Aims
Activation of transient receptor potential vanilloid type-1 (TRPV1) channels may affect lipid storage and the cellular inflammatory response. Now, we tested the hypothesis that activation of ...TRPV1 channels attenuates atherosclerosis in apolipoprotein E knockout mice (ApoE−/−) but not ApoE−/−TRPV1−/− double knockout mice on a high-fat diet.
Methods and results
Both TRPV1 mRNA and protein expression were identified in vascular smooth muscle cells (VSMC) and in aorta from C57BL/6J mice using RT-PCR, immunoblotting, and immunohistochemistry. In vitro, activation of TRPV1 by the specific agonists capsaicin and resiniferatoxin dose-dependently increased cytosolic calcium and significantly reduced the accumulation of lipids in VSMC from C57BL/6J mice but not from TRPV1−/− mice. TRPV1 activation increased ATP-binding cassette transporter A1 (ABCA1) expression and reduced low-density lipoprotein-related protein 1 (LRP1) expression in VSMC by calcium-dependent and calcineurin- and protein kinase A-dependent mechanisms. These results showed increased cellular cholesterol efflux and reduced cholesterol uptake. In vivo, long-term activation of TRPV1 by capsaicin for 24 weeks increased ABCA1 and reduced LRP1 expression in aorta from ApoE−/− mice on a high-fat diet. Long-term activation of TRPV1 significantly reduced lipid storage and atherosclerotic lesions in the aortic sinus and in the thoracoabdominal aorta from ApoE−/− mice but not from ApoE−/−TRPV1−/− mice on a high-fat diet. These findings indicated that TRPV1 activation ameliorates high-fat diet-induced atherosclerosis.
Conclusion
Activation of TRPV1 may be a novel therapeutic tool to attenuate atherosclerosis caused by a high-fat diet.
Aberrant proliferation of vascular smooth muscle cells (VSMC) is a critical contributor to the pathogenesis of atherosclerosis (AS). Our previous studies have demonstrated that apelin‐13/APJ confers ...a proliferative response in VSMC, however, its underlying mechanism remains elusive. In this study, we aimed to investigate the role of mitophagy in apelin‐13‐induced VSMC proliferation and atherosclerotic lesions in apolipoprotein E knockout (ApoE‐/‐) mice. Apelin‐13 enhances human aortic VSMC proliferation and proliferative regulator proliferating cell nuclear antigen expression in dose and time‐dependent manner, while is abolished by APJ antagonist F13A. We observe the engulfment of damage mitochondria by autophagosomes (mitophagy) of human aortic VSMC in apelin‐13 stimulation. Mechanistically, apelin‐13 increases p‐AMPKα and promotes mitophagic activity such as the LC3I to LC3II ratio, the increase of Beclin‐1 level and the decrease of p62 level. Importantly, the expressions of PINK1, Parkin, VDAC1, and Tom20 are induced by apelin‐13. Conversely, blockade of APJ by F13A abolishes these stimulatory effects. Human aortic VSMC transfected with AMPKα, PINK1, or Parkin and subjected to apelin‐13 impairs mitophagy and prevents proliferation. Additional, apelin‐13 not only increases the expression of Drp1 but also reduces the expressions of Mfn1, Mfn2, and OPA1. Remarkably, the mitochondrial division inhibitor‐1(Mdivi‐1), the pharmacological inhibition of Drp1, attenuates human aortic VSMC proliferation. Treatment of ApoE‐/‐ mice with apelin‐13 accelerates atherosclerotic lesions, increases p‐AMPKα and mitophagy in aortic wall in vivo. Finally, PINK1‐/‐ mutant mice with apelin‐13 attenuates atherosclerotic lesions along with defective in mitophagy. PINK1/Parkin‐mediated mitophagy promotes apelin‐13‐evoked human aortic VSMC proliferation by activating p‐AMPKα and exacerbates the progression of atherosclerotic lesions.
PINK1/Parkin‐mediated mitophagy promotes apelin‐13‐induced human aortic vascular smooth muscle cell proliferation through activating AMPKα in vitro. Mitophagy exacerbates atherosclerotic lesions of ApoE‐/‐ mice with apelin‐13 stimulation in vivo. Apelin‐13 also increases mitochondrial fission and decreases mitochondrial fusion via AMPKα, thus contributing to the regulation of mitochondrial dynamics. PINK1 deficiency results in defective mitophagy and attenuates vascular smooth muscle cells (VSMC) proliferation induced by apelin‐13. AMPKα‐PINK1‐Parkin axis plays a crucial role in apelin‐13‐induced human aortic VSMC proliferation and atherosclerotic plaques in vitro and in vivo, and consequently atherosclerosis.
Background Circular RNAs (circRNAs) have been considered as pivotal biomarkers in Diabetic nephropathy (DN). CircRNA ARP2 actin-related protein 2 homolog (circ-ACTR2) could promote the HG-induced ...cell injury in DN. However, how circ-ACTR2 acts in DN is still unclear. This study aimed to explore the molecular mechanism of circ-ACTR2 in DN progression, intending to provide support for the diagnostic and therapeutic potentials of circ-ACTR2 in DN. Methods RNA expression analysis was conducted by the quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Cell growth was measured via Cell Counting Kit-8 and EdU assays. Inflammatory response was assessed by Enzyme-linked immunosorbent assay. The protein detection was performed via western blot. Oxidative stress was evaluated by the commercial kits. The molecular interaction was affirmed through dual-luciferase reporter and RNA immunoprecipitation assays. Results Circ-ACTR2 level was upregulated in DN samples and high glucose (HG)-treated human renal mesangial cells (HRMCs). Silencing the circ-ACTR2 expression partly abolished the HG-induced cell proliferation, inflammation and extracellular matrix accumulation and oxidative stress in HRMCs. Circ-ACTR2 was confirmed as a sponge for miR-205-5p. Circ-ACTR2 regulated the effects of HG on HRMCs by targeting miR-205-5p. MiR-205-5p directly targeted high-mobility group AT-hook 2 (HMGA2), and HMGA2 downregulation also protected against cell injury in HG-treated HRMCs. HG-mediated cell dysfunction was repressed by miR-205-5p/HMGA2 axis. Moreover, circ-ACTR2 increased the expression of HMGA2 through the sponge effect on miR-205-5p in HG-treated HRMCs. Conclusion All data have manifested that circ-ACTR2 contributed to the HG-induced DN progression in HRMCs by the mediation of miR-205-5p/HMGA2 axis. Keywords: Circ-ACTR2, Renal mesangial cells, Diabetic nephropathy, miR-205-5p, HMGA2
The heavy-duty moving average window (MAW) method, used for heavy-duty diesel vehicle (HDDV) real driving emission certification, has been long criticized for its unreasonable results. To ...quantitively analyze the problem, causes, and impacts of the MAW method, five China VI HDDVs were tested under real driving conditions. The specific method and MAW method with different boundaries are applied for data analysis. The results illustrate that cold start occupied 40.82 ± 11.22% of the total NOx emission within 5.77 ± 1.21% of the duration. Compared to the specific method, the MAW result gap is observed varying from −16.92% to 100.24% and didn’t show any pattern. Three reasons could explain biased MAW results: the 20% power threshold excludes the cold data; the 90th accumulative percentile window brings large uncertainty to the result and leaves the highest 10% window without supervision; the initial data gets low utilization. The MAW method could lead to ineffective NOx supervision and exhaust cheating. The future emission limits and emission inventories based on these results are also less reasonable. The above-discussed three reasons and the cold start data exclusion should be considered together to consummate the MAW method. These results could be used for future emission legislation and NOx control optimization.
•China VI heavy-duty moving average window (MAW) method was evaluated quantitatively.•The cold-start occupied 40.82 ± 11.83% of the total NOx within 5.77 ± 1.34% of the duration.•The MAW method weakens the real driving tests due to its ineffective NOx supervision.•The power threshold and 90th percentile window bring large uncertainty to the result.•The MAW boundaries are closely coupled and they should be reconsidered together.
Various environmental stresses strongly influence plant development. Among these stresses is drought, which is a serious threat that can reduce agricultural productivity and obstruct plant growth. ...Although the mechanism of plants in response to drought has been studied extensively, the adaptive strategies of
Amygdalus mira
(
Koehne
) Yü et Lu grown in drought and rewatered habitats remain undefined.
Amygdalus mira
from the Tibetan Plateau has outstanding nutritional and medicinal values and can thrive in extreme drought. In this study, the physiological and proteomic responses in leaves of
A. mira
were investigated during drought and recovery period. The changes in plant growth, photosynthesis, enzymes, and non-enzymatic antioxidant under drought and rewatering were also analyzed in leaves. Compared with controls,
A. mira
showed stronger adaptive and resistant characteristics to drought. In addition, the proteomic technique was also used to study drought tolerance mechanisms in
A. mira
leaves. Differentially expressed proteins were identified using mass spectrometry. Accordingly, 103 proteins involved in 10 functional categories: cytoskeleton dynamics, energy metabolism, carbohydrate metabolism, photosynthesis, transcription and translation, transport, stress and defense, molecular chaperones, other materials metabolism, and unknown function were identified. These results showed that an increase of stress-defense-related proteins in leaves after drought treatment contributed to coping with drought. Importantly,
A. mira
developed an adaptive mechanism to scavenge reactive oxygen species (ROS), including enhancing antioxidant enzyme activities and non-enzymatic antioxidant contents, reducing energy, and adjusting the efficiency of gas exchanges. These results may help to understand the acclimation of
A. mira
to drought.
Flower bud development is a defining feature of walnut, which contributes to the kernel yield, yield stability, fruit quality and commodity value. However, little is known about the mechanism of the ...flower bud development in walnut. Here, the stages of walnut female flower bud development were divided into five period (P01-05) by using histological observation. They were further studied through PacBio Iso-Seq and RNA-seq analysis. Accordingly, we obtained 52,875 full-length transcripts, where 4,579 were new transcripts, 3,065 were novel genes, 1,437 were consensus lncRNAs and 20,813 were alternatively spliced isoforms. These transcripts greatly improved the current genome annotation and enhanced our understanding of the walnut transcriptome. Next, RNA sequencing of female flower buds at five periods revealed that circadian rhythm-plant was commonly enriched along with the flower bud developmental gradient. A total of 14 differentially expressed genes (DEGs) were identified, and six of them were confirmed by real-time quantitative analysis. Additionally, six and two differentially expressed clock genes were detected to be regulated by AS events and lncRNAs, respectively. All these detected plant circadian genes form a complex interconnected network to regulate the flower bud development. Thus, investigation of key genes associated with the circadian clock could clarify the process of flower bud development in walnut.
Primary central nervous system lymphoma (PCNSL) is a rare type of extra-nodal non-Hodgkin lymphoma, but the prognostic value of blood parameters indicating systemic inflammation and nutritional ...status remains unknown. We aim to explore the prognostic role of blood parameters in PCNSL.
All PCNSL patients diagnosed at West China Hospital between February 2011 and February 2020 were retrospectively screened. For patients who were initially treated with high-dose methotrexate (HD-MTX)-based therapy, clinical data were collected. Survival analyses were performed using the Kaplan-Meier method and multivariable Cox proportional regression. The accuracies of different multivariate models were assessed by Harrell's
statistical analysis (
-index).
Sixty patients were included. Median overall survival (OS) was 4.8 ± 3.7 years, and median progression-free survival (PFS) was 1.9 ± 1.3 years. In the multivariate analysis, hemoglobin (Hb) (HR 3.940,
= 0.013), neutrophil-lymphocyte ratio (NLR) (HR 10.548,
= 0.034), and total bilirubin (TBIL) (HR 3.429,
= 0.004) had independent prognostic values for PFS, while lymphocyte-monocyte ratio (LMR) (HR 6.195,
= 0.039), systemic immune-inflammation index (SII) (HR 5.144,
= 0.012), and TBIL (HR 3.892,
= 0.009) were independently related to OS. The
-index of the Memorial Sloan-Kettering Cancer Center (MSKCC) score increased from 0.57 to 0.72 when SII and TBIL were combined.
Our study indicated that pretreatment Hb, NLR, SII, LMR, and TBIL were convenient prognostic factors in PCNSL. Adding SII and TBIL to the MSKCC score can better predict the survival of PCNSL based on HD-MTX regimens.
In this study, we report atomically precise gold nanoclusters-embedded natural polysaccharide carrageenan as a novel hydrogel platform for single near-infrared light-triggered photothermal (PTT) and ...photodynamic (PDT) antibacterial therapy. Briefly, atomically precise captopril-capped Au nanoclusters (Au25Capt18) prepared by an alkaline NaBH4 reduction method and then embedded them into the biosafe carrageenan to achieve superior PTT and PDT dual-mode antibacterial effect. In this platform, the embedded Au25Capt18, as simple-component phototherapeutic agents, exhibit superior thermal effects and singlet oxygen generation under a single near-infrared (NIR, 808 nm) light irradiation, which enables rapid elimination of bacteria. Carrageenan endows the hydrogel platform with superior gelation characteristics and wound microenvironmental regulation. The Au25Capt18-embedded hydrogels exhibited good water retention, hemostasis, and breathability, providing a favorable niche environment for promoting wound healing. In vitro experiments confirmed the excellent antibacterial activity of the Au25Capt18 hydrogels against Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli. The antibacterial effect and promoting wound healing function were further validated in a S. aureus-infected wound model. Biosafety evaluation showed that the Au25Capt18 hydrogel has excellent biocompatibility. This PTT/PDT dual-mode therapy offers an alternative strategy for battling bacterial infections without antibiotics. More importantly, this hydrogel is facile to prepare which is helpful for expanding applications.
•A novel Au25Capt18 hydrogel with superior PTT and PDT dual-mode antibacterial effect was demonstrated.•The photothermal conversion efficiency of Au25Capt18 is as high as 34.4 %.•The contribution of PTT to antibacterial elimination is more significant than that of PDT in Au25Capt18 hydrogels.•Wound healing experiment in vivo confirms the antibacterial effect and biocompatibility.
Early prediction of recurrence and death risks is significant to the treatment of hepatocellular carcinoma (HCC) patients. We aimed to develop and validate prognosis nomogram models based on the ...gamma-glutamyl transpeptidase (GGT)-to-platelet (PLT) ratio (GPR) for HCC and to explore the relationship between the GPR and inflammation-related signaling pathways.
All data were obtained from 2000 to 2012 in the Affiliated Hospital of Qingdao University. In the training cohort, factors included in the nomograms were determined by univariate and multivariate analyses. In the training and validation cohorts, the concordance index (C-index) and calibration curves were used to assess predictive accuracy, and receiver operating characteristic curves were used to assess discriminative ability. Clinical utility was evaluated using decision curve analysis. Moreover, improvement of the predictive accuracy of the nomograms was evaluated by calculating the decision curve analysis, the integrated discrimination improvement, and the net reclassification improvement. Finally, the relationship between the GPR and inflammation-related signaling pathways was evaluated using the independent-samples t-test.
A larger tumor size and higher GPR were common independent risk factors for both disease-free survival (DFS) and overall survival (OS) in HCC (P < 0.05). Good agreement between our nomogram models' predictions and actual observations was detected by the C-index and calibration curves. Our nomogram models showed significantly better performance in predicting the HCC prognosis compared to other models (P < 0.05). Online webserver and scoring system tables were built based on the proposed nomogram for convenient clinical use. Notably, including the GPR greatly improved the predictive ability of our nomogram models (P < 0.05). In the validation cohort, p38 mitogen-activated protein kinase (P38MAPK) expression was significantly negatively correlated with the GPR (P < 0.01) and GGT (P = 0.039), but was not correlated with PLT levels (P = 0.063). And we found that P38MAPK can regulate the expression of GGT by quantitative real-time PCR and Western blotting experiments.
The dynamic nomogram based on the GPR provides accurate and effective prognostic predictions for HCC, and P38MAPK-GGT may be a suitable therapeutic target to improve the prognosis of HCC patients.
Wild germplasm resources are crucial for gene mining and molecular breeding because of their special trait performance. Haplotype-resolved genome is an ideal solution for fully understanding the ...biology of subgenomes in highly heterozygous species. Here, we surveyed the genome of a wild walnut tree from Gongliu County, Xinjiang, China, and generated a haplotype-resolved reference genome of 562.99 Mb (contig N50 = 34.10 Mb) for one haplotype (hap1) and 561.07 Mb (contig N50 = 33.91 Mb) for another haplotype (hap2) using PacBio high-fidelity (HiFi) reads and Hi-C technology. Approximately 527.20 Mb (93.64%) of hap1 and 526.40 Mb (93.82%) of hap2 were assigned to 16 pseudochromosomes. A total of 41039 and 39744 protein-coding gene models were predicted for hap1 and hap2, respectively. Moreover, 123 structural variations (SVs) were identified between the two haplotype genomes. Allele-specific expression genes (ASEGs) that respond to cold stress were ultimately identified. These datasets can be used to study subgenome evolution, for functional elite gene mining and to discover the transcriptional basis of specific traits related to environmental adaptation in wild walnut.
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