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•AEE is an effective antioxidant.•AEE might have no significant therapeutic effect on PQ-induced lung injury in rats.•AEE had a significant protective effect on PQ-induced lung injury ...in rats.•AEE could reduce the injury of A549 cells induced by PQ.
Paraquat (PQ) is an effective and commercially important herbicide that is widely used worldwide. However, PQ is highly toxic and can cause various complications and acute organ damage. Aspirin eugenol ester (AEE) is a potential new compound with anti-inflammatory and antioxidant stress pharmacological activity. The present study was to reveal the therapeutic effects and the protective effect of AEE against PQ-induced acute lung injury (ALI) with the help of PQ-induced oxidative damage in A549 cells and PQ-induced lung injury in rats. AEE might have no significant therapeutic effect on PQ-induced lung injury in rats. However, AEE had a significant protective effect on PQ-induced lung injury in rats. AEE pretreatment significantly reduced the stimulatory effect of PQ on malondialdehyde (MDA), the inhibitory effect of PQ on catalase (CAT) activity, superoxide dismutase (SOD) activity, glutathione peroxidase (GPx) activity, the ratio of GSH/GSSH, the activity of caspase-3 and the overexpression of p38 mitogen-activated protein kinase (MAPK) phosphorylation in vivo. In vitro, A549 cells were treated with 250 μM PQ for 24 h. Incubation of A549 cells with PQ led to apoptosis, and increased the level of superoxide anions, reactive oxygen species (ROS), malondialdehyde and the activity of caspase-3 and up-regulation of phosphorylated p38-MAPK, reduced mitochondrial membrane potential (ΔΨm) and the activity of SOD. However, after 24 h on AEE pretreatment of A549 cells, the above-mentioned adverse reactions caused by PQ were significantly alleviated. In addition, AEE pretreatment reduced p38-MAPK phosphorylation in PQ-treated A549 cells. SB203580, the specific p38-MAPK inhibitor, and p38-MAPK shRNA attenuated the activation of the p38-MAPK signaling pathway. N-acetylcysteine (NAC) reduced the level of phosphorylated p38-MAPK and the production of intracellular ROS and inhibited apoptosis. The results showed that AEE may inhibit PQ-induced cell damage through ROS/p38-MAPK-mediated mitochondrial apoptosis pathway.
Resveratrol has anti-inflammatory, anti-cancer, and anti-aging pharmacological activities. There is currently a gap in academic research regarding the uptake, transport, and reduction of H
O
-induced ...oxidative damage of resveratrol in the Caco-2 cell model. This study investigated the role of resveratrol in the uptake, transport, and alleviation of H
O
-induced oxidative damage in Caco-2 cells. In the Caco-2 cell transport model, it was observed that the uptake and transport of resveratrol (10, 20, 40, and 80 μM) were time dependent and concentration dependent. Different temperatures (37 °C vs. 4 °C) could significantly affect the uptake and transportation of resveratrol. The apical to basolateral transport of resveratrol was markedly reduced by STF-31, a GLUT1 inhibitor, and siRNA intervention. Furthermore, resveratrol pretreatment (80 μM) improves the viability of Caco-2 cells induced by H
O
. In a cellular metabolite analysis combined with ultra-high performance liquid chromatography-tandem mass spectrometry, 21 metabolites were identified as differentials. These differential metabolites belong to the urea cycle, arginine and proline metabolism, glycine and serine metabolism, ammonia recycling, aspartate metabolism, glutathione metabolism, and other metabolic pathways. The transport, uptake, and metabolism of resveratrol suggest that oral resveratrol could prevent intestinal diseases caused by oxidative stress.
Long‐term weightlessness in animals can cause changes in myocardial structure and function, in which mitochondria play an important role. Here, a tail suspension (TS) Kunming mouse (Mus musculus) ...model was used to simulate the effects of weightlessness on the heart. We investigated the effects of 2 and 4 weeks of TS (TS2 and TS4) on myocardial mitochondrial ultrastructure and oxidative respiratory function and on the molecular mechanisms of apoptosis and mitochondrial fission, autophagy and fusion‐related signalling. Our study revealed significant changes in the ultrastructural features of cardiomyocytes in response to TS. The results showed: (1) mitochondrial swelling and disruption of cristae in TS2, but mitochondrial recovery and denser cristae in TS4; (2) an increase in the total number of mitochondria and number of sub‐mitochondria in TS4; (3) no significant changes in the nuclear ultrastructure or DNA fragmentation among the two TS groups and the control group; (4) an increase in the bax/bcl‐2 protein levels in the two TS groups, indicating increased activation of the bax‐mediated apoptosis pathway; (5) no change in the phosphorylation ratio of dynamin‐related protein 1 in the two TS groups; (6) an increase in the protein levels of optic atrophy 1 and mitofusin 2 in the two TS groups; and (7) in comparison to the TS2 group, an increase in the phosphorylation ratio of parkin and the ratio of LC3II to LC3I in TS4, suggesting an increase in autophagy. Taken together, these findings suggest that mitochondrial autophagy and fusion levels increased after 4 weeks of TS, leading to a restoration of the bax‐mediated myocardial apoptosis pathway observed after 2 weeks of TS.
New Findings
What is the central question of this study?
What are the effects of 2 and 4 weeks of tail suspension on myocardial mitochondrial ultrastructure and oxidative respiratory function and on the molecular mechanisms of apoptosis and mitochondrial fission, autophagy and fusion‐related signalling?
What is the main finding and its importance?
Increased mitochondrial autophagy and fusion levels after 4 weeks of tail suspension help to reshape the morphology and increase the number of myocardial mitochondria.
Feeding is essential for animal survival and reproduction and is regulated by both internal states and external stimuli. However, little is known about how internal states influence the perception of ...external sensory cues that regulate feeding behavior. Here, we investigated the neuronal and molecular mechanisms behind nutritional state-mediated regulation of gustatory perception in control of feeding behavior in the brown planthopper and Drosophila. We found that feeding increases the expression of the cholecystokinin-like peptide, sulfakinin (SK), and the activity of a set of SK-expressing neurons. Starvation elevates the transcription of the sugar receptor Gr64f and SK negatively regulates the expression of Gr64f in both insects. Interestingly, we found that one of the two known SK receptors, CCKLR-17D3, is expressed by some of Gr64f-expressing neurons in the proboscis and proleg tarsi. Thus, we have identified SK as a neuropeptide signal in a neuronal circuitry that responds to food intake, and regulates feeding behavior by diminishing gustatory receptor gene expression and activity of sweet sensing GRNs. Our findings demonstrate one nutritional state-dependent pathway that modulates sweet perception and thereby feeding behavior, but our experiments cannot exclude further parallel pathways. Importantly, we show that the underlying mechanisms are conserved in the two distantly related insect species.
Oocyte quality is critical for the mammalian reproduction due to its necessity on fertilization and early development. During aging, the declined oocytes showing with organelle dysfunction and ...oxidative stress lead to infertility. AMP-activated protein kinase (AMPK) is a serine/threonine protein kinase which is important for energy homeostasis for metabolism. Little is known about the potential relationship between AMPK with oocyte aging.
In present study we reported that AMPK was related with low quality of oocytes under post ovulatory aging and the potential mechanism. We showed the altered AMPK level during aging and inhibition of AMPK activity induced mouse oocyte maturation defect. Further analysis indicated that similar with its upstream regulator PKD1, AMPK could reduce ROS level to avoid oxidative stress in oocytes, and this might be due to its regulation on mitochondria function, since loss of AMPK activity induced abnormal distribution, reduced ATP production and mtDNA copy number of mitochondria. Besides, we also found that the ER and Golgi apparatus distribution was aberrant after AMPK inhibition, and enhanced lysosome function was also observed.
Taken together, these data indicated that AMPK is important for the organelle function to reduce oxidative stress during oocyte meiotic maturation.
Aspirin eugenol ester (AEE) possesses anti-thrombotic, anti-atherosclerotic and anti-oxidative effects. The study aims to clarify the mechanism underlying the anti-atherosclerotic effects of AEE on ...vascular endothelial dysfunction. Both the high-fat diet (HFD)-induced atherosclerotic rat model and the H
O
-induced human umbilical vein endothelial cells (HUVECs) model were used to investigate the effects of AEE on vascular endothelial dysfunction. UPLC/QTOF-MS coupled with a multivariate data analysis method were used to profile the variations in the metabolites of HUVECs in response to different treatments. Pretreatment of HUVECs with AEE significantly ameliorated H
O
-induced apoptosis, the overexpression of E-selectin and VCAM-1, and the adhesion of THP-1 cells. Putative endogenous biomarkers associated with the inhibition of endothelial dysfunction were identified in HUVECs pretreated with AEE in the absence or presence of H
O
, and these biomarkers were involved in important metabolic pathways, including amino acid metabolism, carbohydrate metabolism, and glutathione metabolism. Moreover, in vivo, AEE also significantly reduced vascular endothelial dysfunction and decreased the overexpression of VCAM-1 and E-selectin. Based on our findings, the mechanism underlying the anti-atherosclerotic effects of AEE might be related to a reduction in vascular endothelial dysfunction mediated by ameliorating alterations in metabolism, inhibiting oxidative stress, and decreasing the expression of adhesion molecules.
The relationships between multiple visual rating scales based on structural magnetic resonance imaging (sMRI) with disease severity and cerebrospinal fluid (CSF) biomarkers in patients with ...Alzheimer’s disease (AD) were ambiguous. In this study, a total of 438 patients with clinically diagnosed AD were recruited. All participants underwent brain sMRI scan, and medial temporal lobe atrophy (MTA), posterior atrophy (PA), global cerebral atrophy-frontal sub-scale (GCA-F), and Fazekas rating scores were visually evaluated. Meanwhile, disease severity was assessed by neuropsychological tests such as the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Clinical Dementia Rating (CDR). Among them, 95 patients were tested for CSF core biomarkers, including Aβ
1–42
, Aβ
1–40
, Aβ
1–42/
Aβ
1–40
, p-tau, and t-tau. As a result, the GCA-F and Fazekas scales showed positively significant correlations with onset age (
r
= 0.181,
p
< 0.001;
r
= 0.411,
p
< 0.001, respectively). Patients with late-onset AD (LOAD) showed higher GCA-F and Fazekas scores (
p
< 0.001,
p
< 0.001). With regard to the disease duration, the MTA and GCA-F were positively correlated (
r
= 0.137,
p
< 0.05;
r
= 0.106,
p
< 0.05, respectively). In terms of disease severity, a positively significant association emerged between disease severity and the MTA, PA GCA-F, and Fazekas scores (
p
< 0.001,
p
< 0.001,
p
< 0.001,
p
< 0.05, respectively). Moreover, after adjusting for age, gender, and
APOE
alleles, the MTA scale contributed to moderate to severe AD in statistical significance independently by multivariate logistic regression analysis (
p
< 0.05). The model combining visual rating scales, age, gender, and
APOE
alleles showed the best performance for the prediction of moderate to severe AD significantly (AUC = 0.712, sensitivity = 51.5%, specificity = 84.6%). In addition, we observed that the MTA and Fazekas scores were associated with a lower concentration of Aβ
1–42
(
p
< 0.031,
p
< 0.022, respectively). In summary, we systematically analyzed the benefits of multiple visual rating scales in predicting the clinical status of AD. The visual rating scales combined with age, gender, and
APOE
alleles showed best performance in predicting the severity of AD. MRI biomarkers in combination with CSF biomarkers can be used in clinical practice.
Recent findings found that TiO2 nanoparticles (TiO2-NPs) have male reproductive toxicity. However, few reports have studied the toxicity of TiO2-NPs in crustaceans. In this study, we first chose the ...freshwater crustacean Eriocheir sinensis (E. sinensis) to explore the male toxicity of TiO2-NP exposure and the underlying mechanisms. Three nm and 25 nm TiO2-NPs at a dose of 30 mg/kg bw induced apoptosis and damaged the integrity of the haemolymph-testis-barrier (HTB, a structure similar to the blood-testis-barrier) and the structure of the seminiferous tubule. The 3-nm TiO2-NPs caused more severe spermatogenesis dysfunction than the 25-nm TiO2-NPs. We initially confirmed that TiO2-NP exposure affected the expression patterns of adherens junctions (α-catenin and β-catenin) and induced tubulin disorganization in the testis of E. sinensis. TiO2-NP exposure caused reactive oxygen species (ROS) generation and an imbalance of mTORC1-mTORC2 (mTORC1/rps6/Akt levels were increased, while mTORC2 activity was not changed). After using the ROS scavenger NAC to inhibit ROS generation, both the mTORC1-mTORC2 imbalance and alterations in AJs were rescued. More importantly, the mTORC1 inhibitor rapamycin abolished mTORC1/rps6/Akt hyperactivation and partially restored the alterations in AJs and tubulin. Collectively, the mTORC1-mTORC2 imbalance induced by TiO2-NPs was involved in the mechanism of AJ and HTB disruption, resulting in spermatogenesis in E. sinensis.
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•Exposure to TiO2-NPs disrupted the haemolymph-testis-barrier.•Exposure to TiO2-NPs changed the expression patterns of adhesion junctions.•ROS were the initiating factor of AJ and HTB impairment.•The mTORC1/rps6/Akt cascade signalling involved in AJ and HTB disruption.
Abstract
Background
Anterolateral thigh (ALT) free flap and jejunal flap (JF) were commonly used in tissue reconstruction for pharyngoesophageal squamous cell carcinoma (PESCC) with worsening tissue ...adhesion and necrosis after radiotherapy failure. However, the results of tissue reconstruction and postoperative complications of these two flaps are controversial. The purpose of this study was to compare outcomes between group ALT free flap and group JF in PESCC after radiotherapy failure.
Methods
Intraoperative information and postoperative outcomes of patients with PESCC after radiotherapy failure who underwent ALT and JF reconstruction from January 2005 to December 2019 were compared and analyzed.
Results
The defect size of ALT (Numbers, 34) and JF (Numbers, 31) was 36.19 ± 11.35 cm
2
and 35.58 ± 14.32 cm
2
(p = 0.884), respectively. ALT and JF showed no significant difference in operation time (p = 0.683) and blood loss (p = 0.198). For postoperative outcomes within 30 days both in recipient site and donor site including wound bleeding, wound dehiscence, wound infection, and pharyngocutaneous fistula, ALT free flap and JF showed similar results. Flap compromise (Numbers, 2 VS.3, p = 0.663), flap take backs (Numbers, 1 VS.1, p = 1.000), partial flap failures (Numbers, 4 VS.2, p = 0.674), and total flap failures (Numbers, 0 VS.0, p = 1.000) showed no difference between the two groups. In addition, no significance was found in hypoproteinemia between the two groups (Numbers, 4 VS.2, p = 0.674). ALT free flap was not statistically different from JF in the incidence of dysphagia at the postoperative 6 months (Numbers of liquid diet, 5VS.5; Numbers of partial tube feeding, 6VS.7; Numbers of total tube feeding, 3VS.1, p = 0.790) and 12 months (Numbers of liquid diet, 8VS.7; Numbers of partial tube feeding, 8VS.7; Numbers of total tube feeding, 5VS.5, p = 0.998). The cause of dysphagia not found to differ between the two groups both in postoperative 6 months (p = 0.814) and 12 months (p = 0.845).
Conclusion
Compared with JF, ALT free flap for PESCC patients after radiotherapy failure showed similar results in postoperative outcomes. ALT free flap may serve as a safe and feasible alternative for PESCC patients after radiotherapy failure.
The spikelet number per spike (SNS) contributes greatly to grain yield in wheat. Identifying various genes that control wheat SNS is vital for yield improvement. This study used a recombinant inbred ...line population genotyped by the Wheat55K single-nucleotide polymorphism array to identify two major and stably expressed quantitative trait loci (QTLs) for SNS. One of them (QSns.sau-2SY-2D.1) was reported previously, while the other (QSns.sau-2SY-7A) was newly detected and further analyzed in this study. QSns.sau-2SY-7A had a high LOD value ranging from 4.46 to 16.00 and explained 10.21–40.78％ of the phenotypic variances. QSns.sau-2SY-7A was flanked by the markers AX-110518554 and AX-110094527 in a 4.75-cM interval on chromosome arm 7AL. The contributions and interactions of both major QTLs were further analyzed and discussed. The effect of QSns.sau-2SY-7A was successfully validated by developing a tightly linked kompetitive allele specific PCR marker in an F2:3 population and a panel of 101 high-generation breeding wheat lines. Furthermore, several genes including the previously reported WHEAT ORTHOLOG OF APO1 (WAPO1), an ortholog of the rice gene ABERRANT PANICLE ORGANIZATION 1 (APO1) related to SNS, were predicted in the interval of QSns.sau-2SY-7A. In summary, these results revealed the genetic basis of the multi-spikelet genotype of wheat line 20828 and will facilitate subsequent fine mapping and breeding utilization of the major QTLs.
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