Implications of C1q/TNF-related protein superfamily in patients with coronary artery disease.

The C1q complement/TNF-related protein superfamily (CTRPs) displays differential effects on the regulation of metabolic homeostasis, governing cardiovascular function. However, whether and how they may serve as predictor/pro-diagnosis factors for assessing the risks of coronary artery disease (CAD) remains controversial. Therefore, we performed a clinical study to elaborate on the implication of CTRPs (CTRP1, CTRP5, CTRP7, and CTRP15) in CAD. CTRP1 were significantly increased, whereas CTRP7 and CTRP15 levels were decreased in CAD patients compared to the non-CAD group. Significant differences in CTRP1 levels were discovered between the single- and triple-vascular-vessel lesion groups. ROC analysis revealed that CTRP7 and CTRP15 may serve as CAD markers, while CTRP1 may serve as a marker for the single-vessel lesion of CAD. CTRP1 and CTRP5 can serve as markers for the triple-vessel lesion. CTRP1 may serve as an independent risk predictor for triple-vessel lesion, whereas CTRP15 alteration may serve for a single-vessel lesion of CAD. CTRP1 may serve as a novel superior biomarker for diagnosis of severity of vessel-lesion of CAD patients. CTRP7, CTRP15 may serve as more suitable biomarker for the diagnosis of CAD patients, whereas CTRP5 may serve as an independent predictor for CAD. These findings suggest CTRPs may be the superior predictive factors for the vascular lesion of CAD and represent novel therapeutic targets against CAD

Nicotine aggravates vascular adiponectin resistance via ubiquitin-mediated adiponectin receptor degradation in diabetic Apolipoprotein E knockout mouse

There is limited and discordant evidence on the role of nicotine in diabetic vascular disease. Exacerbated endothelial cell dysregulation in smokers with diabetes is associated with the disrupted adipose function. Adipokines possess vascular protective, anti-inflammatory, and anti-diabetic properties. However, whether and how nicotine primes and aggravates diabetic vascular disorders remain uncertain. In this study, we evaluated the alteration of adiponectin (APN) level in high-fat diet (HFD) mice with nicotine (NIC) administration. The vascular pathophysiological response was evaluated with vascular ring assay. Confocal and co-immunoprecipitation analysis were applied to identify the signal interaction and transduction. These results indicated that the circulating APN level in nicotine-administrated diabetic Apolipoprotein E-deficient (ApoE−/−) mice was elevated in advance of 2 weeks of diabetic ApoE−/− mice. NIC and NIC addition in HFD groups (NIC + HFD) reduced the vascular relaxation and signaling response to APN at 6 weeks. Mechanistically, APN receptor 1 (AdipoR1) level was decreased in NIC and further significantly reduced in NIC + HFD group at 6 weeks, while elevated suppressor of cytokine signaling 3 (SOCS3) expression was induced by NIC and further augmented in NIC + HFD group. Additionally, nicotine provoked SOCS3, degraded AdipoR1, and attenuated APN-activated ERK1/2 in the presence of high glucose and high lipid (HG/HL) in human umbilical vein endothelial cells (HUVECs). MG132 (proteasome inhibitor) administration manifested that AdipoR1 was ubiquitinated, while inhibited SOCS3 rescued the reduced AdipoR1. In summary, this study demonstrated for the first time that nicotine primed vascular APN resistance via SOCS3-mediated degradation of ubiquitinated AdipoR1, accelerating diabetic endothelial dysfunction. This discovery provides a potential therapeutic target for preventing nicotine-accelerated diabetic vascular dysfunction

The mediating role of coping styles between nurses’ workplace bullying and professional quality of life

Abstract Aims This study aimed to explore the relationship between workplace bullying among nurses and their professional quality of life, as well as the mediating role of coping styles between the two factors. Background In China, the overall status of nurses' professional quality of life is not optimistic, and the problems of low compassion satisfaction and high compassion fatigue persist. Workplace bullying, which is a serious global issue, can negatively impact the mental health and professional quality of nurses. However, it has still not attracted enough attention from managers. Methods The study used a cross-sectional research design and surveyed 297 clinical nurses from two tertiary grade A hospitals in Wuhan, China. Data were collected through an online questionnaire survey from March to May 2022. The data were analyzed using descriptive statistical methods, including Pearson correlation analysis and structural equation modeling. Results The score for nurses' workplace bullying was 38.72 ± 12.30. The scores for the three dimensions of professional quality of life were 27.56 ± 4.79 for compassion satisfaction, 30.51 ± 4.33 for burnout, and 28.47 ± 4.65 for secondary trauma stress. The scores for positive coping style and negative coping style were 34.59 ± 5.72 and 20.34 ± 5.08 points, respectively. Workplace bullying had a direct negative effect on compassion satisfaction, as well as positive direct effects on burnout and secondary traumatic stress. Coping styles played a mediating effect between workplace bullying and the pairwise relationships of compassion satisfaction, burnout, and secondary trauma stress. Conclusion Workplace bullying hurts nurses' professional quality of life while coping styles plays an mediating role between workplace bullying and professional quality of life. Nursing managers can improve nurses' professional quality of life by reducing workplace bullying and enhancing positive coping style. Implications for nursing management Nursing managers can employ management wisdom and techniques to mitigate the presence and detrimental effects of workplace bullying. This, in turn, promotes a positive work environment and enhances the professional quality of life for nurses

Angiotensin II type 1a receptor knockout ameliorates high-fat diet-induced cardiac dysfunction by regulating glucose and lipid metabolism

Obesity-related cardiovascular diseases are associated with overactivation of the renin-angiotensin system (RAS). However, the underlying mechanisms remain elusive. In this study, we investigate the role of angiotensin II (Ang II) in high-fat diet (HFD)-induced cardiac dysfunction by focusing on cardiac glucose and lipid metabolism and energy supply. Ang II plays a role in cardiovascular regulation mainly by stimulating angiotensin II type 1 receptor (AT1R), among which AT1aR is the most important subtype in regulating the function of the cardiovascular system. AT1aR gene knockout (AT1aR‒/‒) rats and wild-type (WT) rats are randomly divided into four groups and fed with either a normal diet (ND) or a HFD for 12 weeks. The myocardial lipid content, Ang II level and cardiac function are then evaluated. The expressions of a number of genes involved in glucose and fatty acid oxidation and mitochondrial dynamics are measured by quantitative polymerase chain reaction and western blot analysis. Our results demonstrate that AT1aR knockout improves HFD-induced insulin resistance and dyslipidemia as well as lipid deposition and left ventricular dysfunction compared with WT rats fed a HFD. In addition, after feeding with HFD, AT1aR‒/‒ rats not only show further improvement in glucose and fatty acid oxidation but also have a reverse effect on increased mitochondrial fission proteins. In conclusion, AT1aR deficiency ameliorates HFD-induced cardiac dysfunction by enhancing glucose and fatty acid oxidation, regulating mitochondrial dynamics-related protein changes, and further promoting cardiac energy supply

TXNIP inhibition in the treatment of type 2 diabetes mellitus: design, synthesis, and biological evaluation of quinazoline derivatives

AbstractThioredoxin interacting protein (TXNIP) is a potential drug target for type 2 diabetes mellitus (T2DM) treatment. A series of quinazoline derivatives were designed, synthesised, and evaluated to inhibit TXNIP expression and protect from palmitate (PA)-induced β cell injury. In vitro cell viability assay showed that compounds D-2 and C-1 could effectively protect β cell from PA-induced apoptosis, and subsequent results showed that these two compounds decreased TXNIP expression by accelerating its protein degradation. Mechanistically, compounds D-2 and C-1 reduced intracellular reactive oxygen species (ROS) production and modulated TXNIP-NLRP3 inflammasome signalling, and thus alleviating oxidative stress injury and inflammatory response under PA insult. Besides, these two compounds were predicted to possess better drug-likeness properties using SwissADME. The present study showed that compounds D-2 and C-1, especially compound D-2, were potent pancreatic β cell protective agents to inhibit TXNIP expression and might serve as promising lead candidates for the treatment of T2DM

Endoplasmic reticulum stress caused by traumatic injury promotes cardiomyocyte apoptosis through acetylation modification of GRP78

Cardiomyocyte apoptosis is an important cause of trauma-induced secondary cardiac injury (TISCI), in which the endoplasmic reticulum stress (ERS)-mediated apoptosis signaling pathway is known to be first activated, but the mechanism remains unclear. In this study, rat models of traumatic injury are established by using the Noble-Collip trauma device. The expression of glucose-regulating protein 78 (GRP78, a molecular chaperone of the cardiomyocyte ER), acetylation modification of GRP78 and apoptosis of cardiomyocytes are determined. The results show that ERS-induced GRP78 elevation does not induce cardiomyocyte apoptosis in the early stage of trauma. However, with prolonged ERS, the GRP78 acetylation level is elevated, and the apoptosis of cardiomyocytes also increases significantly. In addition, in the early stage of trauma, the expression of histone acetyl-transferase (HAT) P300 is increased and that of histone deacetylase 6 (HDAC6) is decreased in cardiomyocytes. Inhibition of HDAC function could induce the apoptosis of traumatic cardiomyocytes by increasing the acetylation level of GRP78. Our present study demonstrates for the first time that post-traumatic protracted ERS can promote cardiomyocyte apoptosis by increasing the acetylation level of GRP78, which may provide an experimental basis for seeking early molecular events of TISCI

TXNIP aggravates cardiac fibrosis and dysfunction after myocardial infarction in mice by enhancing the TGFB1/Smad3 pathway and promoting NLRP3 inflammasome activation

Myocardial infarction (MI) results in high mortality. The size of fibrotic scar tissue following MI is an independent predictor of MI outcomes. Thioredoxin-interacting protein (TXNIP) is involved in various fibrotic diseases. Its role in post-MI cardiac fibrosis, however, remains poorly understood. In the present study, we investigate the biological role of TXNIP in post-MI cardiac fibrosis and the underlying mechanism using mouse MI models of the wild-type (WT), Txnip-knockout (Txnip-KO) type and Txnip-knock-in (Txnip-KI) type. After MI, the animals present with significantly upregulated TXNIP levels, and their fibrotic areas are remarkably expanded with noticeably impaired cardiac function. These changes are further aggravated under Txnip-KI conditions but are ameliorated in Txnip-KO animals. MI also leads to increased protein levels of the fibrosis indices Collagen I, Collagen III, actin alpha 2 (ACTA2), and connective tissue growth factor (CTGF). The Txnip-KI group exhibits the highest levels of these proteins, while the lowest levels are observed in the Txnip-KO mice. Furthermore, Txnip-KI significantly upregulates the levels of transforming growth factor (TGF)B1, p-Smad3, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), Cleaved Caspase-1, and interleukin (IL)1B after MI, but these effects are markedly offset by Txnip-KO. In addition, after MI, the Smad7 level significantly decreases, particularly in the Txnip-KI mice. TXNIP may aggravate the progression of post-MI fibrosis and cardiac dysfunction by activating the NLRP3 inflammasome, followed by IL1B generation and then the enhancement of the TGFB1/Smad3 pathway. As such, TXNIP might serve as a novel potential therapeutic target for the treatment of post-MI cardiac fibrosis