Fenofibrate induces liver enlargement in aging mice via activating the PPARα-YAP signaling pathway.

Fenofibrate is a clinically prescribed drug for treating hypertriglyceridemia, which is also a classic peroxisome proliferator activated receptor α (PPARα) agonist. We previously reported that fenofibrate induced liver enlargement in adult mice partially through yes-associated protein (YAP) signaling pathway. However, the effects of fenofibrate on liver enlargement and the YAP signaling pathway in aging mice remain unclear. In this study, D-galactose-induced aging mice, naturally aging mice and senescence accelerated mice P8 (SAMP8) were used to investigate the effects of aging on fenofibrate-induced liver enlargement and YAP signaling activation. The results showed that fenofibrate-induced liver enlargement in aging mice was consistent with that of adult mice. The effect of fenofibrate on hepatocyte enlargement around the central vein (CV) area and hepatocyte proliferation around the portal vein (PV) area was comparable between adult and aging mice. There was no significant difference in the upregulation of PPARα downstream proteins between the two groups following fenofibrate treatment. Fenofibrate treatment also increased the expression of proliferation-related proteins and activated the YAP signaling pathway to a similar degree in both groups. In summary, these results demonstrated that the fenofibrate-induced liver enlargement and activation of the YAP pathway are consistent between adult and aging mice, indicating that the effect of fenofibrate on promoting liver enlargement and its activation of the PPARα and YAP pathway were independent of aging. These findings provide a new perspective for the clinical use of fenofibrate in elderly patients and provide a new insight for role of PPARα in liver enlargement.

The reversal of PXR or PPARα activation-induced hepatomegaly.

The activation of pregnane X receptor (PXR) or peroxisome proliferator-activated receptor α (PPARα) can induce liver enlargement. Recently, we reported that PXR or PPARα activation-induced hepatomegaly depends on yes-associated protein (YAP) signaling and is characterized by hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area. However, it remains unclear whether PXR or PPARα activation-induced hepatomegaly can be reversed after the withdrawal of their agonists. In this study, we investigated the regression of enlarged liver to normal size following the withdrawal of PCN or WY-14643 (typical agonists of mouse PXR or PPARα) in C57BL/6 mice. The immunohistochemistry analysis of CTNNB1 and KI67 showed a reversal of hepatocyte size and a decrease in hepatocyte proliferation after the withdrawal of agonists. In details, the expression of PXR or PPARα downstream proteins (CYP3A11, CYP2B10, ACOX1, and CYP4A) and the expression of proliferation-related proteins (CCNA1, CCND1, and PCNA) returned to the normal levels. Furthermore, YAP and its downstream proteins (CTGF, CYR61, and ANKRD1) also restored to the normal states, which was consistent with the change in liver size. These findings demonstrate the reversibility of PXR or PPARα activation-induced hepatomegaly and provide new data for the safety of PXR and PPARα as drug targets.

Innexin hemichannel activation by Microplitis bicoloratus ecSOD monopolymer reduces ROS.

The extracellular superoxide dismutases (ecSODs) secreted by Microplitis bicoloratus reduce the reactive oxygen species (ROS) stimulated by the Microplitis bicoloratus bracovirus. Here, we demonstrate that the bacterial transferase hexapeptide (hexapep) motif and bacterial-immunoglobulin-like (BIg-like) domain of ecSODs bind to the cell membrane and transiently open hemichannels, facilitating ROS reductions. RNAi-mediated ecSOD silencing in vivo elevated ROS in host hemocytes, impairing parasitoid larva development. In vitro, the ecSOD-monopolymer needed to be membrane bound to open hemichannels. Furthermore, the hexapep motif in the beta-sandwich of ecSOD49 and ecSOD58, and BIg-like domain in the signal peptides of ecSOD67 were required for cell membrane binding. Hexapep motif and BIg-like domain deletions induced ecSODs loss of adhesion and ROS reduction failure. The hexapep motif and BIg-like domain mediated ecSOD binding via upregulating innexins and stabilizing the opened hemichannels. Our findings reveal a mechanism through which ecSOD reduces ROS, which may aid in developing anti-redox therapy.

Simulating immunosuppressive mechanism of Microplitis bicoloratus bracovirus coordinately fights Spodoptera frugiperda.

Parasitoid wasps control pests via a precise attack leading to the death of the pest. However, parasitoid larvae exhibit self-protection strategies against bracovirus-induced reactive oxygen species impairment. This has a detrimental effect on pest control. Here, we report a strategy for simulating Microplitis bicoloratus bracovirus using Mix-T dsRNA targeting 14 genes associated with transcription, translation, cell-cell communication, and humoral signaling pathways in the host, and from wasp extracellular superoxide dismutases. We implemented either one-time feeding to the younger instar larvae or spraying once on the corn leaves, to effectively control the invading pest Spodoptera frugiperda. This highlights the conserved principle of "biological pest control," as elucidated by the triple interaction of parasitoid-bracovirus-host in a cooperation strategy of bracovirus against its pest host.

NETO2-GluK2 interaction contributes to postoperative pain hypersensitivity through inducing PKCγ activation and synaptic incorporation of AMPA receptor GluR1 subunits in rat dorsal horn.

Important roles in the initiation and maintenance of postoperative pain are played by the functional control of kainate (KA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors in the rat dorsal horn (DH). However, the mechanisms underpinning the cross-talk between spinal KA and AMPA receptors in postoperative pain are poorly understood. We hypothesized that after the rat's plantar incision, the synaptic incorporation of AMPA receptor GluR1 subunits in the DH ipsilateral to the incision would increase due to the interaction between GluK2 and neuropilin tolloid-like 2 (NETO2). Our findings showed that incision stimuli caused severe pain responses, as measured by cumulative pain scores. GluK2-NETO2 but not GluK2-NETO1interaction was upregulated in ipsilateral dorsal horn neurons (DHNs) at 6 h post-incision. At 6 h post-incision, NETO2 small interfering ribonucleic acid (siRNA) intrathecal pretreatment increased mechanical withdrawal thresholds to von Freys and decreased ipsilateral paw cumulative pain scores. Further, PKCγactivation and synaptic abundance of GluK2 and GluR1 subunits in the ipsilateral DH were decreased by intrathecal pretreatment with NETO2 siRNA at 6 h post-incision. In conclusion, our findings imply that GluK2-NETO2 interaction could trigger PKCγactivation and the synaptic incorporation of AMPA receptor GluR1 subunits in rat DHs, which in turn led to the enhanced pain hypersensitivity after surgery. It sheds light on the interplay between KA and AMPA receptors in DHNs, which is thought to contribute to postoperative pain.

YAP regulates the liver size during the fasting-refeeding transition in mice.

Liver is the central hub regulating energy metabolism during feeding-fasting transition. Evidence suggests that fasting and refeeding induce dynamic changes in liver size, but the underlying mechanisms remain unclear. Yes-associated protein (YAP) is a key regulator of organ size. This study aims to explore the role of YAP in fasting- and refeeding-induced changes in liver size. Here, fasting significantly reduced liver size, which was recovered to the normal level after refeeding. Moreover, hepatocyte size was decreased and hepatocyte proliferation was inhibited after fasting. Conversely, refeeding promoted hepatocyte enlargement and proliferation compared to fasted state. Mechanistically, fasting or refeeding regulated the expression of YAP and its downstream targets, as well as the proliferation-related protein cyclin D1 (CCND1). Furthermore, fasting significantly reduced the liver size in AAV-control mice, which was mitigated in AAV Yap (5SA) mice. Yap overexpression also prevented the effect of fasting on hepatocyte size and proliferation. Besides, the recovery of liver size after refeeding was delayed in AAV Yap shRNA mice. Yap knockdown attenuated refeeding-induced hepatocyte enlargement and proliferation. In summary, this study demonstrated that YAP plays an important role in dynamic changes of liver size during fasting-refeeding transition, which provides new evidence for YAP in regulating liver size under energy stress.

Peroxisome proliferator-activated receptor α agonist induces mouse hepatomegaly through the spatial hepatocyte enlargement and proliferation.

Peroxisome proliferator-activated receptor alpha (PPARα) activation-induced hepatomegaly is accompanied by hepatocyte hypertrophy around the central vein (CV) area and hepatocyte proliferation around the portal vein (PV) area. However, the molecular mechanisms underlying this spatial change of hepatocytes remains unclear. In this study, we examined the characteristics and possible reasons for the zonation distinction of hypertrophy and proliferation during PPARα activation-induced mouse liver enlargement. Mice were injected with corn oil or a typical mouse PPARα agonist WY-14643 (100 mg·kg-1·d-1, i.p.) for 1, 2, 3, 5 or 10 days. At each time point, the mice were sacrificed after the final dose, and liver tissues and serum were harvested for analysis. We showed that PPARα activation induced zonal changes in hepatocyte hypertrophy and proliferation in the mice. In order to determine the zonal expression of proteins related to hepatocyte hypertrophy and proliferation in PPARα-induced liver enlargement, we performed digitonin liver perfusion to separately destroy the hepatocytes around the CV or PV areas, and found that PPARα activation-induced increase magnitude of its downstream targets such as cytochrome P450 (CYP) 4 A and acyl-coenzyme A oxidase 1 (ACOX1) levels around the CV area were higher compared with those around the PV area. Upregulation of proliferation-related proteins such as cell nuclear antigen (PCNA) and cyclin A1 (CCNA1) after WY-14643-induced PPARα activation mainly occurred around the PV area. This study reveals that the zonal expression of PPARα targets and proliferation-related proteins is responsible for the spatial change of hepatocyte hypertrophy and proliferation after PPARα activation. These findings provide a new insight into the understanding of PPARα activation-induced liver enlargement and regeneration.

ß-catenin/TCF4 inhibitors ICG-001 and LF3 alleviate BDL-induced liver fibrosis by suppressing LECT2 signaling.

Liver fibrosis can be characterized by the over-deposition of extracellular matrix (ECM). It has been reported that ß-catenin/TCF4 interaction was enhanced in bile duct ligation (BDL) model, which implicated the critical role of ß-catenin/TCF4 interaction during the progression of fibrosis. However, whether inhibiting ß-catenin/TCF4 signaling attenuates liver fibrosis remains unknown. In the current study, we used ICG-001, an inhibitor that disrupts the interaction between CREB binding protein (CBP) and ß-catenin, to inhibit ß-catenin/TCF4 transcriptional activity. We also used LF3, a small molecule antagonist, to inhibit ß-catenin/TCF4 interaction. The antifibrotic effect of ICG-001 and LF3 was assessed on BDL-induced liver fibrosis model. The results indicated both ICG-001 and LF3 significantly reduced the positive staining area of Sirius Red and α-SMA. The protein expression levels of α-SMA, Collagen Ⅰ and CD31 were also significantly downregulated in BDL + ICG-001 and BDL + LF3 groups. Besides, ICG-001 and LF3 promoted portal angiogenesis and inhibited sinusoids capillarization in fibrotic livers. For mechanistic study, we measured the level of leukocyte cell-derived chemotaxin 2 (LECT2), a direct target of ß-catenin/TCF4, which was recently reported to participate in hepatic fibrosis by regulating angiogenesis. The results showed that both ICG-001 and LF3 reduced LECT2 expression in BDL mice. LF3 also downregulated pSer 675 ß-catenin and nuclear ß-catenin. In conclusion, this study demonstrated that inhibiting ß-catenin/TCF4 signaling by ICG-001 or LF3 mitigated liver fibrosis by downregulating LECT2, promoting portal angiogenesis and inhibiting sinusoids capillarization, which provided new evidence that ß-catenin/TCF4 signaling might be a target for the treatment of liver fibrosis.

Schisandrol B protects against cholestatic liver injury by inhibiting pyroptosis through pregnane X receptor.

Previously, we demonstrated that Schisandrol B (SolB) protected against lithocholic acid (LCA)-induced cholestatic liver injury (CLI) through pregnane X receptor (PXR). Additionally, growing evidence has revealed that pyroptosis is involved in CLI. Whether the hepatoprotective effect of SolB driven by PXR activation is related to pyroptosis in CLI remains unclear. First, the hepatoprotective effect of SolB was confirmed, as evidenced by the decreased mortality, morphological and histopathological changes, and biochemical parameters. The upregulated serum lactic dehydrogenase (LDH) level, increased number of TUNEL-positive cells, and formation of hepatocyte membrane pores induced by LCA were significantly alleviated after SolB pretreatment, indicating that SolB attenuated LCA-induced hepatocyte damage. Further analysis revealed that both NOD-like receptor protein 3 (NLRP3) inflammasome-induced canonical pyroptosis and apoptosis protease activating factor-1 (Apaf-1) pyroptosome-induced noncanonical pyroptosis were significantly inhibited after SolB pretreatment, as illustrated by the decreased expression levels of NLRP3, ASC, caspase-1, and GSDMD and the levels of Apaf-1, caspase-11 p20, caspase-3 p20, and GSDME. Furthermore, the activation of the NF-κB and FoxO1 signaling pathways was inhibited after SolB pretreatment. In addition, the activation of PXR via SolB was proven by luciferase reporter gene assays and the upregulation of PXR targets. The results illustrated that SolB could significantly inhibit NLRP3 inflammasome-induced canonical pyroptosis through the PXR/NF-κB/NLRP3 axis and inhibit Apaf-1 pyroptosome-induced noncanonical pyroptosis through the PXR/FoxO1/Apaf-1 axis. Collectively, this study revealed that SolB protected against CLI by inhibiting pyroptosis through PXR, providing new insights for understanding the molecular mechanism of SolB as a promising anti-cholestatic agent.

Upregulation of Hevin contributes to postoperative pain hypersensitivity by inducing neurexin1ß/neuroligin1-mediated synaptic targeting of GluA1-containing AMPA receptors in rat dorsal horn.

The astrocytes-secreted active molecule, Hevin considerably contributes in the transsynaptic bridge of neurexin1ß/neuligin1 in excitatory synapse. Previous studies have demonstrated that activity-dependent synaptic recruitment of spinal neuroligin1 and GluA1-containing AMPA receptors (AMPARs) is involved in incisional, inflammatory and neuropathic pain. Here, we hypothesized that Hevin induced postoperative pain hypersensitivity by enhancing the neurexin1ß/neuroligin1-mediated synaptic targeting of GluA1-containing AMPARs in spinal dorsal horns (DH). Our results showed that plantar incision induced significant postoperative pain behavior, which was described by the cumulative pain scores. At 1 d and 3 d post-incision, Hevin expression was considerably elevated in ipsilateral DHs, although it recovered to baseline value at 5 d following the incision. At 1 d post plantar incision, the neurexin1ß/neuroligin1 interactions significantly increased in ipsilateral DHs in rats subjected to incision when compared with those in control rats. Intrathecal pretreatments of small interference RNA targeting Hevin substantially suppressed postoperative pain hypersensitivity and reduced the neurexin1ß/neurolgin1 interaction as well as the synaptic targeting of GluA1 in ipsilateral spinal DHs. These data suggest that Hevin induced postoperative pain hypersensitivity by enhancing the neurexin1ß/neuroligin1 interaction and subsequent synaptic targeting of GluA1-containing AMPARs in ipsilateral spinal DHs. It provides new insights into the role of Hevin-mediated trans-synaptic regulation in postoperative pain hypersensitivity, which would help develop a novel therapeutic strategy.

Neutrophil Percentage to Albumin Ratio was Associated with Clinical Outcomes in Coronary Care Unit Patients.

Background: Neutrophil percentage to albumin ratio (NPAR) has been shown to be correlated with the prognosis of various diseases. This study aimed to explore the effect of NPAR on the prognosis of patients in coronary care units (CCU). Method: All data in this study were extracted from the Medical Information Mart for Intensive Care III (MIMIC-III, version1.4) database. All patients were divided into four groups according to their NPAR quartiles. The primary outcome was in-hospital mortality. Secondary outcomes were 30-day mortality, 365-day mortality, length of CCU stay, length of hospital stay, acute kidney injury (AKI), and continuous renal replacement therapy (CRRT). A multivariate binary logistic regression analysis was performed to confirm the independent effects of NPAR. Cox regression analysis was performed to analyze the association between NPAR and 365-day mortality. The curve in line with overall trend was drawn by local weighted regression (Lowess). Subgroup analysis was used to determine the effect of NPAR on in-hospital mortality in different subgroups. Receiver operating characteristic (ROC) curves were used to evaluate the ability of NPAR to predict in-hospital mortality. Kaplan-Meier curves were constructed to compare the cumulative survival rates among different groups. Result: A total of 2364 patients in CCU were enrolled in this study. The in-hospital mortality rate increased significantly as the NPAR quartiles increased (p < 0.001). In multivariate logistic regression analysis, NPAR was independently associated with in-hospital mortality (quartile 4 versus quartile 1: odds ratio [OR], 95% confidence interval [CI]: 1.83, 1.20-2.79, p = 0.005, p for trend < 0.001). In Cox regression analysis, NPAR was independently associated with 365-day mortality (quartile 4 versus quartile 1: OR, 95% CI: 1.62, 1.16-2.28, p = 0.005, p for trend < 0.001). The Lowess curves showed a positive relationship between NPAR and in-hospital mortality. The moderate ability of NPAR to predict in-hospital mortality was demonstrated through ROC curves. The area under the curves (AUC) of NPAR was 0.653 (p < 0.001), which is better than that of the platelet to lymphocyte ratio (PLR) (p < 0.001) and neutrophil count (p < 0.001) but lower than the Sequential Organ Failure Assessment (p = 0.046) and Simplified Acute Physiology Score II (p < 0.001). Subgroup analysis did not reveal any obvious interactions in most subgroups. However, Kaplan-Meier curves showed that as NPAR quartiles increased, the 30-day (log-rank, p < 0.001) and 365-day (log-rank, p < 0.001) cumulative survival rates decreased significantly. NPAR was also independently associated with AKI (quartile 4 versus quartile 1: OR, 95% CI: 1.57, 1.19-2.07, p = 0.002, p for trend = 0.001). The CCU and hospital stay length was significantly prolonged in the higher NPAR quartiles. Conclusions: NPAR is an independent risk factor for in-hospital mortality in patients in CCU and has a moderate ability to predict in-hospital mortality.

Association between Neutrophil Percentage-to-Albumin Ratio and All-Cause Mortality in Critically Ill Patients with Coronary Artery Disease.

BACKGROUND: Neutrophil percentage-to-albumin ratio (NPAR) has been proved to be associated with clinical outcome of many diseases. This study was aimed at exploring the independent effect of NPAR on all-cause mortality of critically ill patients with coronary artery disease (CAD). METHOD: NPAR was calculated as neutrophil percentage numerator divided by serum albumin concentration. Clinical endpoints were 30-day, 90-day, and 365-day all-cause mortality. Multivariable Cox proportional hazard models were performed to confirm the association between NPAR and all-cause mortality. RESULT: 3106 patients with CAD were enrolled. All-cause mortality rates of 30 days (P < 0.001), 90 days (P < 0.001), and 365 days (P < 0.001) increased as NPAR tertiles increased. And after adjusting for possible confounding variables, NPAR was still independently associated with 30-day (third tertile group versus first tertile group: HR, 95% CI: 1.924, 1.471-2.516; P for trend < 0.001), 90-day (third tertile group versus first tertile group: HR, 95% CI: 2.053, 1.646-2.560; P for trend < 0.001), and 365-day (third tertile group versus first tertile group: HR, 95% CI: 2.063, 1.717-2.480; P for trend < 0.001) all-cause mortality in patients with CAD. Subgroup analysis did not find obvious interaction in most subgroups. CONCLUSION: NPAR was independently correlated with 30-day, 60-day, and 365-day all-cause mortality in critically ill patients with CAD.

Anion Gap Was Associated with Inhospital Mortality and Adverse Clinical Outcomes of Coronary Care Unit Patients.

BACKGROUND: Anion gap (AG) has been proved to be associated with prognosis of many cardiovascular diseases. This study is aimed at exploring the association of AG with inhospital all-cause mortality and adverse clinical outcomes in coronary care unit (CCU) patients. METHOD: All data of this study was extracted from Medical Information Mart for Intensive Care III (MIMIC-III, version 1.4) database. All patients were divided into four groups according to AG quartiles. Primary outcome was inhospital all-cause mortality. Lowess smoothing curve was drawn to describe the overall trend of inhospital mortality. Binary logistic regression analysis was performed to determine the independent effect of AG on inhospital mortality. RESULT: A total of 3593 patients were enrolled in this study. In unadjusted model, as AG quartiles increased, inhospital mortality increased significantly, OR increased stepwise from quartile 2 (OR, 95% CI: 1.01, 0.74-1.38, P = 0.958) to quartile 4 (OR, 95% CI: 2.72, 2.08-3.55, P < 0.001). After adjusting for possible confounding variables, this association was attenuated, but still remained statistically significant (quartile 1 vs. quartile 4: OR, 95% CI: 1.02, 0.72-1.45 vs. 1.49, 1.07-2.09, P = 0.019). Moreover, CCU mortality (P < 0.001) and rate of acute kidney injury (P < 0.001) were proved to be higher in the highest AG quartiles. Length of CCU (P < 0.001) and hospital stay (P < 0.001) prolonged significantly in higher AG quartiles. Maximum sequential organ failure assessment score (SOFA) (P < 0.001) and simplified acute physiology score II (SAPSII) (P < 0.001) increased significantly as AG quartiles increased. Moderate predictive ability of AG on inhospital (AUC: 0.6291), CCU mortality (AUC: 0.6355), and acute kidney injury (AUC: 0.6096) was confirmed. The interactions were proved to be significant in hypercholesterolemia, congestive heart failure, chronic lung disease, respiratory failure, oral anticoagulants, Beta-blocks, angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB), and vasopressin treatment subgroups. CONCLUSION: AG was an independent risk factor of inhospital all-cause mortality and was associated with adverse clinical outcomes in CCU patients.

A comparison of information functions and search strategies for sensor planning in target classification.

This paper investigates the comparative performance of several information-driven search strategies and decision rules using a canonical target classification problem. Five sensor models are considered: one obtained from classical estimation theory and four obtained from Bernoulli, Poisson, binomial, and mixture-of-binomial distributions. A systematic approach is presented for deriving information functions that represent the expected utility of future sensor measurements from mutual information, Rènyi divergence, Kullback-Leibler divergence, information potential, quadratic entropy, and the Cauchy-Schwarz distance. The resulting information-driven strategies are compared to direct-search, alert-confirm, task-driven (TS), and log-likelihood-ratio (LLR) search strategies. Extensive numerical simulations show that quadratic entropy typically leads to the most effective search strategy with respect to correct-classification rates. In the presence of prior information, the quadratic-entropy-driven strategy also displays the lowest rate of false alarms. However, when prior information is absent or very noisy, TS and LLR strategies achieve the lowest false-alarm rates for the Bernoulli, mixture-of-binomial, and classical sensor models.

Information-driven sensor path planning by approximate cell decomposition.

A methodology is developed for planning the sensing strategy of a robotic sensor deployed for the purpose of classifying multiple fixed targets located in an obstacle-populated workspace. Existing path planning techniques are not directly applicable to robots whose primary objective is to gather sensor measurements using a bounded field of view (FOV). This paper develops a novel approximate cell-decomposition method in which obstacles, targets, sensor's platform, and FOV are represented as closed and bounded subsets of an Euclidean workspace. The method constructs a connectivity graph with observation cells that is pruned and transformed into a decision tree from which an optimal sensing strategy can be computed. The effectiveness of the optimal sensing strategies obtained by this methodology is demonstrated through a mine-hunting application. Numerical experiments show that these strategies outperform shortest path, complete coverage, random, and grid search strategies, and are applicable to nonoverpass capable robots that must avoid targets as well as obstacles.

Information-driven search strategies in the board game of CLUE.

This paper presents an information-driven sensor management problem, referred to as treasure hunt, which is relevant to mobile-sensor applications such as mine hunting, monitoring, and surveillance. The objective is to infer a hidden variable or treasure by selecting a sequence of measurements associated with multiple fixed targets distributed in the sensor workspace. The workspace is represented by a connectivity graph, where each node represents a possible sensor deployment, and the arcs represent possible sensor movements. An additive conditional entropy reduction function is presented to efficiently compute the expected benefit of a measurement sequence over time. Then, the optimal treasure hunt strategy is determined by a novel label-correcting algorithm operating on the connectivity graph. The methodology is illustrated through the board game of CLUE, which is shown to be a benchmark example of the treasure hunt problem. The game results show that a computer player implementing the strategies developed in this paper outperforms players implementing Bayesian networks, Q-learning, or constraint satisfaction, as well as human players.