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.

Sleep deprivation aggravates lipopolysaccharide-induced anxiety, depression and cognitive impairment: The role of pro-inflammatory cytokines and synaptic plasticity-associated proteins.

Growing evidence indicates that neuroinflammation plays a critical role in anxiety, depression, and cognitive impairment. Sleep loss disrupts the host's immune balance and increases neuroinflammation. This study explored whether chronic sleep deprivation aggravates lipopolysaccharide-induced anxiety, depression, and cognitive impairment and assessed the underlying mechanisms. Lipopolysaccharide (250 µg/kg) was administered to adult mice for 9 days, accompanied with daily intermittent sleep deprivation from 12:00 to 18:00 by using an activity wheel. Anxiety, depression, and cognitive function were evaluated using a task battery consisting of an open field, elevated plus maze, tail suspension, forced swimming, and Morris water maze tests. The levels of pro-inflammatory cytokines and synaptic plasticity-associated proteins were examined by enzyme-linked immunosorbent assay and western blot, respectively. The results showed that lipopolysaccharide increased anxiety- and depression-like behaviors, impaired cognitive function, uprelated interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), and decreased brain-derived neurotrophic factor (BDNF), postsynaptic density-95 (PSD-95), and synaptophysin (SYN), which were aggravated by chronic sleep deprivation. These results suggest that chronic sleep deprivation exerted adverse effects on lipopolysaccharide-induced anxiety, depression, and cognitive impairment, which was associated with changes in pro-inflammatory cytokines and synaptic plasticity associated proteins.

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.

Effects of Sleep Reactivity on Sleep Macro-Structure, Orderliness, and Cortisol After Stress: A Preliminary Study in Healthy Young Adults.

Purpose: To investigate changes and links of stress and high sleep reactivity (H-SR) on the macro-structure and orderliness of sleep and cortisol levels in good sleepers (GS). Patients and Methods: Sixty-two GS (18-40 years old) were recruited, with 32 in the stress group and 30 in the control group. Each group was further divided into H-SR and low SR subgroups based on the Ford Insomnia Response to Stress Test. All participants completed two nights of polysomnography in a sleep laboratory. Before conducting polysomnography on the second night, the stress group completed the Trier Social Stress Test and saliva was collected. Results: The duration of NREM sleep stages 1, 2 (N1, N2) and rapid eye movement sleep (REM) decreased, and the values of approximate entropy, sample entropy, fuzzy entropy, and multiscale entropy increased under stress and SR effects. Stress increased rapid eye movement density, and H-SR increased cortisol reactivity. Conclusion: Stress can damage the sleep and increase cortisol release in GS, especially those with H-SR. N1, N2 and REM sleep are more easily affected, while NREM sleep stage 3 sleep is relatively stable.

Resveratrol ameliorates maternal separation-induced anxiety- and depression-like behaviors and reduces Sirt1-NF-kB signaling-mediated neuroinflammation.

Maternal separation in early life has a detrimental effect on the physiological and biochemical functions of the brains of offspring and can lead to anxiety- and depression-like behaviors later in life. Resveratrol possesses a variety of pharmacological properties, including anti-inflammatory, anxiolytic, and anti-depressive effects. In rodents, resveratrol can attenuate anxiety- and depression-like behaviors induced by chronic unpredictable mild stress, estrogen deficiency, and lipopolysaccharide. However, whether resveratrol administration during adolescence can counteract these behaviors when they result from maternal separation is unknown. In this study, male C57BL/6J mice were separated from their mothers for 4 h per day from postnatal day 2 (PND 2) to PND 21; starting on PND 61, resveratrol was administered intraperitoneally at 40 mg/(kg/day-1) for 4 weeks. At 3 months of age, anxiety and depression-like behaviors were assessed in the male offspring using a series of tasks consisting of an open field test, an elevated plus maze test, a forced swimming test, and a tail suspension test. The hippocampal levels of interleukin (IL)-1ß, IL-6, and tumor necrosis factor-alpha (TNF-α) were measured by ELISA, while those of sirtuin 1 (Sirt1) and nuclear factor kappa B (NF-κB) p65 were determined by western blotting and PCR. The results showed that maternal separation led to increased anxiety- and depression-like behaviors, enhanced the levels of pro-inflammatory cytokines, and downregulated the Sirt1/NF-κB signaling pathway in the male offspring; however, these effects could be reversed by treatment with resveratrol. Our findings suggested that resveratrol can ameliorate inflammation and anxiety- and depression-like behaviors induced by maternal separation via the activation of the Sirt1/NF-κB pathway.

Long-term environmental enrichment overcomes depression, learning, and memory impairment in elderly CD-1 mice with maternal sleep deprivation exposure.

Early-life stress disrupts central nervous system development and increases the risk of neuropsychiatric disorder in offspring based on rodent studies. Maternal sleep deprivation (MSD) in rodents has also been associated with depression and cognitive decline in adult offspring. However, it is not known whether these issues persist into old age. Environmental enrichment is a non-pharmacological intervention with proven benefits in improving depression and cognitive impairment; however, it is unclear whether these benefits hold for aging mice following MSD exposure. The aim of this study was to explore the effects of MSD on depression and cognition in elderly offspring CD-1 mice and to determine whether long-term environmental enrichment could alleviate these effects by improving neuroinflammation and synaptic plasticity. The offspring mice subjected to MSD were randomly assigned to either a standard environment or an enriched environment. At 18 months of age, the forced swimming and tail suspension tests were used to evaluated depression-like behaviors, and the Morris water maze test was used to evaluate cognitive function. The expression levels of hippocampal proinflammatory cytokines and synaptic plasticity-associated proteins were also measured. MSD increased depression-like behaviors and impaired cognition function in aging CD-1 offspring mice. These effects were accompanied by upregulated interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α expression, and downregulated brain-derived neurotrophic factor, tyrosine kinase receptor B, postsynaptic density-95, and synaptophysin expression in the hippocampus. All of these changes were reversed by long-term exposure to an enriched environment. These findings suggest that MSD exerts long-term effects on the behaviors of offspring in mice, leading to depression and cognitive impairment in older age. Importantly, long-term environmental enrichment could counteract the behavior difficulties induced by MSD through improving hippocampal proinflammatory cytokines and synaptic plasticity-associated proteins.

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.

Patient-level comparison of heart failure patients in clinical phenotype and prognosis from China and Sweden.

BACKGROUND: Clinical phenotype and prognosis of heart failure (HF) may be variable among different racial populations. Therefore, a patient-level comparison of hospitalized HF patients in two university hospitals from China and Sweden was performed. METHODS AND RESULTS: This study was a pooled data analysis of the patients prospectively enrolled in two single-center studies in China (n = 949) and Sweden (n = 1639) from 2011 to 2015. Clinical characteristics and 6-month all-cause mortality were collected. Higher systolic blood pressure (126.1 ± 20.3 vs. 114.2 ± 15.4 mmHg, p < 0.001) and NT-proBNP level (4540 vs. 3251 pg/mL, p = 0.013) were found in the Swedish cohort, also more patients with ischemic heart disease (32.0% vs. 19.2%), hypertension (64.2% vs. 36.8%), valvular heart disease (40.9% vs.31.6%) and atrial fibrillation (55.3% vs. 39.6%) (all p < 0.001). The use of ACEIs/ARBs (48.8% vs. 80.8%) or beta-blockers (58.8% vs. 86.5%) (both p < 0.001) was lower in Chinese cohort. Given younger age in Chinese cohort (61.6 vs. 76.4 years, p < 0.001), age-stratified analyses were conducted, as there were similar patient numbers in 50-74 years in Chinese (n = 550) and Swedish (n = 554) cohorts, therefore baseline characteristics and prognosis were further compared. The age- and sex-adjusted outcome (HR 0.80 [95% CI 0.55-1.19], p = 0.273) was comparable between the two populations. The NT-proBNP and eGFR independently predicted 6-month mortality in both Chinese (HR [95% CI] 1.006 [1.003-1.008], 0.986 [0.976-0.999]) and Swedish cohort (1.003 [1.000-1.007], 0.988 [0.976-0.999]). CONCLUSIONS: Patient-level comparison of real-world HF populations from China and Sweden demonstrated different clinical phenotypes and therapy but similar prognosis and their predictors.

Relationships Between a Range of Inflammatory Biomarkers and Subjective Sleep Quality in Chronic Insomnia Patients: A Clinical Study.

PURPOSE: To examine whether associations exist between chronic insomnia disorder (CID) and overlooked inflammatory factors (Serum amyloid protein A [SAA]), tumor necrosis factor [TNF]-α, granulocyte-macrophage colony-stimulating factor [GM-CSF], and regulated on activation and normal T cell expressed and presumably secreted [RANTES]). PATIENTS AND METHODS: A total of 65 CID patients and 39 sex- and age-matched good sleeper (GS) controls participated in this study. They completed a baseline survey to collect data on demographics, and were elevated sleep and mood by Pittsburgh Sleep Quality Index (PSQI), Athens Insomnia Scale (AIS), 17-item Hamilton Depression Rating Scale (HAMD-17) and 14-item Hamilton Anxiety Rating Scale (HAMA-14), respectively. The blood samples were collected and tested the serum levels of SAA, TNF-α, GM-CSF and RANTES. RESULTS: The CID group had higher serum levels of SAA, TNF-α, and GM-CSF and a lower level of RANTES than the GS group. In the Spearman correlation analysis, SAA and GM-CSF positively correlated with the PSQI and AIS scores. After controlling for sex, HAMD-17 score, and HAMA-14 score, the partial correlation analysis showed that GM-CSF was positively correlated with PSQI score. Further stepwise linear regression analyses showed that GM-CSF was positively associated with the PSQI and AIS scores, while RANTES was negatively associated with them, and SAA was positively associated with just the AIS score. CONCLUSION: The serum levels of inflammatory mediators (SAA, TNF-α, and GM-CSF) were significantly elevated and the level of RANTES was significantly decreased in CID patients and, to some extent, the changes are related to the severity of insomnia. These findings may help us to improve interventions to prevent the biological consequences of CID by inhibiting inflammation, thereby promoting health.

Liver X receptor ß is required for the survival of single-positive thymocytes by regulating IL-7Rα expression.

Liver X receptors (LXRs) are known as key transcription factors in lipid metabolism and have been reported to play an important role in T-cell proliferation. However, whether LXRs play a role in thymocyte development remains largely unknown. Here, we demonstrated that LXRß deficiency caused a reduction in single-positive (SP) thymocytes, whereas the transitions from the double-negative to SP stage were normal. Meanwhile, LXRß-null SP thymocytes exhibited increased apoptosis and impairment of the IL-7Rα-Bcl2 axis. In addition, the LXR agonist T0901317 promoted the survival of SP thymocytes with enhanced IL-7Rα expression in wild-type mice but not in LXRß-deficient mice. Mechanistically, LXRß positively regulated the expression of IL-7Rα via direct binding to the Il7r allele in SP thymocytes, and forced expression of IL-7Rα or Bcl2 restored the survival of LXRß-defective SP thymocytes. Thus, our results indicate that LXRß functions as an important transcription factor upstream of IL-7Rα to promote the survival of SP thymocytes.

New indices of arterial stiffness correlate with disease severity and mid-term prognosis in acute decompensated heart failure.

Arterial stiffness has been implicated in pathophysiology of heart failure (HF) since it is involved in the ventricular-vascular coupling. Recently, new indices obtained by a cuff oscillometric technique, the arterial velocity pulse index (AVI) for the stiffness of central arteries and the arterial pressure volume index (API) for the stiffness of peripheral arteries have been developed and validated. However, the AVI and API measurement has not been attempted in HF population. This study aimed to investigate the relationship between the AVI, API and clinical parameters and outcomes in HF patients. A prospective cohort of patients with acute decompensated HF were enrolled within 6 months, who were admitted to a tertiary referral hospital in China. Measurement of the AVI and API (AVE-1500, Shisei Datum, Tokyo, Japan) was performed on the day of admission and discharge. Patients were followed up to 6 months for the composite endpoint of all-cause death and rehospitalization for HF. A total of 127 patients were recruited for analysis (60 ± 15 years, 70% male). 80% of the patients were in New York Heart Association (NYHA) Class III or IV at admission with mean left ventricular ejection fraction (LVEF) of 34 ± 9%. During hospitalization, all patients received guideline-directed medical therapy if not contraindicated. The AVI (27.3 ± 5.0 vs. 28.6 ± 6.7, P = 0.002) and API (24.9 ± 4.9 vs. 26.0 ± 6.5, P = 0.05) were lower at discharge than at admission. By dividing the patients into mild to severe group based on systolic blood pressure (SBP) and LVEF or into tertiles according to the amino-terminal pro-brain natriuretic peptide (NT-proBNP), transmitral E velocity over mitral annular e' velocity (E/e' ratio), it was observed that the AVI increased with a higher level of NT-proBNP (P for trend < 0.001), a larger E/e' (P for trend < 0.001) and a lower LVEF (P for trend = 0.0183), while the API increased as the E/e' and systolic blood pressure became higher (both P for trend < 0.05). The improvement in AVI at discharge was correlated with LVEF (R = - 0.3024, P < 0.05) and NT-proBNP improvement (R = 0.3118, P < 0.05), while the change in API was positively correlated with SBP change (R = 0.3897, P < 0.001). In 6 months after discharge, there were 52 predefined events including 15 deaths and 44 rehospitalization for HF. Apart from the level of NT-proBNP, the AVI at discharge of ≥ 26 showed a trend of being associated with the composite outcome (HR 2.747, 95% CI 1.411-5.349, P < 0.001 for univariate analysis; HR 1.864, 95% CI 0.892-3.893, P = 0.09761 for multivariate analysis). New noninvasive arterial stiffness indices as the AVI and API reflected severity of illness and midterm prognosis in admitted HF patients. Further studies are warranted for understanding its mechanisms and developing clinical applications.