Macrod1 suppresses diabetic cardiomyopathy via regulating PARP1-NAD+-SIRT3 pathway.

Diabetic cardiomyopathy (DCM), one of the most serious long-term consequences of diabetes, is closely associated with oxidative stress, inflammation and apoptosis in the heart. MACRO domain containing 1 (Macrod1) is an ADP-ribosylhydrolase 1 that is highly enriched in mitochondria, participating in the pathogenesis of cardiovascular diseases. In this study, we investigated the role of Macrod1 in DCM. A mice model was established by feeding a high-fat diet (HFD) and intraperitoneal injection of streptozotocin (STZ). We showed that Macrod1 expression levels were significantly downregulated in cardiac tissue of DCM mice. Reduced expression of Macrod1 was also observed in neonatal rat cardiomyocytes (NRCMs) treated with palmitic acid (PA, 400 µM) in vitro. Knockout of Macrod1 in DCM mice not only worsened glycemic control, but also aggravated cardiac remodeling, mitochondrial dysfunction, NAD+ consumption and oxidative stress, whereas cardiac-specific overexpression of Macrod1 partially reversed these pathological processes. In PA-treated NRCMs, overexpression of Macrod1 significantly inhibited PARP1 expression and restored NAD+ levels, activating SIRT3 to resist oxidative stress. Supplementation with the NAD+ precursor Niacin (50 µM) alleviated oxidative stress in PA-stimulated cardiomyocytes. We revealed that Macrod1 reduced NAD+ consumption by inhibiting PARP1 expression, thereby activating SIRT3 and anti-oxidative stress signaling. This study identifies Macrod1 as a novel target for DCM treatment. Targeting the PARP1-NAD+-SIRT3 axis may open a novel avenue to development of new intervention strategies in DCM. Schematic illustration of macrod1 ameliorating diabetic cardiomyopathy oxidative stress via PARP1-NAD+-SIRT3 axis.

ADP-ribosylation: An emerging direction for disease treatment.

ADP-ribosylation (ADPr) is a dynamically reversible post-translational modification (PTM) driven primarily by ADP-ribosyltransferases (ADPRTs or ARTs), which have ADP-ribosyl transfer activity. ADPr modification is involved in signaling pathways, DNA damage repair, metabolism, immunity, and inflammation. In recent years, several studies have revealed that new targets or treatments for tumors, cardiovascular diseases, neuromuscular diseases and infectious diseases can be explored by regulating ADPr. Here, we review the recent research progress on ART-mediated ADP-ribosylation and the latest findings in the diagnosis and treatment of related diseases.

Brevilin A ameliorates sepsis-induced cardiomyopathy through inhibiting NLRP3 inflammation.

Background: Sepsis is a systemic inflammatory disease, and Brevilin A (BA) has a powerful anti-inflammatory effect. However, whether BA has a similar effect on septic cardiomyopathy remains unclear. This study aimed to investigate the effect and mechanism of BA in septic cardiomyopathy. Methods: First, a model of septic cardiomyopathy was constructed in vitro and in vivo. The expression of the cardiac injury markers, NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammation factors and its upstream modulator NF-κB was detected by real-time polymerase chain reaction and western blotting. Cardiac function was measured using echocardiography, cell viability was detected using the methyl thiazolyl tetrazolium assay. To further investigate the effects of BA on septic cardiomyopathy, different concentrations of BA were used. The experiment was divided into control group, LPS induced- group, LPS+2.5, 5.0, 10.0 µM BA treatment group of the vitro model, and the Sham, CLP, CLP+10, 20, 30 mg/kg BA treatment groups of the rat vivo model. Lastly, cardiac injury, NLRP3 inflammation, and cardiac function were assessed in each group. Results: The mRNA and protein expression of cardiac inflammation and injury genes were significantly increased in the in vitro and in vivo sepsis cardiomyopathy models. When different concentrations of BA were used in sepsis cardiomyopathy in vivo and in vitro, the above-mentioned myocardial inflammation and injury factors were suppressed to varying degrees, cell viability increased, cardiac function improved, and the survival rate of rats also increased. Conclusion: BA ameliorated sepsis cardiomyopathy by inhibiting NF-κB/NLRP3 inflammation activation.

OSMR deficiency aggravates pressure overload-induced cardiac hypertrophy by modulating macrophages and OSM/LIFR/STAT3 signalling.

BACKGROUND: Oncostatin M (OSM) is a secreted cytokine of the interleukin (IL)-6 family that induces biological effects by activating functional receptor complexes of the common signal transducing component glycoprotein 130 (gp130) and OSM receptor ß (OSMR) or leukaemia inhibitory factor receptor (LIFR), which are mainly involved in chronic inflammatory and cardiovascular diseases. The effect and underlying mechanism of OSM/OSMR/LIFR on the development of cardiac hypertrophy remains unclear. METHODS AND RESULTS: OSMR-knockout (OSMR-KO) mice were subjected to aortic banding (AB) surgery to establish a model of pressure overload-induced cardiac hypertrophy. Echocardiographic, histological, biochemical and immunological analyses of the myocardium and the adoptive transfer of bone marrow-derived macrophages (BMDMs) were conducted for in vivo studies. BMDMs were isolated and stimulated with lipopolysaccharide (LPS) for the in vitro study. OSMR deficiency aggravated cardiac hypertrophy, fibrotic remodelling and cardiac dysfunction after AB surgery in mice. Mechanistically, the loss of OSMR activated OSM/LIFR/STAT3 signalling and promoted a proresolving macrophage phenotype that exacerbated inflammation and impaired cardiac repair during remodelling. In addition, adoptive transfer of OSMR-KO BMDMs to WT mice after AB surgery resulted in a consistent hypertrophic phenotype. Moreover, knockdown of LIFR in myocardial tissue with Ad-shLIFR ameliorated the effects of OSMR deletion on the phenotype and STAT3 activation. CONCLUSIONS: OSMR deficiency aggravated pressure overload-induced cardiac hypertrophy by modulating macrophages and OSM/LIFR/STAT3 signalling, which provided evidence that OSMR might be an attractive target for treating pathological cardiac hypertrophy and heart failure.

Photosynthetic regulation in fluctuating light under combined stresses of high temperature and dehydration in three contrasting mosses.

Photosynthesis regulation is fundamental for the response to environmental dynamics, especially for bryophytes during their adaptation to terrestrial life. Alternative electron flow mediated by flavodiiron proteins (FLV) and cyclic electron flow (CEF) around photosystem I (PSI) play seminal roles in the response to abiotic stresses in mosses; nevertheless, their correlation and relative contribution to photoprotection of mosses exposed to combined stresses remain unclear. In the present study, the photosynthetic performance and recovery capacity of three moss species from different growth habitats were examined during heat and dehydration with fluctuating light. Our results showed that dehydration at 22 °C for 24 h caused little photodamage, and most of the parameters recovered to their original values after rehydration. In contrast, dehydration at 38 °C caused drastic injuries, especially to PSII, which was mainly caused by the inactivation of non-photochemical quenching (NPQ). Dehydration also induced a high accumulation of O2- and H2O2. A consistently higher CEF as well as a positive correlation between CEF and FLV was observed in resistant R. japonicum, implying CEF played a more important protective role for R. japonicum. In H. plumaeforme and P. cuspidatum, the positive relationship under mild stress switched to negative when stress became severe. Therefore, FLV pathway was sensitive to environmental fluctuations and maybe less efficient than CEF thus, readily to be lost during land colonization and evolution in angiosperms. Our work provides insights into the coordination of various pathways to fine-tune photosynthetic protection and can be used as a basis for species screening and development of breeding strategies for degraded ecosystem restoration with pioneering mosses.

RGS6 Drives Spinal Cord Injury by Inhibiting AMPK Pathway in Mice.

Objective: Oxidative stress and inflammation play critical roles in the pathogenesis of spinal cord injury (SCI). Regulator of G protein signaling 6 (RGS6) is involved in controlling ROS generation and inflammatory response under different contexts. This study is aimed at investigating its role and underlying mechanism in SCI. Methods: Contusive SCI mouse models were generated, and lentiviral vectors were injected to silence or overexpress RGS6 in the spinal cord. To inhibit AMP-activated protein kinase (AMPK) activity, SCI mice were intraperitoneally injected with compound C (20 mg/kg) every two days. Oxidative and inflammatory markers were detected. Results: Spinal RGS6 expression was elevated upon SCI stimulation. RGS6 knockdown suppressed, while RGS6 overexpression aggravated oxidative stress, inflammation, and SCI in mice. Mechanistically, RGS6 elevation during SCI deactivated AMPK pathway, thereby exacerbating oxidative stress and inflammation in SCI mice. Conclusion: RGS6 is required for the initiation and progression of SCI, and knocking down RGS6 may provide promising therapeutic strategies for SCI patients.

The neonatal PROC gene rs1799809 polymorphism modifies the association between prenatal air pollutants exposure and PROC promoter methylation.

Prenatal air pollution, protein C (PROC) gene abnormal methylation, and genetic mutation can cause a series of neonatal diseases, but the complex relationship between them remains unclear. Here, we recruited 552 mothers and their own babies during January 2010-January 2012 in Zhengzhou to explore such association. The air pollutant data was obtained from the Environmental Monitoring Stations. The rs1799809 genotype and the methylation levels at the promoter region of PROC in genomic DNA samples were detected respectively by TaqMan probe and quantitative methylation specific PCR using real-time PCR system. The results show that the levels of neonatal PROC methylation were negatively associated with concentrations of NO2 during the entire pregnancy, particularly during the third trimester. Of particular significance, only in newborns carrying rs1799809 AA genotype, negatively significant associations between PROC methylation levels and exposure concentrations of air pollutants were observed. Further, we observed a significant interactive effect between neonatal rs1799809 genotype and SO2 exposure during the entire pregnancy on neonatal PROC methylation levels. Prenatal exposure to ambient air pollutants specifically was associated with the neonatal PROC promoter methylation level of newborns carrying the rs1799809 AA genotype. Taken together, these findings suggest that neonatal PROC methylation levels are associated with prenatal exposure to ambient air pollutants, and this association can be modified by rs1799809 genotype.

MiR-195-5p represses inflammation, apoptosis, oxidative stress, and endoplasmic reticulum stress in sepsis-induced myocardial injury by targeting activating transcription factor 6.

Myocardial injury (MI) is a common complication of sepsis. MicroRNAs (miRNAs) have been suggested as potential biomarkers of MI; however, their mechanisms in sepsis-induced MI remain unclear. A sepsis rat model was constructed by use of cecal ligation and puncture (CLP). The levels of miR-195-5p and activating transcription factor 6 (ATF6) expression were determined by quantitative reverse-transcription polymerase chain reaction, and cytokine levels were detected by ELISA. The levels of oxidative stress (OS)-related indicators and endoplasmic reticulum stress (ERS)-related proteins were examined, and the regulatory effect of miR-195-5p on ATF6 was determined by using the luciferase reporter assay. Our results showed that miR-195-5p expression was downregulated and ATF6 expression was upregulated in lipopolysaccharide-induced cardiomyocytes and mice with CLP-induced sepsis. We also found that miR-195-5p could markedly attenuate the inflammation, apoptosis, OS, and ERS associated with sepsis-induced MI. Additionally, we verified that miR-195-5p could relieve sepsis-induced MI by targeting ATF6. This study identified potential targets for treating MI after sepsis.

Photosynthetic regulation in response to fluctuating light conditions under temperature stress in three mosses with different light requirements.

Under natural field conditions, mosses experience fluctuating light intensities combined with temperature stress. Alternative electron flow mediated by flavodiiron proteins (FLVs) and cyclic electron flow (CEF) around photosystem I (PSI) allow mosses to growth under fluctuating light conditions. However, little is known about the roles of FLVs and CEF in the regulation of photosynthesis under temperature stress combined with fluctuating light. Here, we measured chlorophyll fluorescence and P700 redox state under fluctuating light conditions at 4 °C, 20 °C, and 35 °C in three mosses with different light requirements. Upon a sudden increase in light intensity, electron flow from photosystem II initially increased and then gradually decreased at 20 °C and 35 °C, indicating that the operation of FLV-dependent flow lasted much longer than previously thought. Furthermore, the absolute rates of FLV-dependent flow and CEF were enhanced under fluctuating light at 35 °C, pointing to their important roles in photoprotection when exposed to fluctuating light at moderate high temperature. Furthermore, the downregulation of FLV activity at 4 °C was partially compensated for by enhanced CEF activity. These results suggested the subtle coordination between FLV activity and CEF under fluctuating light and temperature stress. Racomitrium japonicum and Hypnum plumaeforme, which usually grow under relatively high light levels, exhibited higher FLV activity and CEF than the shade-grown moss Plagiomnium ellipticum. Based on our results, we conclude that photosynthetic acclimation to fluctuating light and temperature stress in different mosses is largely linked to the adjustment of FLV activity and CEF.

Splenic Artery Pseudoaneurysm in Chronic Pancreatitis Causing Obstructive Jaundice: Endovascular Management.

BACKGROUND: Splenic artery pseudoaneurysm (SAP) around the pancreatic head causing obstructive jaundice is an extremely rare complication but can be life threatening once occurs. This case report is to raise awareness of this catastrophic complication and share our experience of successful endovascular management. METHODS: A 47-year-old male with a history of chronic pancreatitis clinically presented with epigastric pain and jaundice. Proximal SAP complicated with obstructive jaundice was confirmed by laboratory and imaging investigations. The SAP was successfully treated by transarterial coil embolization, and the jaundice subsequently improved. RESULTS: Abdominal contrast-enhanced computed tomography 11 months after embolization showed complete occlusion and reduction in the volume of the SAP as well as normal biliary tract. CONCLUSIONS: SAP complicated with obstructive jaundice should be managed timeously and aggressively once diagnosed, given its potential adverse consequences. Transarterial embolization using the isolation technique may be a safe and effective strategy for treating this disease.

Potential role of lncRNA HULC/miR­128­3p/RAC1 axis in the inflammatory response during LPS­induced sepsis in HMEC­1 cells.

Sepsis is a serious clinical condition characterized by systemic inflammation. The long noncoding RNA (lncRNA) highly upregulated in liver cancer (HULC) was validated to partake in the development of sepsis. The present study aimed to investigate the potential mechanism of HULC in lipopolysaccharide (LPS)­induced sepsis. Reverse transcription­quantitative polymerase chain reaction (RT­qPCR) and western blot analysis was employed to examine the expression of HULC, microRNA (miR)­128­3p, Rac family small GTPase 1 (RAC1) and pro­inflammatory factors [IL­6, TNF­α, intercellular adhesion molecule (ICAM1) and vascular cell adhesion molecule (VCAM1)] in the serum of patients with sepsis or LPS­induced human dermal microvascular endothelial cells (HMEC­1). Flow cytometry and western blot assays were performed to detect cell apoptosis. The targeted relationship among HULC, miR­128­3p and RAC1 was confirmed by a dual­luciferase reporter assay, RNA binding protein immunoprecipitation (RIP) assay and RNA pull­down assay. HULC and RAC1 were found to be upregulated, and miR­128­3p was downregulated in the serum of patients with sepsis and LPS­stimulated HMEC­1 cells. LPS promoted apoptosis and inflammation, which were decreased by silencing of HULC. HULC targeted miR­128­3p and negatively regulated its expression. HULC knockdown protected HMEC­1 cells from LPS­induced injury by upregulating miR­128­3p. RAC1 was a target of miR­128­3p, and gain of RAC1 also relieved the silencing of HULC­mediated suppressive effects on apoptosis and inflammation in LPS­stimulated HMEC­1 cells. In conclusion, HULC knockdown partially reversed LPS­induced sepsis via the regulation of miR­128­3p/RAC1 axis.

Prognostic Value of C-Reactive Protein in Patients With Coronavirus 2019.

BACKGROUND: An elevated serum C-reactive protein (CRP) level was observed in most patients with coronavirus disease 2019 (COVID-19). METHODS: Data for COVID-19 patients with clinical outcome in a designated hospital in Wuhan, China, were retrospectively collected and analyzed from 30 January 2020 to 20 February 2020. The prognostic value of admission CRP was evaluated in patients with COVID-19. RESULTS: Of 298 patients enrolled, 84 died and 214 recovered. Most nonsurvivors were male, older, or with chronic diseases. Compared with survivors, nonsurvivors showed significantly elevated white blood cell and neutrophil counts, neutrophil to lymphocyte ratio (NLR), systemic immune inflammation index (defined by platelet count multiplied by NLR), CRP, procalcitonin, and D-dimer and showed decreased red blood cell, lymphocyte, and platelet counts. Age, neutrophil count, platelet count, and CRP were identified as independent predictors of adverse outcome. The area under the receiver operating characteristic (ROC) curve (AUC) of CRP (0.896) was significantly higher than that of age (0.833), neutrophil count (0.820), and platelet count (0.678) in outcome prediction (all P < .05). With a cutoff value of 41.4, CRP exhibited sensitivity of 90.5%, specificity of 77.6%, positive predictive value of 61.3%, and negative predictive value of 95.4%. CRP was also an independent discriminator of severe/critical illness on admission with an AUC (0.783) comparable to age (0.828) and neutrophil count (0.729) (both P > .05). CONCLUSIONS: In patients with COVID-19, admission CRP correlated with disease severity and tended to be a good predictor of adverse outcome.

Shifts in the relative abundance of bacteria after wine-lees-derived biochar intervention in multi metal-contaminated paddy soil.

The impact of biochar application on soil ecological functions depends on the diversity of soil conditions and of the feedstocks from which biochar is obtained. Moreover, little information is available on the effect of biochar on dynamic changes in microorganisms with the development of rice plants in multi-metal-contaminated paddy soil amended with wine-lees-derived biochar. In this paper, biochar obtained from the pyrolysis of wine lees at 600°C was used to investigate the potential role of biochar in maintaining soil ecological functions, with consideration of the alteration of the microbial population over periods of rice growth. Biochar increased the soil nutrient availability, suppressed the toxicity of heavy metals and benefited the rice growth. Enzymic activities initially increased and then decreased with increasing biochar addition as well as with the growth stage. High-throughput sequencing results indicated that biochar application shifted the soil microbial community, increased the bacterial diversity and reduced the bacterial richness. The relative abundances of Actinobacteria, Firmicutes, Proteobacteria, Planctomycetes and Cyanobacteria increased with increasing biochar addition, whereas the abundance of Gemmatimonadetes decreased at higher biochar applications. With increasing biochar application, Nitrospirae, which were lowest in the 1% biochar addition treatment, first decreased and then increased. The results from this study indicated that biochar addition increased N2 fixation and improved C cycling. Redundancy analysis (RDA) indicated that RI (potential ecological risk index), AN (available nitrogen) and AP (available phosphorus) were the most important factors for bacteria and accounted for 68.7%, 58.3% and 52.4% of the variation, respectively. Therefore, the reduction of metal toxicity and the improvement of soil fertility are important mechanisms for higher bacterial abundances.

[In vitro generation of insulin-producing cells from the neonatal rat bone marrow mesenchymal stem cells].

OBJECTIVE: To observe the differentiation of the neonatal rat bone marrow mesenchymal stem cells (MSCs) into insulin-producing cells and detect the expressions of insulin, pancreatic duodenal homebox-1 (PDX-1) and nestin. METHODS: MSCs were isolated from the neonatal rats and cultured in the modified medium composed of 10 µg/L human epidermal growth factor (EGF), 10 µg/L basic fibroblast growth factor (bFGF), 10 µg/L hepatocyte growth factor (HGF), 10 µg/L human B cell regulin, 20 mmol/L nicotinamide and 20 g/L B27. After the induction, the mRNA expressions of insulin, PDX-1 and nestin were examined by reverse transcription-PCR, and the insulin, PDX-1 and nestin protein levels were detected by immunocytochemistry. RESULTS: The insulin and PDX-1 mRNA expressions increased and the nestin mRNA expression decreased in the differentiation of the neonatal rat MSCs into insulin-producing cells. The nestin, PDX-1 and insulin proteins were co-expressed in insulin-producing cells. CONCLUSION: MSCs can be induced to differentiate into insulin-producing cells.