Caffeine is one of the world's most consumed drugs. Recently, several studies showed that its consumption is associated with lower risk for nonalcoholic fatty liver disease (NAFLD), an ...obesity‐related condition that recently has become the major cause of liver disease worldwide. Although caffeine is known to stimulate hepatic fat oxidation, its mechanism of action on lipid metabolism is still not clear. Here, we show that caffeine surprisingly is a potent stimulator of hepatic autophagic flux. Using genetic, pharmacological, and metabolomic approaches, we demonstrate that caffeine reduces intrahepatic lipid content and stimulates β‐oxidation in hepatic cells and liver by an autophagy‐lysosomal pathway. Furthermore, caffeine‐induced autophagy involved down‐regulation of mammalian target of rapamycin signaling and alteration in hepatic amino acids and sphingolipid levels. In mice fed a high‐fat diet, caffeine markedly reduces hepatosteatosis and concomitantly increases autophagy and lipid uptake in lysosomes. Conclusion: These results provide novel insight into caffeine's lipolytic actions through autophagy in mammalian liver and its potential beneficial effects in NAFLD. (Hepatology 2014;59:1366‐1380)
Abstract
Peptide-like molecules, which have a close connection with the origin of life, have been detected in the Universe. Mapping observations of HCONH
2
and CH
3
CONH
2
, two of the simplest ...peptide-like molecules, are performed toward the Sagittarius B2 (Sgr B2) complex with the IRAM 30 m telescope. Seven transitions of HCONH
2
and five transitions of CH
3
CONH
2
are used in the analysis. The spatial distributions of the excitation temperature and column density of HCONH
2
in the molecular envelope of Sgr B2 are obtained by rotation diagrams. Assuming the same excitation temperature of HCONH
2
, the column densities of CH
3
CONH
2
are also calculated. The results show that the excitation temperature ranges from 6 to 46 K in the molecular envelope of Sgr B2. The abundance ratios between HCONH
2
and CH
3
CONH
2
are calculated to explore the relationship between them, as are those between HCONH
2
and HNCO. The abundance ratio of CH
3
CONH
2
/HCONH
2
varies from 10% to 20%, while that of HCONH
2
/HNCO ranges from 1.5% to 10%. CH
3
CONH
2
is enhanced with respect to HCONH
2
in the northwest region of Sgr B2. One transition of H
13
CONH
2
is detected toward 12 positions of Sgr B2, from which a
12
C/
13
C ratio of 28.7 is obtained. A time-dependent chemical model with a short-duration X-ray burst is used to explain the observed abundances of HCONH
2
and CH
3
CONH
2
, with the best-fitting result at
T
dust
= 53–56 K. More chemical reactions are required to be included in the model since the modeled abundance is lower than the observed one at the observed
T
dust
.
For secondary school students, peer support is an essential component of social support, which might significantly influence their academic achievement. However, the mediating mechanism between peer ...support and academic achievement needs to be further explored, especially in teaching English as a foreign language (EFL). The present study explored the relationship between peer support, foreign language (FL) self-concept, and EFL achievement based on the data of 499 Chinese secondary EFL learners. Structural equation modelling (SEM) and mediation analysis results demonstrated that peer support positively affected EFL achievement. FL self-concept fully mediated the relationship between peer support and EFL achievement after controlling for gender and age. The direction and strength of the mediating effect of FL self-concept between peer support and EFL achievement clarify the complex relationship between peer support and EFL achievement and helps EFL teachers and educators take intervention measures. Implications, limitations and directions for future research are discussed.
Currently, there is limited understanding about hormonal regulation of mitochondrial turnover. Thyroid hormone (T
3
) increases oxidative phosphorylation (OXPHOS), which generates reactive oxygen ...species (ROS) that damage mitochondria. However, the mechanism for maintenance of mitochondrial activity and quality control by this hormone is not known. Here, we used both in vitro and in vivo hepatic cell models to demonstrate that induction of mitophagy by T
3
is coupled to oxidative phosphorylation and ROS production. We show that T
3
induction of ROS activates CAMKK2 (calcium/calmodulin-dependent protein kinase kinase 2, β) mediated phosphorylation of PRKAA1/AMPK (5′ AMP-activated protein kinase), which in turn phosphorylates ULK1 (unc-51 like autophagy activating kinase 1) leading to its mitochondrial recruitment and initiation of mitophagy. Furthermore, loss of ULK1 in T
3
-treated cells impairs both mitophagy as well as OXPHOS without affecting T
3
induced general autophagy/lipophagy. These findings demonstrate a novel ROS-AMPK-ULK1 mechanism that couples T
3
-induced mitochondrial turnover with activity, wherein mitophagy is necessary not only for removing damaged mitochondria but also for sustaining efficient OXPHOS.
Monocytes can develop an exhausted memory state characterized by reduced differentiation, pathogenic inflammation, and immune suppression that drives immune dysregulation during sepsis. Chromatin ...alterations, notably via histone modifications, underlie innate immune memory, but the contribution of DNA methylation remains poorly understood. Using an ex vivo sepsis model, we show altered DNA methylation throughout the genome of exhausted monocytes, including genes implicated in immune dysregulation during sepsis and COVID-19 infection (e.g., Plac8). These changes are recapitulated in septic mice induced by cecal slurry injection. Methylation profiles developed in septic mice are maintained during ex vivo culture, supporting the involvement of DNA methylation in stable monocyte exhaustion memory. Methylome reprogramming is driven in part by Wnt signaling inhibition in exhausted monocytes and can be reversed with DNA methyltransferase inhibitors, Wnt agonists, or immune training molecules. Our study demonstrates the significance of altered DNA methylation in the maintenance of stable monocyte exhaustion memory.
Display omitted
•Monocytes experience broad DNA methylation reprogramming during innate immune exhaustion•Altered DNA methylation at enhancers correlates with disrupted immune gene expression•TICAM2 signaling and Wnt suppression contribute to altered methylome in exhausted cells•Therapeutic intervention with immune training agents restores healthy DNA methylation
Caldwell et al. demonstrate that DNA methylation reprogramming contributes to monocyte exhaustion during sepsis. Altered DNA methylation is driven in part by TICAM2 signaling and Wnt suppression and can be reversed with immune training compounds. These results highlight an underexplored facet of chromatin regulation in innate immune memory.
Mitophagy is an important type of selective autophagy for specific elimination of damaged mitochondria. PTEN-induced putative kinase protein 1 (PINK1)-catalyzed phosphorylation of ubiquitin (Ub) ...plays a critical role in the onset of PINK1-Parkin-mediated mitophagy. Phosphatase and tensin homolog (PTEN)-long (PTEN-L) is a newly identified isoform of PTEN, with addition of 173 amino acids to its N-terminus. Here we report that PTEN-L is a novel negative regulator of mitophagy via its protein phosphatase activity against phosphorylated ubiquitin. We found that PTEN-L localizes at the outer mitochondrial membrane (OMM) and overexpression of PTEN-L inhibits, whereas deletion of PTEN-L promotes, mitophagy induced by various mitochondria-damaging agents. Mechanistically, PTEN-L is capable of effectively preventing Parkin mitochondrial translocation, reducing Parkin phosphorylation, maintaining its closed inactive conformation, and inhibiting its E3 ligase activity. More importantly, PTEN-L reduces the level of phosphorylated ubiquitin (pSer65-Ub) in vivo, and in vitro phosphatase assay confirms that PTEN-L dephosphorylates pSer65-Ub via its protein phosphatase activity, independently of its lipid phosphatase function. Taken together, our findings demonstrate a novel function of PTEN-L as a protein phosphatase for ubiquitin, which counteracts PINK1-mediated ubiquitin phosphorylation leading to blockage of the feedforward mechanisms in mitophagy induction and eventual suppression of mitophagy. Thus, understanding this novel function of PTEN-L provides a key missing piece in the molecular puzzle controlling mitophagy, a critical process in many important human diseases including neurodegenerative disorders such as Parkinson's disease.
Drawing up the control-value theory, the present study attempted to understand the relationships among Chinese secondary school students’ English learning anxiety, behavioural engagement, and English ...performance. A total of 230 (113 males, 117 females) English as a foreign language (EFL) learners from one Chinese secondary school completed the academic anxiety scale and behavioural engagement scale. Participants final examination scores measured their English achievement. Structural equation model (SEM) analyses demonstrated that EFL-related anxiety could directly affect EFL achievement and indirectly via the mediator of behavioural engagement. EFL-related anxiety was able to explain 44.9% of the variance in behavioural engagement and 22.6% of the variance in English achievement. Implications for English education and limitations and directions for future studies are discussed.
Epigallocatechin gallate (EGCG) is a major polyphenol in green tea that has been shown to have anti-inflammatory, anti-cancer, anti-steatotic effects on the liver. Autophagy also mediates similar ...effects; however, it is not currently known whether EGCG can regulate hepatic autophagy. Here, we show that EGCG increases hepatic autophagy by promoting the formation of autophagosomes, increasing lysosomal acidification, and stimulating autophagic flux in hepatic cells and in vivo. EGCG also increases phosphorylation of AMPK, one of the major regulators of autophagy. Importantly, siRNA knockdown of AMPK abrogated autophagy induced by EGCG. Interestingly, we observed lipid droplet within autophagosomes and autolysosomes and increased lipid clearance by EGCG, suggesting it promotes lipid metabolism by increasing autophagy. In mice fed with high-fat/western style diet (HFW; 60% energy as fat, reduced levels of calcium, vitamin D3, choline, folate, and fiber), EGCG treatment reduces hepatosteatosis and concomitantly increases autophagy. In summary, we have used genetic and pharmacological approaches to demonstrate EGCG induction of hepatic autophagy, and this may contribute to its beneficial effects in reducing hepatosteatosis and potentially some other pathological liver conditions.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Based on the Expectancy-Value Theory (EVT), this study examined the interactive relation between expectancy of success and attainment value, and how they predicate students’ Foreign Language (FL) ...performance via behavioral engagement. Self-report data were collected from 522 Chinese non-English majors aged 18 to 22 years in their sophomore year. Results of structural equation modeling indicated that expectancy of success and attainment value interacted in predicting Chinese sophomores’ FL performance. The expectancy of success had both direct and indirect effects on FL performance when investigating the mediating role of behavioral engagement. Both theoretical and practical implications are discussed.
Background
Within the field of oncotherapy, research interest regarding immunotherapy has risen to the point that it is now seen as a key application. However, inherent disadvantages of immune ...checkpoint inhibitors (ICIs), such as their low response rates and immune‐related adverse events (irAEs), currently restrict their clinical application. Were these disadvantages to be overcome, more patients could derive prolonged benefits from ICIs. At present, many basic experiments and clinical studies using hyperthermia combined with ICI treatment (HIT) have been performed and shown the potential to address the above challenges. Therefore, this review extensively summarizes the knowledge and progress of HIT for analysis and discusses the effect and feasibility.
Methods
In this review, we explored the PubMed and clinicaltrials.gov databases, with regard to the searching terms “immune checkpoint inhibitor, immunotherapy, hyperthermia, ablation, photothermal therapy”.
Results
By reviewing the literature, we analyzed how hyperthermia influences tumor immunology and improves the efficacy of ICI. Hyperthermia can trigger a series of multifactorial molecular cascade reactions between tumors and immunization and can significantly induce cytological modifications within the tumor microenvironment (TME). The pharmacological potency of ICIs can be enhanced greatly through the immunomodulatory amelioration of immunosuppression, and the activation of immunostimulation. Emerging clinical trials outcome regarding HIT have verified and enriched the theoretical foundation of synergistic sensitization.
Conclusion
HIT research is now starting to transition from preclinical studies to clinical investigations. Several HIT sensitization mechanisms have been reflected and demonstrated as significant survival benefits for patients through pioneering clinical trials. Further studies into the theoretical basis and practical standards of HIT, combined with larger‐scale clinical studies involving more cancer types, will be necessary for the future
Our review analyses and discusses the recent basic research and clinical application of hyperthermia combined with immune checkpoint inhibitors for malignant tumors treatment. And the development tendency of this therapy is set forth constructively, which aims to provide a helpful guide to follow‐up practice.
PDF
