Adipocytes play important roles in regulating cardiovascular health and disease. However, the molecular mechanism underlying the endocrine role of brown adipose tissue (BAT) in pathological cardiac ...remodeling remains unknown. Herein we show that adenosine A2A receptor (A2AR) knockout (A2ARKO) causes interscapular BAT (iBAT) dysfunction, leading to accelerated cardiac remodeling in hypertension compared with wild-type (WT) mice. Surgical iBAT depletion induces dramatic cardiac remodeling in WT but not in A2ARKO hypertensive mice. AMPK/PGC1α signaling-induced fibroblast growth factor 21 (FGF21) in brown adipocytes is required for A2AR-mediated inhibition of hypertensive cardiac remodeling. Recombinant FGF21 administration improves cardiac remodeling in iBAT-depleted hypertensive mice. More importantly, brown adipocyte-specific A2ARKO inhibits FGF21 production and accelerates cardiac damage in hypertension. Consistently, brown adipocyte-specific FGF21 knockout abolishes the effects of A2AR agonism in attenuating hypertensive cardiac remodeling. Our findings reveal a distinctive endocrine role of BAT in hypertensive cardiac remodeling via activating A2AR/FGF21 pathway.
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•Brown adipocyte is a direct target of A2AR in hypertension•A2AR activation promotes FGF21 in brown adipocytes•A2AR/FGF21 axis provides a link between brown adipocyte and cardiac remodeling
Ruan et al. uncover a direct crosstalk between brown adipose tissue (BAT) and the heart. Adenosine A2A receptor (A2AR) signaling in BAT mediates the release of the batokine, FGF21, which prevents hypertension-related cardiac damage.
Pre‐eclampsia (PE) is a life‐threatening multisystem disorder leading to maternal and neonatal mortality and morbidity. Emerging evidence showed that activation of the complement system is implicated ...in the pathological processes of PE. However, little is known about the detailed cellular and molecular mechanism of complement activation in the development of PE. In this study, we reported that complement 5a (C5a) plays a pivotal role in aberrant placentation, which is essential for the onset of PE. We detected an elevated C5a deposition in macrophages and C5a receptor (C5aR) expression in trophoblasts of pre‐eclamptic placentas. Further study showed that C5a stimulated trophoblasts towards an anti‐angiogenic phenotype by mediating the imbalance of angiogenic factors such as soluble fms‐like tyrosine kinase 1 (sFlt1) and placental growth factor (PIGF). Additionally, C5a inhibited the migration and tube formation of trophoblasts, while, C5aR knockdown with siRNA rescued migration and tube formation abilities. We also found that maternal C5a serum level was increased in women with PE and was positively correlated with maternal blood pressure and arterial stiffness. These results demonstrated that the placental C5a/C5aR pathway contributed to the development of PE by regulating placental trophoblasts dysfunctions, suggesting that C5a may be a novel therapeutic possibility for the disease.
The accumulation of palmitic acid (PA), implicated in obesity, can induce apoptotic cell death and inflammation of astrocytes. Caveolin-1 (Cav-1), an essential protein for astrocytes survival, can be ...degraded by autophagy, which is a double-edge sword that can either promote cell survival or cell death. The aim of this study was to delineate whether the autophagic degradation of Cav-1 is involved in PA-induced apoptosis and inflammation in hippocampal astrocytes. In this study we found that: (1) PA caused apoptotic death and inflammation by autophagic induction; (2) Cav-1 was degraded by PA-induced autophagy and PA induced autophagy in a Cav-1-independent manner; (3) the degradation of Cav-1 was responsible for PA-induced autophagy-dependent apoptotic cell death and inflammation; (4) chronic high-fat diet (HFD) induced Cav-1 degradation, apoptosis, autophagy, and inflammation in the hippocampal astrocytes of rats. Our results suggest that the autophagic degradation of Cav-1 contributes to PA-induced apoptosis and inflammation of astrocytes. Therefore, Cav-1 may be a potential therapeutic target for central nervous system injuries caused by PA accumulation.
Aging is an independent risk factor for vascular diseases. Perivascular adipose tissue (PVAT), an active component of the vasculature, contributes to vascular dysfunction during aging. Identification ...of underlying cell types and their changes during aging may provide meaningful insights regarding the clinical relevance of aging‐related vascular diseases. Here, we take advantage of single‐cell RNA sequence to characterize the resident stromal cells in the PVAT (PVASCs) and identified different clusters between young and aged PVASCs. Bioinformatics analysis revealed decreased endothelial and brown adipogenic differentiation capacities of PVASCs during aging, which contributed to neointimal hyperplasia after perivascular delivery to ligated carotid arteries. Mechanistically, in vitro and in vivo studies both suggested that aging‐induced loss of peroxisome proliferator‐activated receptor‐γ coactivator‐1 α (PGC1α) was a key regulator of decreased brown adipogenic differentiation in senescent PVASCs. We further demonstrated the existence of human PVASCs (hPVASCs) and overexpression of PGC1α improved hPVASC delivery‐induced vascular remodeling. Our finding emphasizes that differentiation capacities of PVASCs alter during aging and loss of PGC1α in aged PVASCs contributes to vascular remodeling via decreased brown adipogenic differentiation.
Loss of peroxisome proliferator‐activated receptor‐γ coactivator‐1 α (PGC1α) in aged PVASCs showed decreased endothelial and adipogenic differentiation, especially brown adipocyte generation, which contribute to neointimal hyperplasia after injured arteries.
Modulating the magnetic anisotropy of ferromagnetic thin films is crucial for constructing high-density and energy efficient magnetic memory devices. Ta/W(N)/Co/Pt multilayers were deposited on ...silicon substrates by magnetron sputtering at room temperature. The influences of N dopant on the magnetic anisotropy of the multilayers were investigated by preparing the sample with N incorporation. The results indicate that when sputtering W target with only argon gas (Ar), Ta/W/Co/Pt sample shows in-plane magnetic anisotropy (IMA). When sputtering W target at a different amount of N
2
and Ar atmosphere, it can induce perpendicular magnetic anisotropy (PMA) for proper N-doped Ta/W(N)/Co/Pt sample. When the gas flow ratio of Ar:N
2
is 16:6, the effective magnetic anisotropy constant reach its maximum value of 1.68 × 10
5
J·m
−3
, which enhanced by about 400% than our past works (annealing treatment is necessary to induce PMA in Pt/Co/MgO system). X-ray diffraction (XRD) and X-ray reflection (XRR) results demonstrate that N dopants can effectively promote the formation of β-W phase and reduce the roughness of W(N)/Co interface, which are beneficial for PMA. X-ray electron spectroscopy (XPS) analysis reveals that N doping redistributes Co charges, nitrogen ions participate in electron allocation of Co and attract some electrons of Co to form orbital hybridization between Co 3d and N 2p. This may be another important reason for the PMA formation.
Graphic abstract
The abnormally hyperphosphorylated tau is thought to be implicated in diabetes-associated cognitive deficits. The role of mammalian target of rapamycin (mTOR) / S6 kinase (S6K) signalling in the ...formation of tau hyperphosphorylation has been previously studied. Caveolin-1 (Cav-1), the essential structure protein of caveolae, promotes neuronal survival and growth, and inhibits glucose metabolism. In this study, we aimed to investigate the role of Cav-1 in the formation of tau hyperphosphorylation under chronic hyperglycemic condition (HGC). Diabetic rats were induced by streptozotocin (STZ). Primary hippocampal neurons with or without molecular intervention such as the transient over-expression or knock-down were subjected to HGC. The obtained experimental samples were analyzed by real time quantitative RT-PCR, Western blot, immunofluorescence or immunohistochemisty. We found: 1) that a chronic HGC directly decreases Cav-1 expression, increases tau phosphorylation and activates mTOR/S6K signalling in the brain neurons of diabetic rats, 2) that overexpression of Cav-1 attenuates tau hyperphosphorylation induced by chronic HGC in primary hippocampal neurons, whereas down-regulation of Cav-1 using Cav-1 siRNA dramatically worsens tau hyperphosphorylation via mTOR/S6K signalling pathway, and 3) that the down-regulation of Cav-1 induced by HGC is independent of mTOR signalling. Our results suggest that tau hyperphosphorylation and the sustained over-activated mTOR signalling under hyperglycemia may be due to the suppression of Cav-1. Therefore, Cav-1 is a potential therapeutic target for diabetes-induced cognitive dysfunction.
ABSTRACT
Perivascular adipose tissue (PVAT)‐derived adiponectin (APN) is a secreted adipokine that protects against hypertension‐related cardiovascular injury. However, the regulation of APN ...expression in hypertension remains to be explored. In this study, we demonstrated that down‐regulation of APN was associated with complement activation in the PVAT of desoxycorticosterone acetate (DOCA)‐salt hypertensive mice. Complement 3‐deficient hypertensive mice were protected from ANP decrease in the PVAT. APN deficiency blockaded the protective effects of complement inhibition against hypertensive vascular injury. Mechanistically, complement 5a (C5a)‐induced TNF‐α secretion from macrophages is required for inhibiting APN expression in adipocytes. Macrophage depletion reversed C5a agonist peptide‐induced TNF‐α up‐regulation and APN down‐regulation in the PVAT of DOCA mice. Moreover, we detected increased macrophage infiltration and C5a expression associated with decreased APN expression in adipose tissue from patients with aldosterone‐producing adenoma. These results identify a novel interaction between macrophages and adipocytes in the PVAT, where complement‐mediated inhibition of APN acts as a potential risk factor for hypertensive vascular inflammation.—Ruan, C.‐C., Ma, Y., Ge, Q., Li, Y., Zhu, L.‐M., Zhang, Y., Kong, L.‐R., Wu, Q‐H., Li, F., Cheng, L., Zhao, A. Z., Zhu, D.‐L., Gao, P.‐J. Complement‐mediated inhibition of adiponectin regulates perivascular inflammation and vascular injury in hypertension. FASEB J. 31, 1120–1129 (2017). www.fasebj.org
Gastric cancer (GC) ranks fifth in global cancer incidence and third in mortality rate among all cancer types. Circular RNAs (circRNAs) have been extensively demonstrated to regulate multiple ...malignant biological behaviors in GC. Emerging evidence suggests that several circRNAs derived from FNDC3B play pivotal roles in cancer. However, the role of circFNDC3B in GC remains elusive.
We initially screened circFNDC3B with translation potential via bioinformatics algorithm prediction. Subsequently, Sanger sequencing, qRT-PCR, RNase R, RNA-FISH and nuclear-cytoplasmic fractionation assays were explored to assess the identification and localization of circ0003692, a circRNA derived from FNDC3B. qRT-PCR and ISH were performed to quantify expression of circ0003692 in human GC tissues and adjacent normal tissues. The protein-encoding ability of circ0003692 was investigated through dual-luciferase reporter assay and LC/MS. The biological behavior of circ0003692 in GC was confirmed via in vivo and in vitro experiments. Additionally, Co-IP and rescue experiments were performed to elucidate the interaction between the encoded protein and c-Myc.
We found that circ0003692 was significantly downregulated in GC tissues. Circ0003692 had the potential to encode a novel protein FNDC3B-267aa, which was downregulated in GC cells. We verified that FNDC3B-267aa, rather than circ0003692, inhibited GC migration in vitro and in vivo. Mechanistically, FNDC3B-267aa directly interacted with c-Myc and promoted proteasomal degradation of c-Myc, resulting in the downregulation of c-Myc-Snail/Slug axis.
Our study revealed that the novel protein FNDC3B-267aa encoded by circ0003692 suppressed GC metastasis through binding to c-Myc and enhancing proteasome-mediated degradation of c-Myc. The study offers the potential applications of circ0003692 or FNDC3B-267aa as therapeutic targets for GC.
Fiber-optic distributed acoustic sensing (DAS) has proven to be a revolutionary technology for the detection of seismic and acoustic waves with ultralarge scale and ultrahigh sensitivity, and is ...widely used in oil/gas industry and intrusion monitoring. Nowadays, the single-frequency laser source in DAS becomes one of the bottlenecks limiting its advance. Here, we report a dual-comb-based coherently parallel DAS concept, enabling linear superposition of sensing signals scaling with the comb-line number to result in unprecedented sensitivity enhancement, straightforward fading suppression, and high-power Brillouin-free transmission that can extend the detection distance considerably. Leveraging 10-line comb pairs, a world-class detection limit of 560 fε/√Hz@1 kHz with 5 m spatial resolution is achieved. Such a combination of dual-comb metrology and DAS technology may open an era of extremely sensitive DAS at the fε/√Hz level, leading to the creation of next-generation distributed geophones and sonars.
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