Hepatocellular carcinoma (HCC) is a malignant tumor that threatens global human health. High PKM2 expression is widely reported in multiple cancers, especially in HCC. This study aimed to explore the ...effects of PKM2 on global gene expression, metabolic damages, patient prognosis, and multiple transcriptional regulation relationships, as well as to identify several key metabolic genes and screen some small-molecule drugs.
Transcriptome and clinical HCC data were downloaded from the NIH-GDC repository. Information regarding the metabolic genes and subsystems was collected from the Recon 2 human metabolic model. Drug-protein interaction data were obtained from the DrugBank and UniProt databases. We defined patients with PKM2 expression levels ≥11.25 as the high-PKM2 group, and those with low PKM2 expression (< 11.25) were defined as the low-PKM2 group.
The results showed that the global metabolic gene expression levels were obviously divided into the high- or low-PKM2 groups. In addition, a greater number of affected metabolic subsystems were observed in the high-PKM2 group. Furthermore, we identified 98 PKM2-correlated deregulated metabolic genes that were associated with poor overall patient survival. Together, these findings suggest more comprehensive influences of PKM2 on HCC. In addition, we screened several small-molecule drugs that target these metabolic enzymes, some of which have been used in antitumor clinical studies.
HCC patients with high PKM2 expression showed more severe metabolic damage, transcriptional regulation imbalance and poor prognosis than low-PKM2 individuals. We believe that our study provides valuable information for pathology research and drug development for HCC.
Many lines of evidence suggest that Parkinson's disease (PD) and Alzheimer's disease (AD) have common characteristics, such as mitochondrial dysfunction and oxidative stress. As the underlying ...molecular mechanisms are unclear, we perform a meta-analysis with 9 microarray datasets of PD studies and 7 of AD studies to explore it. Functional enrichment analysis revealed that PD and AD both showed dysfunction in the synaptic vesicle cycle, GABAergic synapses, phagosomes, oxidative phosphorylation, and TCA cycle pathways, and AD had more enriched genes. Comparing the differentially expressed genes between AD and PD, we identified 54 common genes shared by more than six tissues. Among them, 31 downregulated genes contained the antioxidant response element (ARE) consensus sequence bound by NRF2. NRF2 is a transcription factor, which protects cells against oxidative stress through coordinated upregulation of ARE-driven genes. To our surprise, although NRF2 was upregulated, its target genes were all downregulated. Further exploration found that MAFF was upregulated in all tissues and significantly negatively correlated with the 31 NRF2-dependent genes in diseased conditions. Previous studies have demonstrated over-expressed small MAFs can form homodimers and act as transcriptional repressors. Therefore, MAFF might play an important role in dysfunction of NRF2 regulatory network in PD and AD.
Increased megamitochondria formation and impaired mitophagy in hepatocytes have been linked to the pathogenesis of alcohol-associated liver disease (ALD). This study aims to determine the mechanisms ...by which alcohol consumption increases megamitochondria formation in the pathogenesis of ALD.
Human alcoholic hepatitis (AH) liver samples were used for electron microscopy, histology, and biochemical analysis. Liver-specific dynamin-related protein 1 (DRP1; gene name DNM1L, an essential gene regulating mitochondria fission ) knockout (L-DRP1 KO) mice and wild-type mice were subjected to chronic plus binge alcohol feeding. Both human AH and alcohol-fed mice had decreased hepatic DRP1 with increased accumulation of hepatic megamitochondria. Mechanistic studies revealed that alcohol feeding decreased DRP1 by impairing transcription factor EB-mediated induction of DNM1L . L-DRP1 KO mice had increased megamitochondria and decreased mitophagy with increased liver injury and inflammation, which were further exacerbated by alcohol feeding. Seahorse flux and unbiased metabolomics analysis showed alcohol intake increased mitochondria oxygen consumption and hepatic nicotinamide adenine dinucleotide (NAD + ), acylcarnitine, and ketone levels, which were attenuated in L-DRP1 KO mice, suggesting that loss of hepatic DRP1 leads to maladaptation to alcohol-induced metabolic stress. RNA-sequencing and real-time quantitative PCR analysis revealed increased gene expression of the cGAS-stimulator of interferon genes (STING)-interferon pathway in L-DRP1 KO mice regardless of alcohol feeding. Alcohol-fed L-DRP1 KO mice had increased cytosolic mtDNA and mitochondrial dysfunction leading to increased activation of cGAS-STING-interferon signaling pathways and liver injury.
Alcohol consumption decreases hepatic DRP1 resulting in increased megamitochondria and mitochondrial maladaptation that promotes AH by mitochondria-mediated inflammation and cell injury.
Peptide-mediated cell-to-cell signaling has crucial roles in coordination and definition of cellular functions in plants. Peptide-receptor matching is important for understanding the mechanisms ...underlying peptide-mediated sig- naling. Here we report the structure-guided identification of root meristem growth factor （RGF） receptors important for plant development. An assay based on a signature ligand recognition motif （Arg-x-Arg） conserved in a subfamily of leucine-rich repeat receptor kinases CLRR-RKs） identified the functionally uncharacterized LRR-RK At4926540 as a receptor of RGF1 （RGFR1）. We further solved the crystal structure of RGF1 in complex with the LRR domain of RGFR1 at a resolution of 2.6 A, which reveals that the Arg-x-Gly-Gly （RxGG） motif is responsible for specific rec- ognition of the sulfate group of RGF1 by RGFR1. Based on the RxGG motif, we identified additional four RGFRs. Participation of the five RGFRs in RGF-induced signaling is supported by biochemical and genetic data. We also of- fer evidence showing that SERKs function as co-receptors for RGFs. Taken together, our study identifies RGF receptors and co-receptors that can link RGF signals with their downstream components and provides a proof of principle for structure-based matching of LRR-RKs with their peptide ligands.
Background
Recent studies have shown that human and experimental alcohol‐related liver disease (ALD) is robustly associated with dysregulation of bile acid homeostasis, which may in turn modulate ...disease severity. Pharmacological agents targeting bile acid metabolism and signaling may be potential therapeutics for ALD.
Methods
The potential beneficial effects of a gut‐restricted apical sodium‐dependent bile acid transporter (ASBT) inhibitor were studied in a chronic‐plus‐binge ALD mouse model.
Results
Blocking intestinal bile acid reabsorption by the gut‐restricted ASBT inhibitor GSK2330672 attenuated hepatic steatosis and liver injury in a chronic‐plus‐binge ALD mouse model. Alcohol feeding is associated with intestinal bile acid accumulation but paradoxically impaired ileal farnesoid × receptor (FXR) function, and repressed hepatic cholesterol 7α‐hydrolase (CYP7A1) expression despite decreased hepatic small heterodimer partner (SHP) and ileal fibroblast growth factor 15 (FGF15) expression. ASBT inhibitor treatment decreased intestinal bile acid accumulation and increased hepatic CYP7A1 expression, but further decreased ileal FXR activity. Alcohol feeding induces serum bile acid concentration that strongly correlates with a liver injury marker. However, alcohol‐induced serum bile acid elevation is not due to intrahepatic bile acid accumulation but is strongly and positively associated with hepatic multidrug resistance‐associated protein 3 (MRP4) and MRP4 induction but poorly associated with sodium‐taurocholate cotransporting peptide (NTCP) expression. ASBT inhibitor treatment decreases serum bile acid concentration without affecting hepatocyte basolateral bile acid uptake and efflux transporters.
Conclusion
ASBT inhibitor treatment corrects alcohol‐induced bile acid dysregulation and attenuates liver injury in experimental ALD.
Bile acids are synthesized from cholesterol in the liver and transported in the enterohepatic circulation where bile acids critically regulate lipid metabolism and inflammatory responses. Recent studies reveal that alcohol‐related liver disease (ALD) is associated with dysregulation of bile acid homeostasis which may in turn modulate ALD severity. Here we report that treatment with an apical sodium‐dependent bile acid transporter (ASBT) inhibitor, which blocks intestinal bile acid re‐uptake, corrects alcohol‐induced bile acid dysregulation and attenuates liver steatosis and injury in an experimental ALD mouse model.
A compound compensation method for car-following model Zhu, Wen-Xing; Jun, Du; Zhang, Li-Dong
Communications in nonlinear science & numerical simulation,
October 2016, 2016-10-00, 20161001, Letnik:
39
Journal Article
Recenzirano
•A compound compensation mechanism was introduced into car-following system.•A stability theorem was proposed and proved aim to compound compensation.•The unit step response and phase margins were ...analyzed based on time domain and frequency domain methods.
A compound compensation mechanism was introduced into the car-following system. Two basic compensation methods were combined to generate a compound control strategy to improve the performance of the traffic flow system. The compensation effect was analyzed with unit step response in time domain and bode diagram in frequency domain, respectively. Two lemmas and one theorem were proved with the use of Routh criteria and small gain theorem. Numerical simulations were conducted in two situations under three types of condition. The simulation results verify the truth that with the increasing compensation parameters the stability of the car-following system is strengthened. It is shown that numerical results are in accordance with analytical results. In general, the performance of car-following model can be improved with an exterior control method.
Abstract
Solution processed perovskite films usually exhibit numerous defect states on the surfaces of the films. Here in this work, oxalic acid (H
2
C
2
O
4
), which has two C=O groups, is selected ...and used to passivate the surface defects of the two‐step deposited perovskite films via post‐treatment. Strong interaction between H
2
C
2
O
4
molecule and the Pb
2+
ions located on the surface of perovskite film has been confirmed via Fourier transform infrared spectroscopy and X‐ray photoelectron spectroscopy, which can result in an effective suppress of the surface defects. Furthermore, time‐resolved PL spectrum indicates that carrier lifetime is prolonged in the H
2
C
2
O
4
passivated perovskite film. After optimizing the H
2
C
2
O
4
concentration, the target perovskite solar cells can demonstrate superior power conversion efficiencies (21.67 % from reverse measurement and 21.54 % from forward measurement) and superior device‐stability.
High‐risk populations are the predominant populations affected by hepatitis C virus (HCV) infection, and there is an urgent need for efficient and cost‐effective HCV testing strategies for high‐risk ...populations to identify potential undiagnosed HCV‐infected individuals. This study compared several commonly used testing strategies and conducted effectiveness and cost analysis to select the appropriate testing strategy for diagnosing HCV infection in high‐risk populations. Among the 2093 samples from high‐risk populations in this study, 1716 were HCV negative, 237 were current HCV infection, 137 were past HCV infection, and three were acute early HCV infection. It was found that out of 237 patients with HCV current infection, Strategy A could detect 225 cases, with a missed detection rate of 5.06%, and the total cost was 33 299 RMB. In addition, Strategy B could detect 237 cases of current HCV infection, and the HCV missed detection rate was 0.00%, and the total cost was 147 221 RMB. While 137 cases of past HCV infection could be distinguished by strategy C, but 14 cases with current HCV infection were missed, with an HCV‐positive missed detection rate of 5.91%, and the total cost for Strategy C was 43 059 RMB. In conclusion, in high‐risk populations, the HCV positivity rate is typically higher. If feasible, the preferred approach is to directly conduct HCV RNA testing, which effectively minimizes the risk of missing cases. However, in situations with limited resources, it is advisable to initially choose a highly sensitive method for anti‐HCV screening, followed by HCV RNA testing on reactive samples.
Background & Aims Alcohol abuse is a major cause of liver injury. The pathologic features of alcoholic liver disease develop over prolonged periods, yet the cellular defense mechanisms against the ...detrimental effects of alcohol are not well understood. We investigated whether macroautophagy, an evolutionarily conserved cellular mechanism that is commonly activated in response to stress, could protect liver cells from ethanol toxicity. Methods Mice were acutely given ethanol by gavage. The effects of ethanol on primary hepatocytes and hepatic cell lines were also studied in vitro. Results Ethanol-induced macroautophagy in the livers of mice and cultured cells required ethanol metabolism, generation of reactive oxygen species, and inhibition of mammalian target of rapamycin signaling. Suppression of macroautophagy with pharmacologic agents or small interfering RNAs significantly increased hepatocyte apoptosis and liver injury; macroautophagy therefore protected cells from the toxic effects of ethanol. Macroautophagy induced by ethanol seemed to be selective for damaged mitochondria and accumulated lipid droplets, but not long-lived proteins, which could account for its protective effects. Increasing macroautophagy pharmacologically reduced hepatotoxicity and steatosis associated with acute ethanol exposure. Conclusions Macroautophagy protects against ethanol-induced toxicity in livers of mice. Reagents that modify macroautophagy might be developed as therapeutics for patients with alcoholic liver disease.
Cascade compensation mechanism was designed to improve the dynamical performance of traffic flow system. Two compensation methods were used to study unit step response in time domain and frequency ...characteristics with different parameters. The overshoot and phase margins are proportional to the compensation parameter in an underdamped condition. Through the comparison we choose the phase-lead compensation method as the main strategy in suppressing the traffic jam. The simulations were conducted under two boundary conditions to verify the validity of the compensator. The conclusion can be drawn that the stability of the system is strengthened with increased phase-lead compensation parameter. Moreover, the numerical simulation results are in good agreement with analytical results.
•Cascade compensation mechanism was introduced into car-following system.•The stability of traffic flow system under different compensation parameters was discussed.•The performance of the model was analyzed in time and frequency domain respectively.
PDF
