A dedicated network model for segmenting structural planes was obtained, and the model achieved a maximum F-measure value of 0.749 when the confidence threshold was set to 0.7, with an accuracy rate of up to 0.85 within the range of recall rate greater than 0.5. Overall, the model has high accuracy for segmenting structural planes and very low mean absolute error, indicating good segmentation accuracy and certain generalization of the network. The research method in this paper can serve as a reference for the study of intelligent identification of structural planes in borehole images.

Novel molecular hepatocellular carcinoma subtypes and RiskScore utilizing apoptosis-related genes.

Hepatocellular carcinoma (HCC) is the third leading cause of global cancer-related deaths. Despite immunotherapy offering hope for patients with HCC, only some respond to it. However, it remains unclear how to pre-screen eligible patients. Our study aimed to address this issue. In this study, we identified 13 prognostic genes through univariate Cox regression analysis of 87 apoptosis-related genes. Subsequently, these 13 genes were analyzed using ConsensusClusterPlus, and patients were categorized into three molecular types: C1, C2, and C3. A prognostic model and RiskScore were constructed using Lasso regression analysis of 132 significant genes identified between C1 and C3. We utilized quantitative polymerase chain reaction to confirm the model's transcript level in Huh7 and THLE2 cell lines. Both molecular subtypes and RiskScores effectively predicted patients benefiting from immunotherapy. Cox regression analysis revealed RiskScore as the most significant prognosis factor, suggesting its clinical application potential and providing a foundation for future experimental research.

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Liquid-liquid phase separation (LLPS) is a reversible process, during which biological macromolecules, including proteins and nucleic acids, condense into liquid membraneless organelles under the influence of weak multivalent interactions. Currently, fluorescence recovery after photobleaching is the primary method used to detect the phase separation of biological macromolecules. Recent studies have revealed the link between abnormal LLPS and the pathogenesis and development of various human cancers. Through phase separation or abnormal phase separation, tumor-related biological macromolecules, such as mRNA, long noncoding RNAs (lncRNAs), and tumor-related proteins, can affect transcriptional translation and DNA damage repair, regulate the autophagy and ferroptosis functions of cells, and thus regulate the development of various tumors. In this review, we summarized the latest research findings on the mechanism of LLPS in the pathogenesis and progression of tumors and elaborated on the promotion or inhibition of autophagy, tumor immunity, DNA damage repair, and cell ferroptosis after abnormal phase separation of biomolecules, including mRNA, lncRNA, and proteins, which subsequently affects the pathogenesis and progression of tumors. According to published findings, many biological macromolecules can regulate transcriptional translation, expression, post-transcriptional modification, cell signal transduction, and other biological processes through phase separation. Therefore, further expansion of the research field of phase separation and in-depth investigation of its molecular mechanisms and regulatory processes hold extensive research potential.

Arachidonic acid metabolism CYP450 pathway is deregulated in hepatocellular carcinoma and associated with microvascular invasion.

Arachidonic acid metabolism plays a crucial role in the development and progression of inflammatory and metabolic liver diseases. However, its role in hepatocellular carcinoma (HCC) remains unclear. In this study, we investigated the expression of key genes involved in the arachidonic acid metabolism pathway in HCC using a combination of bioinformatics, proteomics and immunohistochemistry analyses. Through a comprehensive analysis of publicly available datasets, clinical HCC tissues, and tissue microarrays, we compared the expression of hepatic arachidonic acid metabolic genes. We observed significant downregulation of cytochrome P450 (CYP450) pathway genes at both the messenger RNA and protein levels in HCC tissues compared to normal liver tissues. Furthermore, we observed a strong correlation between the deregulation of the arachidonic acid metabolism CYP450 pathway and the pathological features and prognosis of HCC. Specifically, the expression of CYP2C8/9/18/19 was significantly correlated with pathological grade (r = -.484, p < .0001), vascular invasion (r = -.402, p < .0001), aspartate transaminase (r = -.246, p = .025), gamma-glutamyl transpeptidase (r = -.252, p = .022), alkaline phosphatase (r = -.342, p = .002), alpha-fetoprotein (r = -.311, p = .004) and carbohydrate antigen 19-9 (r = -.227, p = .047). Moreover, we discovered a significant association between CYP450 pathway activity and vascular invasion in HCC. Collectively, these data indicate that arachidonic acid CYP450 metabolic pathway deregulation is implicated in HCC progression and may be a potential predictive factor for early recurrence in patients with HCC.

Adelmidrol ameliorates liver ischemia-reperfusion injury through activating Nrf2 signaling pathway.

Liver ischemia/reperfusion (I/R) injury commonly occurs after various liver surgeries. Adelmidrol, an N- palmitoylethanolamide analog, has anti-inflammatory, anti-oxidant, and anti-injury properties. To investigate whether adelmidrol could reduce liver I/R injury, we established a mouse of liver I/R injury and an AML12 cell hypoxia-reoxygenation model to perform experiments using multiple indicators. Serum ALT and AST levels, and H&E staining were used to measure liver damage; MDA content, superoxide dismutase and glutathione activities, and dihydroethidium staining were used to measure oxidative stress; mRNA expression levels of tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, MCP-1, and Ly6G staining were used to measure inflammatory response; and protein expression of Bax, Bcl-2, C-caspase3, and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling staining were used to measure apoptosis. The experimental results showed that adelmidrol reduced liver I/R injury. In addition, adelmidrol pretreatment elevated AML12 cell activity and reduced I/R-and H/R-induced apoptosis, inflammatory injury, and oxidative stress. ML385, an inhibitor of nuclear factor erythroid2-related factor 2 (Nrf2), reverses liver I/R injury attenuated by adelmidrol. These results suggest that adelmidrol ameliorates liver I/R injury by activating the Nrf2 signaling pathway.

Organ donation decision-making in ICU patients: from the perspectives of organ coordinators and physicians in China - a qualitative study.

OBJECTIVES: Intensive care unit (ICU) dying patients are the most important source of organ donation. This study explores the reasons affecting organ donation in the Chinese sociocultural context from the perspectives of coordinators and physicians, and further seeks countermeasures to alleviate the shortage of organs. DESIGN AND SETTING: Semistructured interviews conducted in a large tertiary hospital in China. PARTICIPANTS AND METHOD: 15 respondents (including 8 organ coordinators and 7 ICU physicians) were interviewed. Participants were invited to describe the factors that influence organ donation and the underlying reasons behind it. Bronfenbrenner's socioecological system model was used as theoretical support to construct a theoretical model of the factors influencing organ donation. Respondents participated in semistructured qualitative interviews that were audio-recorded and transcribed. The relevant data were analysed using thematic analysis. RESULTS: Four themes that influenced organ donation were identified including the influence of the deceased person's attributes, immediate family members, surrounding people and the environment, and the social-level factors. In addition, we obtained four strategies from the interviews to improve the organ shortage to ameliorate the current supply-demand imbalance in organ donation. These include multilevel publicity, relevant policy support, increasing other forms of supply and reducing organ demand. CONCLUSIONS: Factors affecting organ donation after the death of a Chinese citizen include the personal characteristics of the donor, the decisions of family members such as immediate family members and the indirect influence of surrounding people such as collateral family members, in addition to factors related to the humanistic environment, religious beliefs and social opinion.

Intestinal microbiota dysbiosis and liver metabolomic changes during brain death.

Background: Whether a causative link exists between brain death (BD) and intestinal microbiota dysbiosis is unclear, and the distortion in liver metabolism associated with BD requires further exploration. Methods: A rat model of BD was constructed and sustained for 9 h (BD group, n=6). The sham group (n=6) underwent the same procedures, but the catheter was inserted into the epidural space without ballooning. Intestinal contents and portal vein plasma were collected for microbiota sequencing and microbial metabolite detection. Liver tissue was resected to investigate metabolic alterations, and the results were compared with those of a sham group. Results: α-diversity indexes showed that BD did not alter bacterial diversity. Microbiota dysbiosis occurred after 9 h of BD. At the family level, Peptostreptococcaceae and Bacteroidaceae were both decreased in the BD group. At the genus level, Romboutsia, Bacteroides, Erysipelotrichaceae_UCG_004, Faecalibacterium, and Barnesiella were enriched in the sham group, whereas Ruminococcaceae_UCG_007, Lachnospiraceae_ND3007_group, and Papillibacter were enriched in the BD group. Short-chain fatty acids, bile acids, and 132 other microbial metabolites remained unchanged in both the intestinal contents and portal vein plasma of the BD group. BD caused alterations in 65 metabolites in the liver, of which, carbohydrates, amino acids, and organic acids accounted for 64.6%. Additionally, 80.0% of the differential metabolites were decreased in the BD group livers. Galactose metabolism was the most significant metabolic pathway in the BD group. Conclusions: BD resulted in microbiota dysbiosis in rats; however, this dysbiosis did not alter microbial metabolites. Deterioration in liver metabolic function during extended periods of BD may reflect a continuous worsening in energy deficiency.

Novel roles of PIWI proteins and PIWI-interacting RNAs in human health and diseases.

Non-coding RNA has aroused great research interest recently, they play a wide range of biological functions, such as regulating cell cycle, cell proliferation, and intracellular substance metabolism. Piwi-interacting RNAs (piRNAs) are emerging small non-coding RNAs that are 24-31 nucleotides in length. Previous studies on piRNAs were mainly limited to evaluating the binding to the PIWI protein family to play the biological role. However, recent studies have shed more lights on piRNA functions; aberrant piRNAs play unique roles in many human diseases, including diverse lethal cancers. Therefore, understanding the mechanism of piRNAs expression and the specific functional roles of piRNAs in human diseases is crucial for developing its clinical applications. Presently, research on piRNAs mainly focuses on their cancer-specific functions but lacks investigation of their expressions and epigenetic modifications. This review discusses piRNA's biogenesis and functional roles and the recent progress of functions of piRNA/PIWI protein complexes in human diseases. Video Abstract.

[Ultrasound-guided continuous fascia iliaca compartment block for perioperative pain management in elderly patients undergoing hip fracture surgery].

OBJECTIVE: To study the effect of ultrasound-guided fascia iliaca compartment block on perioperative analgesia and postoperative complications in geriatric patients with hip fractures. METHODS: A total of 127 elderly patients undergoing hip fracture surgery from January 2021 to September 2021 were randomized to receive ultrasound-guided continuous fascia iliaca compartment block(group F) either intravenous analgesia control group(group C). There were 62 cases in group F, including 19 males and 43 females with an average age of (82.4±7.2) years old ranging from 66 to 95 years old, involving 25 femoral neck fractures and 37 femoral intertrochanteric fractures. There were 65 cases in control group, including 18 males and 47 females, with an average age of (81.4±8.7) years old ranging from 65 to 94 years old, involving 29 femoral neck fractures and 36 femoral intertrochanteric fractures. The visual analogue scale(VAS), minimental state examination (MMSE), observer's assessment of alertness/sedation(OAA/S) scale, modified Bromage score, postoperative complications and general conditions during hospitalization in two groups were observed. RESULTS: The resting and exercise VAS at 30 min after block, anesthesia placement and 6, 24 and 48 h after surgery were lower than those in group C(P<0.05). In group F, MMSE scores at 12 h before surgery, and 1, 3 d after surgery and OAA/S scores at 3 d after surgery were higher than those in group C(P<0.05). The incidence of adverse effects and the number requiring additional analgesia were lower than those in group C(P<0.05). Group F had better perioperative analgesia satisfaction and hospital stay than group C(P<0.05). But there was no significant difference regarding Bromage score and 30-day mortality between two group(P>0.05). CONCLUSION: Ultrasound-guided continuous fascia iliacus space block was safe and effective for elderly patients with hip fracture, and could significantly reduce perioperative pain, improve postoperative cognitive function, and reduce postoperative complications, thereby shortening hospital stay and improving the quality of life during hospitalization.

Effect of Ursodeoxycholic Acid on Preventing SARS-CoV-2 Infection in Patients With Liver Transplantation: a multicenter retrospective cohort study.

BACKGROUND: Immunosuppressed recipients of liver transplantation (LT) are more likely to develop coronavirus disease 2019 (COVID-19) and may have an increased risk of developing worse outcomes. AIM: To assess the effect of ursodeoxycholic acid (UDCA) on preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in LT recipients. DESIGN: Adult patients (aged ≥ 18 years) who underwent LT between January 1st, 2015, and December 31st, 2022, were included and categorized into two groups according to their use of UDCA. METHODS: The prevalence and severity of COVID-19 among transplantation patients between the UDCA and non-UDCA groups were estimated and compared. RESULTS: Among the 897 LT patients who met the inclusion criteria, infection rate of SARS-CoV-2 was 78.4%, and the rate of severe illness was 5.1% from January 2022 to January 2023 in China. In the multivariate analysis, only UDCA treatment (P = 0.006) was found to be a protective factor against SARS-CoV-2 infection. After propensity score matching, the SARS-CoV-2 infection rate in the UDCA group was lower than that in the non-UDCA group (74.1% vs. 84.6%, P = 0.002). This rate was further reduced to 62.1% (P = 0.002) when the oral administration dose was greater than 15 mg/kg/d. There was no difference in the rates of severe COVID-19 illness, ICU admission, or ventilation rate or length of hospital stay with or without UDCA treatment (all P > 0.05). CONCLUSIONS: The use of UDCA in LT patients significantly reduced the SARS-CoV-2 infection rate and showed a dose-dependent protective effect.

The bidirectional interplay between ncRNAs and methylation modifications in gastrointestinal tumors.

The aberrant expression of methylation and ncRNAs, two crucial regulators of epigenetic modifications, has been widely demonstrated in cancer. The complex interplay between them is essential in promoting malignant phenotype, poor prognosis, and drug resistance in GI tumors (including esophageal, gastric, colorectal, liver, and pancreatic cancers). Therefore, we summarize the interrelation process between ncRNAs and methylation modifications in GI tumors, including the detailed mechanism of methylation enzyme regulation of ncRNAs, the molecular mechanism of ncRNAs regulation of methylation modifications, and the correlation between the interactions between ncRNAs and methylation modifications and clinical features of tumors. Finally, we discuss the potential value of ncRNAs and methylation modifications in clinical diagnosis and therapy.

Pectolinarigenin attenuates hepatic ischemia/reperfusion injury via activation of the PI3K/AKT/Nrf2 signaling pathway.

Hepatic ischemia/reperfusion (I/R) injury is an unavoidable complication of liver hepatectomy, transplantation, and systemic shock. Pectolinarigenin (Pec) is a flavonoid with many biological activities, which include anti-inflammatory, anti-apoptotic, and antioxidant stress. This study explored whether Pec pretreatment could reduce hepatic I/R injury and the potential mechanisms at play. After pretreatment of mice and AML12 cells with Pec, I/R and hypoxia/reoxygenation (H/R) models were established. By examining markers related to liver injury, cell viability, oxidative stress, inflammatory response, and apoptosis, the effect of Pec on important processes involved in hepatic I/R injury was assessed. Protein levels associated with the PI3K/AKT/Nrf2 pathway were analyzed by relative quantification to investigate possible pathways through which Pec plays a role in the I/R process. Pec treatment corrected abnormal transaminase levels resulting from I/R injury, improved liver injury, and increased AML12 cell viability. Moreover, Pec treatment inhibited oxidative stress, inflammation and apoptosis and could activate the PI3K/AKT/Nrf2 pathway during I/R and H/R. Further studies found that LY294002 (PI3K inhibitor) suppressed the protective effect of Pec on hepatic I/R injury. In summary, our results show that Pec inhibits oxidative stress, inflammatory responses, and apoptosis, thereby attenuating I/R-induced liver injury and H/R-induced cell damage via activation of the PI3K/AKT/Nrf2 pathway.

Air-ventilated normothermic machine perfusion alleviates hepatic injury from DCD rat through CYP1A2.

BACKGROUND: Normothermic machine perfusion (NMP) could provide protection to organs from donation after circulatory death (DCD) before transplantation, and its molecular mechanism remains unclear. Our previous study discovered that the air-ventilated NMP confers a better DCD liver recovery than oxygen-ventilated NMP. The purpose in the current study was to investigate the protective mechanism of air-ventilated NMP in a rat model of DCD liver by metabolomics, and to select biomarker to predict liver function recovery. MATERIALS AND METHODS: Peroxisome proliferator activator receptor-α (PPARα) agonist or antagonist was administered via the perfusion circuit in the air-ventilated NMP. Perfusate samples were taken for measurements of aminotransferases using standard biochemical methods, tumor necrosis factor-alpha and interleukin-6. Liver biopsies were allocated for detection of metabolomics, PPARα and cytochrome P450 1A2 (CYP1A2). RESULTS: Metabolomics analysis revealed the significant increased γ-linolenic acid and decreased adrenic acid during the air-ventilated NMP, indicating linoleic acid metabolism pathway was associated with a better DCD liver recovery; as a major enzyme involved in linolenic acid metabolism, CYP1A2 was found correlated with a less inflammation and better liver function with the air-ventilated NMP; PPARα agonist could increase CYP1A2 expression and activity, decrease inflammation response, and improve liver function with the air-ventilated NMP, while PPARα antagonist played the opposite. CONCLUSION: Air-ventilated NMP confers a better liver recovery from DCD rats through the activated linoleic acid metabolism and CYP1A2 upregulation; CYP1A2 expression and activity might function as biomarker to predict DCD liver function recovery with NMP.