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Abstract Innate immune activation is critical for initiating hepatic inflammation during nonalcoholic steatohepatitis (NASH) progression. However, the mechanisms by which immunoregulatory molecules recognize lipogenic, fibrotic, and inflammatory signals remain unclear. Here, we show that high-fat diet (HFD)-induced oxidative stress activates Foxo1, YAP, and Notch1 signaling in hepatic macrophages. Macrophage Foxo1 deficiency (Foxo1M-KO) ameliorated hepatic inflammation, steatosis, and fibrosis, with reduced STING, TBK1, and NF-κB activation in HFD-challenged livers. However, Foxo1 and YAP double knockout (Foxo1/YAPM-DKO) or Foxo1 and Notch1 double knockout (Foxo1/Notch1M-DKO) promoted STING function and exacerbated HFD-induced liver injury. Interestingly, Foxo1M-KO strongly reduced TGF-β1 release from palmitic acid (PA)- and oleic acid (OA)-stimulated Kupffer cells and decreased Col1α1, CCL2, and Timp1 expression but increased MMP1 expression in primary hepatic stellate cells (HSCs) after coculture with Kupffer cells. Notably, PA and OA challenge in Kupffer cells augmented LIMD1 and LATS1 colocalization and interaction, which induced YAP nuclear translocation. Foxo1M-KO activated PGC-1α and increased nuclear YAP activity, modulating mitochondrial biogenesis. Using chromatin immunoprecipitation (ChIP) coupled with massively parallel sequencing (ChIP-Seq) and in situ RNA hybridization, we found that NICD colocalizes with YAP and targets Mb21d1 (cGAS), while YAP functions as a novel coactivator of the NICD, which is crucial for reprogramming STING function in NASH progression. These findings highlight the importance of the macrophage Foxo1–YAP–Notch1 axis as a key molecular regulator that controls lipid metabolism, inflammation, and innate immunity in NASH.

Objective Knowledge, attitude and practice (KAP) models are essential tools for assessing healthcare professionals’ understanding, beliefs and behaviours towards specific health issues. This study aimed to explore the KAP of Chinese doctors in diagnosing and treating spinal vascular malformations (SVM).Design A web-based cross-sectional survey.Setting This study was conducted between October and December 2022 through a self-administered questionnaire.Participants Participants include full-time doctors who voluntarily participate. Doctors in advanced training, regular training or internships were excluded.Primary and secondary outcome measures The KAP scores of Chinese doctors in diagnosing and treating SVM measured by the questionnaire.Results A total of 517 doctors participated in the study, mostly in Shaanxi, China, working in SVM-relevant departments (n=396) or other departments (n=121). The doctors achieved an average knowledge score of 9.66±1.95 (range: 0–12), attitude score of 22.16±1.71 (range: 6–30) and practice scores of 46.13±5.35 for those in SVM-relevant departments (neurosurgery, orthopaedics and neurology) and 8.50±1.25 for those in other departments, respectively, revealing doctors have adequate knowledge, positive attitude and good practice, and those in SVM-relevant departments showing more adeptness compared with those in other departments. Moreover, multivariate logistic regression analysis showed that knowledge about SVM (OR=1.72, 95% CI 1.11 to 2.65, p=0.015), holding a master’s degree (OR=1.85, 95% CI 1.14 to 3.00, p=0.013) and working in orthopaedics (OR=0.34, 95% CI 0.13 to 0.88, p=0.026) were independently associated with good attitude.Conclusion Chinese doctors showed adequate knowledge, moderate attitudes and good practice regarding SVM. A continuing education programme may improve clinical practitioners’ ability to manage SVM.

Background & Aims: Receptor-interacting serine/threonine-protein kinase 3 (RIPK3) is a central player in triggering necroptotic cell death. However, whether macrophage RIPK3 may regulate NOD1-dependent inflammation and calcineurin/transient receptor potential cation channel subfamily M member 7 (TRPM7)-induced hepatocyte death in oxidative stress-induced liver inflammatory injury remains elusive. Methods: A mouse model of hepatic ischaemia–reperfusion (IR) injury, the primary hepatocytes, and bone marrow-derived macrophages were used in the myeloid-specific RIPK3 knockout (RIPK3M-KO) and RIPK3-proficient (RIPK3FL/FL) mice. Results: RIPK3M-KO diminished IR stress-induced liver damage with reduced serum alanine aminotransferase/aspartate aminotransferase levels, macrophage/neutrophil infiltration, and pro-inflammatory mediators compared with the RIPK3FL/FL controls. IR stress activated RIPK3, inositol-requiring transmembrane kinase/endoribonuclease 1α (IRE1α), x-box binding protein 1 (XBP1), nucleotide-binding oligomerisation domain-containing protein 1 (NOD1), NF-κB, forkhead box O1 (Foxo1), calcineurin A, and TRPM7 in ischaemic livers. Conversely, RIPK3M-KO depressed IRE1α, XBP1, NOD1, calcineurin A, and TRPM7 activation with reduced serum tumour necrosis factor α (TNF-α) levels. Moreover, Foxo1M-KO alleviated IR-induced liver injury with reduced NOD1 and TRPM7 expression. Interestingly, chromatin immunoprecipitation coupled with massively parallel sequencing revealed that macrophage Foxo1 colocalised with XBP1 and activated its target gene Zc3h15 (zinc finger CCCH domain-containing protein 15). Activating macrophage XBP1 enhanced Zc3h15, NOD1, and NF-κB activity. However, disruption of macrophage Zc3h15 inhibited NOD1 and hepatocyte calcineurin/TRPM7 activation, with reduced reactive oxygen species production and lactate dehydrogenase release after macrophage/hepatocyte coculture. Furthermore, adoptive transfer of Zc3h15-expressing macrophages in RIPK3M-KO mice augmented IR-triggered liver inflammation and cell death. Conclusions: Macrophage RIPK3 activates the IRE1α–XBP1 pathway and Foxo1 signalling in IR-stress livers. The XBP1–Foxo1 interaction is essential for modulating target gene Zc3h15 function, which is crucial for the control of NOD1 and calcineurin-mediated TRPM7 activation. XBP1 functions as a transcriptional coactivator of Foxo1 in regulating NOD1-driven liver inflammation and calcineurin/TRPM7-induced cell death. Our findings underscore a novel role of macrophage RIPK3 in stress-induced liver inflammation and cell death, implying the potential therapeutic targets in liver inflammatory diseases. Impact and implications: Macrophage RIPK3 promotes NOD1-dependent inflammation and calcineurin/TRPM7-induced cell death cascade by triggering the XBP1–Foxo1 axis and its target gene Zc3h15, which is crucial for activating NOD1 and calcineurin/TRPM7 function, implying the potential therapeutic targets in stress-induced liver inflammatory injury.

Brains are highly metabolically active organs, consuming 20% of a person's energy at resting state. A decline in glucose metabolism is a common feature across a number of neurodegenerative diseases. Another common feature is the progressive accumulation of insoluble protein deposits, it's unclear if the two are linked. Glucose metabolism in the brain is highly coupled between neurons and glia, with glucose taken up by glia and metabolised to lactate, which is then shuttled via transporters to neurons, where it is converted back to pyruvate and fed into the TCA cycle for ATP production. Monocarboxylates are also involved in signalling, and play broad ranging roles in brain homeostasis and metabolic reprogramming. However, the role of monocarboxylates in dementia has not been tested. Here, we find that increasing pyruvate import in Drosophila neurons by over-expression of the transporter bumpel, leads to a rescue of lifespan and behavioural phenotypes in fly models of both frontotemporal dementia and Alzheimer's disease. The rescue is linked to a clearance of late stage autolysosomes, leading to degradation of toxic peptides associated with disease. We propose upregulation of pyruvate import into neurons as potentially a broad-scope therapeutic approach to increase neuronal autophagy, which could be beneficial for multiple dementias.

Abstract Background This study aimed to develop a radiogenomic prognostic prediction model for colorectal cancer (CRC) by investigating the biological and clinical relevance of intratumoural heterogeneity. Methods This retrospective multi-cohort study was conducted in three steps. First, we identified genomic subclones using unsupervised deconvolution analysis. Second, we established radiogenomic signatures to link radiomic features with prognostic subclone compositions in an independent radiogenomic dataset containing matched imaging and gene expression data. Finally, the prognostic value of the identified radiogenomic signatures was validated using two testing datasets containing imaging and survival information collected from separate medical centres. Results This multi-institutional retrospective study included 1601 patients (714 females and 887 males; mean age, 65 years ± 14 [standard deviation]) with CRC from 5 datasets. Molecular heterogeneity was identified using unsupervised deconvolution analysis of gene expression data. The relative prevalence of the two subclones associated with cell cycle and extracellular matrix pathways identified patients with significantly different survival outcomes. A radiogenomic signature-based predictive model significantly stratified patients into high- and low-risk groups with disparate disease-free survival (HR = 1.74, P = 0.003). Radiogenomic signatures were revealed as an independent predictive factor for CRC by multivariable analysis (HR = 1.59, 95% CI:1.03–2.45, P = 0.034). Functional analysis demonstrated that the 11 radiogenomic signatures were predominantly associated with extracellular matrix and immune-related pathways. Conclusions The identified radiogenomic signatures might be a surrogate for genomic signatures and could complement the current prognostic strategies.

Abstract Background Notch signaling is highly conserved and critically involved in cell differentiation, immunity, and survival. Activation of the Notch pathway modulates immune cell functions during the inflammatory response. However, it remains unknown whether and how the macrophage Notch1 may control the innate immune signaling TAK1, and RIPK3-mediated hepatocyte necroptosis in liver ischemia and reperfusion injury (IRI). This study investigated the molecular mechanisms of macrophage Notch1 in modulating TAK1-mediated innate immune responses and RIPK3 functions in liver IRI. Methods Myeloid-specific Notch1 knockout (Notch1M−KO) and floxed Notch1 (Notch1FL/FL) mice (n = 6/group) were subjected to 90 min partial liver warm ischemia followed by 6 h of reperfusion. In a parallel in vitro study, bone marrow-derived macrophages (BMMs) were isolated from these conditional knockout mice and transfected with CRISPR/Cas9-mediated β-catenin knockout (KO) vector followed by LPS (100 ng/ml) stimulation. Results IR stress-induced Notch1 activation evidenced by increased nuclear Notch intracellular domain (NICD) expression in liver macrophages. Myeloid Notch1 deficiency exacerbated IR-induced liver damage, with increased serum ALT levels, macrophage/neutrophil accumulation, and proinflammatory cytokines/chemokines production compared to the Notch1FL/FL controls. Unlike in the Notch1FL/FL controls, Notch1M−KO enhanced TRAF6, TAK1, NF-κB, RIPK3, and MLKL but reduced β-catenin activation in ischemic livers. However, adoptive transfer of lentivirus β-catenin-modified macrophages markedly improved liver function with reduced TRAF6, p-TAK1, RIPK3 and p-MLKL in IR-challenged livers. Moreover, disruption of RIPK3 in Notch1M−KO mice with an in vivo mannose-mediated RIPK3 siRNA delivery system diminished IR-triggered hepatocyte death. In vitro studies showed that macrophage NICD and β-catenin co-localized in the nucleus, whereby β-catenin interacted with NICD in response to LPS stimulation. Disruption of β-catenin with a CRISPR/Cas9-mediated β-catenin KO in Notch1FL/FL macrophage augmented TRAF6 activation leading to enhanced TAK1 function. While CRISPR/Cas9-mediated TRAF6 KO in Notch1M−KO macrophage inhibited RIPK3-mediated hepatocyte necroptosis after co-culture with primary hepatocytes. Conclusions Macrophage Notch1 controls TAK1-mediated innate immune responses and RIPK3-mediated hepatocyte necroptosis through activation of β-catenin. β-catenin is required for the macrophage Notch1-mediated immune regulation in liver IRI. Our findings demonstrate that the macrophage Notch1-β-catenin axis is a crucial regulatory mechanism in IR-triggered liver inflammation and provide novel therapeutic potential in organ IRI and transplant recipients. Video abstract

Traffic state data are key to the proper operation of intelligent transportation systems (ITS). However, traffic detectors often receive environmental factors that cause missing values in the collected traffic state data. Therefore, aiming at the above problem, a method for imputing missing traffic state data based on a Diffusion Convolutional Neural Network–Generative Adversarial Network (DCNN-GAN) is proposed in this paper. The proposed method uses a graph embedding algorithm to construct a road network structure based on spatial correlation instead of the original road network structure; through the use of a GAN for confrontation training, it is possible to generate missing traffic state data based on the known data of the road network. In the generator, the spatiotemporal features of the reconstructed road network are extracted by the DCNN to realize the imputation. Two real traffic datasets were used to verify the effectiveness of this method, with the results of the proposed model proving better than those of the other models used for comparison.

Abstract Background Improved understanding of the stemness regulation mechanism in intrahepatic cholangiocarcinoma (ICC) could identify targets and guidance for adjuvant transarterial chemoembolization (TACE). Methods TCGA database was excavated to identify the ICC stemness-associated genes. The pro-stemness effect of target genes was further analyzed by sphere formation assay, qRT-PCR, western blot, flow cytometric analysis, IHC, CCK8 assay and metabolomic analysis. Based on multivariate analysis, a nomogram for ICC patients with adjuvant TACE was established and our result was further confirmed by a validation cohort. Finally, the effect of dietary methionine intervention on chemotherapy was estimated by in vivo experiment and clinical data. Results In this study, we identified four ICC stemness-associated genes (SDHAF2, MRPS34, MRPL11, and COX8A) that are significantly upregulated in ICC tissues and negatively associated with clinical outcome. Functional studies indicated that these 4-key-genes are associated with self-renewal ability of ICC and transgenic expression of these 4-key-genes could enhance chemoresistance of cholangiocarcinoma cells. Mechanistically, the 4-key-genes-mediated pro-stemness requires the activation of methionine cycle, and their promotion on ICC stemness characteristic is dependent on MAT2A. Importantly, we established a novel nomogram to evaluate the effectiveness of TACE for ICC patients. Further dietary methionine intervene studies indicated that patients with adjuvant TACE might benefit from dietary methionine restriction if they have a relatively high nomogram score (≥ 135). Conclusions Our results show that four ICC stemness-associated genes could serve as novel biomarkers in predicting ICC patient’s response to adjuvant TACE and their pro-stemness ability may be attributed to the activation of the methionine cycle.

Voice print recognition is one of the most mature biometric authentication technologies, and the application of deep neural networks (DNNs) has led to a significant improvement in the accuracy of voice print recognition. However, DNN models can be attacked by backdoor attackers, which poses a serious threat to the security of model for voice print recognition. In this paper, a method is proposed for backdoor defence of voice print recognition model based on speech enhancement and weight pruning. Firstly, input samples are perturbed by superimposing various speech patterns, and the backdoor samples are determined based on the randomness (entropy value) of the prediction classes with perturbed inputs from a given deployment model (malicious or benign). Secondly, the backdoor samples are fed into a network (Deep Complex Convolution Recurrent Network) dedicated for speech enhancement, with which the backdoor samples can be denoised by removing the backdoor noise. Finally, the model is pruned using an automatic progressive weight pruning algorithm, which can avoid the accuracy degradation caused by neurons pruning. Experimental results on the AISHELL speech dataset show that the method not only reduces the success rate of backdoor attacks, but also greatly realizes the purification of the backdoor samples.

Background & Aims: The stimulator of interferon genes (STING)/TANK-binding kinase 1 (TBK1) pathway is vital in mediating innate immune and inflammatory responses during oxidative/endoplasmic reticulum (ER) stress. However, it remains unknown whether macrophage thioredoxin-interacting protein (TXNIP) may regulate TBK1 function and cell death pathways during oxidative/ER stress. Methods: A mouse model of hepatic ischaemia/reperfusion injury (IRI), the primary hepatocytes, and bone marrow-derived macrophages were used in the myeloid-specific TXNIP knockout (TXNIPM-KO) and TXNIP-proficient (TXNIPFL/FL) mice. Results: The TXNIPM-KO mice were resistant to ischaemia/reperfusion (IR) stress-induced liver damage with reduced serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels, macrophage/neutrophil infiltration, and pro-inflammatory mediators compared with the TXNIPFL/FL controls. IR stress increased TXNIP, p-STING, and p-TBK1 expression in ischaemic livers. However, TXNIPM-KO inhibited STING, TBK1, interferon regulatory factor 3 (IRF3), and NF-κB activation with interferon-β (IFN-β) expression. Interestingly, TXNIPM-KO augmented nuclear factor (erythroid-derived 2)-like 2 (NRF2) activity, increased antioxidant gene expression, and reduced macrophage reactive oxygen species (ROS) production and hepatic apoptosis/necroptosis in IR-stressed livers. Mechanistically, macrophage TXNIP deficiency promoted cylindromatosis (CYLD), which colocalised and interacted with NADPH oxidase 4 (NOX4) to enhance NRF2 activity by deubiquitinating NOX4. Disruption of macrophage NRF2 or its target gene 2′,5′ oligoadenylate synthetase-like 1 (OASL1) enhanced Ras GTPase-activating protein-binding protein 1 (G3BP1) and TBK1-mediated inflammatory response. Notably, macrophage OASL1 deficiency induced hepatocyte apoptotic peptidase activating factor 1 (APAF1), cytochrome c, and caspase-9 activation, leading to increased caspase-3-initiated apoptosis and receptor-interacting serine/threonine-protein kinase 3 (RIPK3)-mediated necroptosis. Conclusions: Macrophage TXNIP deficiency enhances CYLD activity and activates the NRF2-OASL1 signalling, controlling IR stress-induced liver injury. The target gene OASL1 regulated by NRF2 is crucial for modulating STING-mediated TBK1 activation and Apaf1/cytochrome c/caspase-9-triggered apoptotic/necroptotic cell death pathway. Our findings underscore a novel role of macrophage TXNIP-mediated CYLD–NRF2–OASL1 axis in stress-induced liver inflammation and cell death, implying the potential therapeutic targets in liver inflammatory diseases. Lay summary: Liver inflammation and injury induced by ischaemia and reperfusion (the absence of blood flow to the liver tissue followed by the resupply of blood) is a significant cause of hepatic dysfunction and failure following liver transplantation, resection, and haemorrhagic shock. Herein, we uncover an underlying mechanism that contributes to liver inflammation and cell death in this setting and could be a therapeutic target in stress-induced liver inflammatory injury.

Abstract Background It has been well documented that social isolation stress (SIS) can induce posttraumatic stress disorder (PTSD)‐like behavior in rodents, however, the underlying mechanism is remained misunderstood. In the current study, we aimed to elucidate the role of NO/NMDAR pathway in PTSD‐like behavior through modulating of astrocyte activity and improvement of oxidative stress. Methods Male NMRI mice were used to evaluate the memory function by using Morris water maze (MWM) and fear memory extinction by using freezing response. We used MK‐801 (NMDAR‐antagonist), L‐NNA (NOS‐inhibitor), NMDA (NMDAR‐agonist), and L‐arginine (NO‐agent) to find a proper treatment. Also, immunohistochemistry, RT‐PCR, and oxidative stress assays were used to evaluate the levels of astrocytes and oxidative stress. We used five mice in each experimental task. Results Our results revealed that SIS could induce learning and memory dysfunction as well as impairment of fear memory extinction in MWM and freezing response tests, respectively. Also, we observed that combined treatment including blockage of NOS (by L‐NNA, 0.5 mg/kg) and NMDAR (by MK‐801, 0.001 mg/kg) at subeffective doses could result in improvement of both memory and fear memory. In addition, we observed that SIS significantly increases the GFAP expression and astrocyte activity, which results in significant imbalance in oxidative stress. Coadministration of MK‐801 and L‐NNA at subeffective doses not only decreases the expression of GFAP, but also regulates the oxidative stress imbalance Conclusion Based on these results, it could be hypothesized that blockage of NO/NMDAR pathway might be a novel treatment for PTSD‐like behavior in animals by inhibiting the astrocyte and regulating oxidative stress level.

The basal-plane surfaces of hexagonal close-packed crystals typically exhibit an alternating sequence of A and B steps with different atomic structures and growth kinetics. Here the authors demonstrate a method to determine whether A or B steps have faster kinetics under specific growth conditions.

Background & Aims: DJ-1 is universally expressed in various tissues and organs and is involved in the physiological processes in various liver diseases. However, the role of DJ-1 in liver ischemia-reperfusion (I/R) injury is largely unknown. Methods: In this study, we first examined the DJ-1 expression changes in the liver tissues of mice and clinical donor after hepatic I/R by both quantitative polymerase chain reaction and Western blotting assays. Then we investigated the role of DJ-1 in I/R injury by using a murine liver I/R model. Results: We demonstrated that DJ-1 down-regulation in both human and mouse liver tissues in response to I/R injury and Dj-1 deficiency in hepatocytes but not in myeloid cells could significantly ameliorate I/R induced liver injury and inflammatory responses. This hepatoprotective effect was dependent on enhanced autophagy in Dj-1 knockout mice, because inhibition of autophagy by 3-methyladenine and chloroquine could reverse the protective effect on hepatic I/R injury in Dj-1 knockout mice. Conclusions: Dj-1 deficiency in hepatocytes significantly enhanced mitochondrial accumulation and protein stability of PARKIN, which in turn promotes the onset of mitophagy resulting in elevated clearance of damaged mitochondria during I/R injury.

Abstract Donor-derived cell-free DNA (dd-cfDNA) has been of major interest recently as a non-invasive marker of graft injury, but has not yet been extensively tested in children. From May to September in 2019, a total of 76 pediatric patients receiving a liver graft were enrolled and there were 27 patients excluded. Ultimately plasma samples and matched liver specimens from 49 patients were successfully collected whenever rejection was suspected clinically. Dd-cfDNA were analyzed and then compared to biopsy. Of these, 11 (22.4%) patients were found to have rejection by biopsy. Dd-cfDNA levels were higher among patients with rejection compared to those with no rejection. In subgroup analysis, dd-cfDNA% among patients with rejection differed from those with EBV/CMV infection and DILI patients. Similarly, observations were available concerning dd-cfDNA (cp/mL). The AUC for dd-cfDNA% and dd-cfDNA (cp/mL) were 0.878, 0.841, respectively, both of which were higher than conventional LFTs. For rejection, dd-cfDNA% ≥ 28.7% yielded a sensitivity of 72.7%, specificity 94.7% and dd-cfDNA (cp/mL) ≥ 2076 cp/mL, yielded a sensitivity of 81.8%, specificity 81.9%. Of note, the dd-cfDNA distribution was significantly different between whole liver and LLS transplantation. In the setting of pediatric LTx, dd-cfDNA appears to be a sensitive biomarker indicating the presence of rejection. International Clinical Trails Registry Platform: ChiCTR1900022406.

Hollow nanoboxes structure have raised great attention as microwave absorption materials on account of their ultralow density and large specific area. By introducing an adjustable interior cavity structure, the dielectric loss and microwave absorption performance were affected by the tunable complex permittivity and impedance matching was improved. In our study, hollow CoS2 nanoboxes with designable interspaces were successfully fabricated based on the surfactant-assisted solution method and followed by an in situ ion-exchange process. The structure, elemental compositions and morphology of the products were characterized by XRD, XPS, EDX, SEM and TEM, respectively. In addition, microwave absorption performance and the intrinsic mechanism are investigated in-depth. The paraffin-based composites with 20 wt.% filling contents exhibited superior microwave absorption capacities in view of both maximum reflection loss value (RLmax, −54.48 dB) and effective absorption bandwidth (EAB, below −10 dB, 6.0 GHz), which can be ascribed to unique hollow structure and good impedance matching. With these considerations in mind, this study provides a reference for the construction of high-performance microwave absorbers with unique hollow structure.

Liver diseases represent a major global health burden accounting for approximately 2 million deaths per year worldwide. The liver functions as a primary immune organ that is largely enriched with various innate immune cells, including macrophages, dendritic cells, neutrophils, NK cells, and NKT cells. Activation of these cells orchestrates the innate immune response and initiates liver inflammation in response to the danger signal from pathogens or injured cells and tissues. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a crucial signaling cascade of the innate immune system activated by cytosol DNA. Recognizing DNA as an immune-stimulatory molecule is an evolutionarily preserved mechanism in initiating rapid innate immune responses against microbial pathogens. The cGAS is a cytosolic DNA sensor eliciting robust immunity via the production of cyclic GMP-AMPs that bind and activate STING. Although the cGAS-STING pathway has been previously considered to have essential roles in innate immunity and host defense, recent advances have extended the role of the cGAS-STING pathway to liver diseases. Emerging evidence indicates that overactivation of cGAS-STING may contribute to the development of liver disorders, implying that the cGAS-STING pathway is a promising therapeutic target. Here, we review and discuss the role of the cGAS-STING DNA-sensing signaling pathway in a variety of liver diseases, including viral hepatitis, nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), primary hepatocellular cancer (HCC), and hepatic ischemia-reperfusion injury (IRI), with highlights on currently available therapeutic options.

Acute lung injury (ALI) is associated with histopathological diffuse alveolar damage. The potential role of mesenchymal stem cells (MSCs) in the treatment of various clinical disorders have been widely documented, such as those for ALI. Recent evidence has demonstrated that exosomes from endothelial progenitor cells can improve outcomes of the lipopolysaccharide (LPS)-induced ALI. However, there has been no research on the potential role of MSC-exosomes in the treatment of sepsis-induced ALI, which is worth further exploration. Thus, the objective of our study was to identify whether the MSC-exosomes could reverse ALI. The ALI model induced by LPS was established in this study. MTT assay was performed to test cell proliferation. Expression of inflammatory factors (TNF-α, IL-6, and IL-10) in the LPS-treated type II alveolar epithelial cells (AECs) (MLE-12) was detected by ELISA. After co-culture of MSC-exosomes with LPS-treated MLE-12 cells, we found that the cell proliferation of MLE-12 cells gradually increased. Furthermore, we selected five of the Nrf-2/ARE- and NF-κB signaling pathway-related genes to explore if MSC-exosomes could reverse LPS-induced ALI through Nrf-2/ARE and NF-κB signaling pathways. QRT-PCR and western blot experiment results showed that the expression of these five genes were significantly regulated after stimulation with high-concentration LPS and exosome intervention. Taken together, these findings highlighted the fact that MSC-exosomes could reverse ALI through the Nrf-2/ARE and NF-κB signaling pathways. The MSC-exosome may be the potential future therapeutic strategy for the treatment of ALI.

Acetaminophen (APAP) overdose is the leading cause of drug-induced liver injury worldwide, and mitochondrial oxidative stress is considered the major event responsible for APAP-associated liver injury (ALI). Despite the identification of N-acetyl cysteine, a reactive oxygen species scavenger that is regarded as an effective clinical treatment, therapeutic effectiveness remains limited due to rapid disease progression and diagnosis at a late phase, which leads to the need to explore various therapeutic approaches. Since the early 1990s, a number of natural products and herbs have been found to have hepatoprotective effects against APAP-induced hepatotoxicity in terms of acute liver failure prevention and therapeutic amelioration of ALI. In this review, we summarize the hepatoprotective effects and mechanisms of medicinal plants, including herbs and fruit extracts, along with future perspectives that may provide guidance to improve the current status of herbal therapy against ALI.

Background/Aims: The role of Rictor in hepatic ischemia/reperfusion (I/R) injury remains unknown. Here, we comprehensively examined the role of Rictor in hepatic I/R injury. Methods: We studied the expression of Rictor during hepatic I/R injury. The regulatory effects of Rictor on inflammatory responses, cytokine and chemokine release, apoptotic and anti-apoptotic responses, and autophagy induction during hepatic I/R injury were identified via the shRNA-mediated knockdown of Rictor. Subsequently, we collected the liver and blood samples of these mice to evaluate liver injury, mRNA and protein levels. Additionally, the signaling pathways induced by Rictor were investigated. Furthermore, the extent of activation of MAPKs in response to Rictor deficiency was investigated in lipopolysaccharide (LPS)-treated RAW264.7 cells. The mRNA expression levels were analyzed by real-time PCR, and the protein expression levels were analyzed using Western blot, immunofluorescence staining and enzyme-linked immunosorbent assay (ELISA). Results: The expression of Rictor was increased during hepatic I/R injury in vivo and hypoxia/reoxygenation (H/R) injury in vitro. Rictor deficiency enhanced the extent of liver injury by increasing macrophage and neutrophil infiltration, promoting cytokine and chemokine release, aggravating hepatocyte apoptosis, suppressing anti-apoptotic responses, and inhibiting autophagy induction during both hepatic I/R and H/R injury. Rictor was associated with the activation of hepatic I/R injury-induced MAPK signaling. In addition, Rictor deficiency affected MAPK activation in LPS-treated RAW264.7 cells. Conclusion: Rictor can substantially ameliorate I/R-induced liver injury. Therefore, our findings strongly suggest a therapeutic value of the Rictor/mTORC2 axis in hepatic I/R injury.

Oxidative stress and inflammation are the most important pathogenic events in the development and progression of liver diseases. Nuclear erythroid 2-related factor 2 (Nrf2) is the master regulator of the cellular protection via induction of anti-inflammatory, antioxidant, and cyto-protective genes expression. Multiple studies have shown that activation or suppression of this transcriptional factor significantly affect progression of liver diseases. Comprehensive understanding the roles of Nrf2 activation/expression and the outcomes of its activators/inhibitors are indispensable for defining the mechanisms and therapeutic strategies against liver diseases. In this current review, we discussed recent advances in the function and principal mechanisms by regulating Nrf2 in liver diseases, including acute liver failure, hepatic ischemia–reperfusion injury (IRI), alcoholic liver disease (ALD), viral hepatitis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma (HCC).

Aldehyde dehydrogenase 2 (ALDH2) is a key enzyme for metabolism of reactive aldehydes, but its role during liver ischemia-reperfusion injury (IRI) remains unclear. In the present study, we investigated the effects of the ALDH2 activator, Alda-1, in liver IRI and elucidated the underlying mechanisms. Mice were pretreated with Alda-1 and subjected to a 90 min hepatic 70% ischemia model, and liver tissues or serum samples were collected at indicated time points after reperfusion. We demonstrated that Alda-1 pretreatment had a hepatoprotective role in liver IRI as evidenced by decreased liver necrotic areas, serum ALT/AST levels, and liver inflammatory responses. Mechanistically, Alda-1 treatment enhanced ALDH2 activity and subsequently reduced the accumulation of reactive aldehydes and toxic protein adducts, which result in decreased hepatocyte apoptosis and mitochondrial dysfunction. We further demonstrated that Alda-1 treatment could activate AMPK and autophagy and that AMPK activation was required for Alda-1-mediated autophagy enhancement. These findings collectively indicate that Alda-1-mediated ALDH2 activation could be a promising strategy to improve liver IRI by clearance of reactive aldehydes and enhancement of autophagy.

The jam flow condition is one of the main traffic states in traffic flow theory and the most difficult state for sectional traffic information acquisition. Since traffic information acquisition is the basis for the application of an intelligent transportation system, research on traffic vehicle counting methods for the jam flow conditions has been worthwhile. A low-cost and energy-efficient type of multi-function wireless traffic magnetic sensor was designed and developed. Several advantages of the traffic magnetic sensor are that it is suitable for large-scale deployment and time-sustainable detection for traffic information acquisition. Based on the traffic magnetic sensor, a basic vehicle detection algorithm (DWVDA) with less computational complexity was introduced for vehicle counting in low traffic volume conditions. To improve the detection performance in jam flow conditions with a “tailgating effect” between front vehicles and rear vehicles, an improved vehicle detection algorithm (SA-DWVDA) was proposed and applied in field traffic environments. By deploying traffic magnetic sensor nodes in field traffic scenarios, two field experiments were conducted to test and verify the DWVDA and the SA-DWVDA algorithms. The experimental results have shown that both DWVDA and the SA-DWVDA algorithms yield a satisfactory performance in low traffic volume conditions (scenario I) and both of their mean absolute percent errors are less than 1% in this scenario. However, for jam flow conditions with heavy traffic volumes (scenario II), the SA-DWVDA was proven to achieve better results, and the mean absolute percent error of the SA-DWVDA is 2.54% with corresponding results of the DWVDA 7.07%. The results conclude that the proposed SA-DWVDA can implement efficient and accurate vehicle detection in jam flow conditions and can be employed in field traffic environments.

To obtain adequate traffic information, the density of traffic sensors should be sufficiently high to cover the entire transportation network. However, deploying sensors densely over the entire network may not be realistic for practical applications due to the budgetary constraints of traffic management agencies. This paper describes several possible spatial distributions of traffic information credibility and proposes corresponding different sensor information credibility functions to describe these spatial distribution properties. A maximum benefit model and its simplified model are proposed to solve the traffic sensor location problem. The relationships between the benefit and the number of sensors are formulated with different sensor information credibility functions. Next, expanding models and algorithms in analytic results are performed. For each case, the maximum benefit, the optimal number and spacing of sensors are obtained and the analytic formulations of the optimal sensor locations are derived as well. Finally, a numerical example is proposed to verify the validity and availability of the proposed models for solving a network sensor location problem. The results show that the optimal number of sensors of segments with different model parameters in an entire freeway network can be calculated. Besides, it can also be concluded that the optimal sensor spacing is independent of end restrictions but dependent on the values of model parameters that represent the physical conditions of sensors and roads.