CCR2 has been proven to play an important role in diabetes. However, the role of CCR2 in diabetic cardiomyopathy has not been examined. In this study, we investigated the effects of cardiac CCR2 on ...diabetic cardiomyopathy. We created a model of streptozotocin (STZ)-induced diabetic cardiomyopathy. Expression of CCR2 was upregulated in the hearts of STZ-induced diabetic mice. CCR2 knockout significantly improved STZ-induced cardiac dysfunction and fibrosis. Moreover, deletion of CCR2 inhibited STZ-induced apoptosis and the production of STZ-induced reactive oxygen species in the heart. CCR2 knockout resulted in M2 polarization in hearts of STZ-treated mice. Treatment with a CCR2 inhibitor reversed hyperglycemia-induced cardiac dysfunction in
mice. These results suggest that CCR2-induced inflammation and oxidative stress in the heart are involved in the development of diabetic cardiomyopathy and that CCR2 could be a novel target for therapy.
A series of mixed lanthanide metal-organic frameworks: (EuxTb1-x)2(TDC)3(CH3OH)2·(CH3OH) ((abbreviated as EuxTb1-x-MOFs, x = 0.5, 0.067, 0.05, 0.01, 0.00833, 0.00667, 0.005, x represents the molar ...ratio of Eu in the total amounts), H2TDC = 2, 5-thiophenedicarboxylic acid) have been prepared under solvothermal condition by adjusting the molar ratio of Eu3+ to Tb3+ ions. The emission colors of EuxTb1-x-MOFs have been tuned by controlling the molar ratio of Eu3+/Tb3+ and changing the excitation wavelength. Fortunately, a white light-emitting material Eu0.00667Tb0.99333-MOF has been obtained at the excitation wavelength of 350 nm. The CIE coordinate of (0.3333, 0.3394) is very close to the standardized coordinate for pure white light (0.3333, 0.3333). Furthermore, the fluorescence sensing performance of Eu0.00667Tb0.99333-MOF for hazardous phenolic compounds and physiological temperature were tested upon excitation at 320 nm. The results reveal that Eu0.00667Tb0.99333-MOF can be used as a multi-target sensor for selective sensing β-naphthol and physiological temperature from 288 to 353 K with good sensing reproducibility.
Eu0.00667Tb0.99333-MOF with the white light emission is used as a multifunctional sensor for selective detection of β-naphthol and physiological temperature from 288 to 353 K with good sensing reproducibility. Display omitted
•The white light emission MOF was obtained by varying the co-doping ratio of Eu3+, Tb3+ ions and excitation wavelength.•The white light emission MOF can selectively detect β-naphthol and temperature with good sensing reproducibility.•As a sensor, the Eu0.00667Tb0.99333-MOF exhibits excellent stability and recyclability.
Resveratrol (RSV), a polyphenol, non‑flavonoid plant‑derived antitoxin, ameliorates hyperuricemia and kidney inflammation. The present study aimed to establish a model of high‑fat diet (HFD)‑induced ...insulin resistance (IR) and to determine the specific mechanism of RSV to improve kidney inflammation and reduce uric acid (UA). C57BL/6J mice were fed a HFD for 12 weeks and their glucose tolerance was evaluated by intraperitoneal glucose tolerance testing. The mice were then administered RSV for 6 weeks, and blood and kidney samples were collected. Serum UA and insulin concentrations were determined using ELISA kits. Hematoxylin and eosin, periodic acid‑Schiff and Masson staining were performed to observe the pathological changes of the kidney, and electron microscopy was used to observe changes in the kidney ultrastructure. The renal concentrations of interleukin (IL)‑6, IL‑18, IL‑1β and tumor necrosis factor‑α (TNF‑α) were measured using ELISA kits, and western blotting evaluated changes in the protein expression levels of various indicators. RSV significantly ameliorated HFD‑induced IR and reduced blood UA levels. Long‑term IR can lead to lipid deposition, glycogen accumulation, inflammatory damage and fibrotic changes in the kidney of mice. This leads to a significant increase in the expression of UA transport‑related proteins, an increase in UA reabsorption and an increase in blood UA levels. Notably, RSV intervention was able to reverse this process. The effect of RSV may be achieved by inhibiting the NOD‑like receptor family, pyrin domain‑containing 3 (NLRP3) inflammasome and Toll‑like receptor 4 (TLR4)/myeloid differentiation factor 88/nuclear factor‑κB signaling pathway. In conclusion, RSV may improve kidney inflammation through TLR4 and NLRP3 signaling pathways, and reduce the expression of UA transporter proteins in the kidney of insulin‑resistant mice, thereby reducing blood UA levels.
CD4+ T cells are key players in regulating the inflammatory processes and physiological repair mechanisms engaged after acute myocardial infarction (AMI). Although signaling through the CD27-CD70 ...co-stimulatory pathway are known to be important in CD4+ T cell activation and proliferation in certain contexts, the role of the CD27-CD70 pathway in AMI remains unclear.
A total of 43 control subjects, 42 unstable angina patients, and 90 AMI patients were enrolled in the present study. The serum levels of soluble CD27 (sCD27) in patients were measured, revealing a significant increase in serum sCD27 levels in AMI patients within 24 h of the cardiac event, after which they decreased. Correlation analyses revealed that serum sCD27 was positively correlated with cardiac troponin I (c-TnI) (r = 0.267, P = 0.011). When anti-CD70 antibody was used to block the CD27-CD70 pathway in MI model mice, we found that this treatment increased left ventricular end-diastolic dimension (LVEDD) (P < 0.01) and left ventricular end-systolic dimension (LVESD) (P < 0.01), and decreased ejection fraction (P < 0.01). Flow cytometric analysis revealed that the percentage of regulatory T cells was lower in blocking antibody-treated mice (P < 0.01), while neutrophils levels were higher (P < 0.01). The number of CD31-positive endothelial cells (P = 0.026) and α-smooth muscle actin-positive arterioles (P < 0.01) were significantly down-regulated in anti-CD70 treated-AMI mice. The formation of the extracellular matrix (ECM) was also impaired.
Serum sCD27 may be a potential biomarker for AMI. Blockade of the CD27-CD70 pathway worsens cardiac dysfunction, aggravates left ventricular remodeling, and impairs scar healing after AMI, resulting in heart failure.
•The circulating sCD27 was increased within 24 h post-MI in patients.•The sCD27 level was correlated with c-TnI.•Blockade of CD27-CD70 pathway enhanced inflammatory response and led to adverse ventricular remodeling.
Obesity, as a worldwide healthcare problem, has attracted more and more attention. Here we identify a long non-coding RNA NRON, which is highly conserved across species, as an important regulator of ...glucose/lipid metabolism and whole-body energy expenditure. Depletion of Nron leads to metabolic benefits in DIO (diet-induced obesity) mice, including reduced body weight and fat mass, improved insulin sensitivity and serum lipid parameters, attenuated hepatic steatosis and enhanced adipose function. Mechanistically, Nron deletion improves hepatic lipid homeostasis via PER2/Rev-Erbα/FGF21 axis coupled with AMPK activation, and enhances adipose function via activating the process of triacylglycerol hydrolysis and fatty acid re-esterification (TAG/FA cycling) and coupled metabolic network. These interactive and integrative effects cooperatively account for a healthier metabolic phenotype in NKO (Nron knockout) mice. Genetic or pharmacological inhibition of Nron may have potential for future therapy of obesity.
•Nron deletion increases whole-body energy expenditure and alleviates obesity-associated metabolic disorder.•Nron deletion improves hepatic lipid homeostasis via PER2/Rev-Erbα/FGF21 axis coupled with AMPK activation.•Nron deletion enhances adipose function via activating the process of TAG/FA cycling and coupled metabolic network.
Primary Sjögren's syndrome is one of the most common autoimmune diseases. So far, genetic studies of Sjögren's syndrome have relied mostly on candidate gene approaches. To identify new genetic ...susceptibility loci for primary Sjögren's syndrome, we performed a three-stage genome-wide association study in Han Chinese. In the discovery stage, we analyzed 556,134 autosomal SNPs in 542 cases and 1,050 controls. We then validated promising associations in 2 replication stages comprising 1,303 cases and 2,727 controls. The combined analysis identified GTF2I at 7q11.23 (rs117026326: Pcombined = 1.31 × 10(-53), combined odds ratio (ORcombined) = 2.20) as a new susceptibility locus for primary Sjögren's syndrome. Our analysis also confirmed previously reported associations in Europeans in the regions of STAT4, TNFAIP3 and the major histocompatibility complex (MHC). Fine mapping of the region around GTF2I showed that rs117026326 in GTF2I had the most significant association, with associated SNPs extending from GTF2I to GTF2IRD1-GTF2I.
The nuclear factor of activated T-cells (NFAT) family was first recognised to play an important role in the differentiation of T cells, but has since been shown to regulate multiple ...pathophysiological processes. However, whether it is involved in the pathogenesis of non-alcoholic steatohepatitis (NASH) remains unknown.
Hepatic NFATc expression and localisation were analysed in C57BL/6 mice on a methionine–choline-deficient diet, as well as in samples from non-alcoholic fatty liver disease patients. Gain- or loss-of-function approaches were used to investigate the role of NFATc4 in NASH.
NFATc4 translocates from the cytoplasm to the nucleus in hepatocytes of both humans and rodents with NASH. NFATc4 knockdown resulted in decreased hepatic steatosis, inflammation, and fibrosis during NASH progression. Mechanistically, we found that activated NFATc4 directly bound to peroxisome proliferator-activated receptor α (PPARα) in the nucleus and negatively regulated its transcriptional activity, thereby impairing the hepatic fatty acid oxidation pathway and increasing lipid deposition in the liver. Moreover, NFATc4 activation increased the production and secretion of osteopontin (OPN) from hepatocytes, which subsequently enhanced the macrophage-mediated inflammatory response and hepatic stellate cell-mediated fibrosis progression via paracrine signalling.
Hepatic NFATc4 activation accelerates the progression of NASH by suppressing PPARα signalling and increasing OPN expression. Genetic or pharmacological inhibition of NFATc4 may have potential for future therapy of NASH.
NFATc4 is activated in the non-alcoholic steatohepatitis of mice and patients. Inhibition of NFATc4 activation alleviates lipid deposition, inflammatory response, and fibrosis progression in the liver.
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•NFATc4 is activated in the non-alcoholic steatohepatitis of mice and patients.•NFATc4 directly binds to PPARα and negatively regulates its transcriptional activity.•NFATc4 activation increases the production of OPN, which subsequently promotes hepatic inflammation and fibrosis via paracrine signalling.•Inhibition of NFATc4 alleviates the progression of non-alcoholic steatohepatitis.
Obesity and an increased free fatty acid (FFA) level are tightly linked, leading to aberrant oxidative stress, inflammation, apoptosis, and progression to cardiovascular disorders. A20 is a ...ubiquitin-modifying enzyme that plays a significant role in the negative regulation of inflammatory response. Here, we study the role of A20 in obesity-induced heart injury and explore the underlying mechanisms. A20 expression was first increased in mouse hearts after 4 weeks of a high-fat diet (HFD) and then was gradually decreased in the following 20 weeks. Cardiac-specific supplementation with A20 via recombinant adeno-associated virus subtype 9 (rAAV9) could reverse myocardial dysfunction, hypertrophy and fibrosis in mice exposed to 24 weeks of HFD, along with reduced cardiac apoptosis and inflammation. The beneficial actions of A20 were closely associated with its ability to repress TAK1 activation and the downstream inhibition of P38, JNK1/2, and the NF-κB pathway. TAK1 over-expression could efficiently retard the above-mentioned positive effects of A20. Therefore, our data uncovered a novel function of A20 in obesity-induced heart injury and presented a therapeutic approach for the treatment of obesity-related cardiovascular disorders.
Key messages
A20 expression is downregulated in obesity-related hearts.
A20 ameliorates HFD-induced lipid accumulation, ROS, inflammation, apoptosis, hypertrophy, fibrosis, and cardiac dysfunction.
A20 represses TAK1 activation and the downstream inhibition of P38, JNK1/2, and the NF-κB pathway.
TAK1 overexpression retards the beneficial effects of A20.
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