Enhanced inflammatory responses to toll-like receptor 2/4 stimulation in type 1 diabetic coronary artery endothelial cells: the effect of insulin

<p>Abstract</p> <p>Background</p> <p>Endothelial inflammatory responses mediated by Toll-like receptors (TLRs), particularly TLR2 and TLR4, play an important role in atherogenesis. While Type 1 diabetes (T1D) promotes the development and progression of atherosclerosis, the effect of T1D on TLR2/4-mediated inflammatory responses in coronary artery endothelial cells (CAECs) remains unclear.</p> <p>Methods</p> <p>We tested the hypothesis that diabetic CAECs have enhanced inflammatory responses to TLR2/4 stimulation. Non-diabetic and diabetic CAECs were treated with TLR2 agonist peptidoglycan and TLR4 agonist lipopolysaccharide. The expression of ICAM-1, IL-6 and IL-8 were analyzed by real-time PCR, immunoblotting and ELISA, and NF-κB activation by immunoblotting and immunostaining. In additional experiments, insulin was added before TLR stimulation to determine whether insulin deficiency alone is responsible for the alteration of TLR2/4-mediated inflammatory responses.</p> <p>Results</p> <p>Stimulation of TLR2 or TLR4 induced NF-κB activation, and the expression of ICAM-1, IL-6 and IL-8. Interestingly, the expression of inflammatory mediators was significantly enhanced in diabetic cells. The enhanced inflammatory responses correlated with augmented NF-κB activation in the absence of a change in TLR2 or TLR4 protein levels. Further, pretreatment of diabetic cells with insulin failed to suppress the enhanced inflammatory responses.</p> <p>Conclusions</p> <p>Diabetic CAECs have enhanced inflammatory responses to stimulation of TLR2 or TLR4, and insulin alone is insufficient to correct the hyper-inflammatory responses. The mechanism underlying the enhanced inflammatory responses appears to be augmentation of pro-inflammatory signaling, rather than up-regulation of levels of TLR2 and TLR4. These findings suggest that diabetic CAECs adopt a hyper-inflammatory phenotype and that this endothelial phenotypic change may predispose coronary artery to atherogenesis.</p

Acute and acute-on-chronic kidney injury of patients with decompensated heart failure: impact on outcomes

BACKGROUND: Acute worsening of renal function, an independent risk factor for adverse outcomes in acute decompensated heart failure (ADHF), occurs as a consequence of new onset kidney injury (AKI) or acute deterioration of pre-existed chronic kidney disease (CKD) (acute-on-chronic kidney injury, ACKI). However, the possible difference in prognostic implication between AKI and ACKI has not been well established. METHODS: We studied all consecutive patients hospitalized with ADHF from 2003 through 2010 in Nanfang Hospital. We classified patients as with or without pre-existed CKD based on the mean estimated glomerular filtration rate (eGFR) over a six-month period before hospitalization. AKI and ACKI were defined by RIFLE criteria according to the increase of the index serum creatinine. RESULTS: A total of 1,005 patients were enrolled. The incidence of ACKI was higher than that of AKI. The proportion of patients with diuretic resistance was higher among patients with pre-existed CKD than among those without CKD (16.9% vs. 9.9%, P = 0.002). Compared with AKI, ACKI was associated with higher risk for in-hospital mortality, long hospital stay, and failure in renal function recovery. Pre-existed CKD and development of acute worsening of renal function during hospitalization were the independent risk factors for in-hospital death after adjustment by the other risk factors. The RIFLE classification predicted all-cause and cardiac mortality in both AKI and ACKI. CONCLUSIONS: Patients with ACKI were at greatest risk of adverse short-term outcomes in ADHF. Monitoring eGFR and identifying CKD should not be ignored in patients with cardiovascular disease

Congestive Heart Failure Exhibited Higher BMI With Lower Energy Intake and Lower Physical Activity Level: Data From the National Health and Examination Nutrition Survey

Background: Despite that nutritional deficiency existed in congestive heart failure (CHF), there is a large amount of CHF patients suffering from obesity. This study aimed to identify the differences for increased BMI or obesity in CHF patients.Methods: This cross-sectional study included adults from the National Health and Nutrition Examination Survey 2007–2016. Differences were compared between CHF participants vs. non-CHF participants, and BMI ≥ 30 kg/m2 vs. BMI &lt; 30 kg/m2 CHF participants.Results: CHF participants were with higher BMI, lower energy and macronutrient intake, lower physical activity level and longer rest time, and lower hematocrit and hemoglobin level (all P &lt; 0.05) than non-CHF participants. The prevalence of BMI ≥ 30 kg/m2 in participants with CHF was 53.48%. There was no significant difference observed in energy and macronutrient intake between CHF participants with BMI ≥ 30 kg/m2 or &lt;30 kg/m2. The water intake (P = 0.032), sedentary time (P = 0.002), and hematocrit (P = 0.028) were significantly different between CHF with BMI ≥ 30 kg/m2 and with &lt;30 kg/m2.Conclusion: Compared with non-CHF participants, CHF participants exhibited higher BMI with lower energy and macronutrient intake, lower physical activity level, longer rest time, and hemodilution with lower hematocrit and hemoglobin level. Among CHF participants with BMI ≥ 30 kg/m2, higher sedentary time and hematocrit were observed

Characteristics of school children's personal exposure to ultrafine particles in Heshan, Pearl River Delta, China - A pilot study.

BACKGROUND: There is a significant lack of scientific knowledge on population exposure to ultrafine particles (UFP) in China to date. This paper quantifies and characterises school children's personal UFP exposure and exposure intensity against their indoor and outdoor activities during a school day (home, school and commuting) in the city of Heshan within the Pearl River Delta (PRD) region, southern China. METHODS: Time-series of UFP number concentrations and average size were measured over 24?h for 24 children (9-13?years old), using personal monitors over two weeks in April 2016. Time-activity diaries and a questionnaire on the general home environment and potential sources of particles at home were also collected for each participating child. The analysis included concurrently measured size distributions of ambient UFP at a nearby fixed reference site (Heshan Supersite). RESULTS: Hourly average UFP concentrations exhibited three peaks in the morning, midday and evening. Time spent indoors at home was found to have the highest average exposure (1.26?×?104?cm-3 during sleeping) and exposure intensity (2.41). While there is always infiltration of outdoor particles indoors (from nearby traffic and general urban background sources), indoor exposure at home was significantly higher than outdoor exposure. Based on the collected questionnaire data, this was considered to be driven predominantly by adults smoking and the use of mosquito repellent incense during the night. Outdoor activities at school were associated with the lowest average exposure (6.87?×?102?cm-3) and exposure intensity (0.52). CONCLUSION: Despite the small sample size, this study characterised, for the first time, children's personal UFP exposure in a city downwind of major pollution sources of the PRD region in China. Particularly, the results highlighted the impact of smoking at home on children's exposure. While the study could not apportion the specific contributions of second hand-smoking and mosquito coil burning, considering the prevalence of smokers among the parents who smoke at home, smoking is a very significant factor. Exposure to second-hand smoke is avoidable, and these findings point out to the crucial role of government authorities and public health educators in engaging with the community on the role of air quality on health, and the severity of the impact of second-hand smoke on children's health

A CRM1 Inhibitor Alleviates Cardiac Hypertrophy and Increases the Nuclear Distribution of NT-PGC-1α in NRVMs

Chromosomal maintenance 1 (CRM1) inhibitors display antihypertrophic effects and control protein trafficking between the nucleus and the cytoplasm. PGC-1α (peroxisome proliferator-activated receptor gamma coactivator-1alpha) is a type of transcriptional coactivator that predominantly resides in the nucleus and is downregulated during heart failure. NT-PGC-1α is an alternative splicing variant of PGC-1α that is primarily distributed in the cytoplasm. We hypothesized that the use of a CRM1 inhibitor could shuttle NT-PGC-1α into the nucleus and activate PGC-1α target genes to potentially improve cardiac function in a mouse model of myocardial infarction (MI). We showed that PGC-1α and NT-PGC-1α were decreased in MI-induced heart failure mice. Phenylephrine and angiotensin II were applied to induce hypertrophy in neonatal rat ventricular myocytes (NRVMs). The antihypertrophic effects of the CRM1-inhibitor Selinexor was verified through profiling the expression of β-MHC and through visualizing the cell cross-sectional area. NRVMs were transfected with adenovirus-NT-PGC-1α or adenovirus-NLS (nucleus localization sequence)-NT-PGC-1α and then exposed to Selinexor. Confocal microscopy was then used to observe the shuttling of NT-PGC-1α. After NT-PGC-1α was shuttled into the nucleus, there was increased expression of its related genes, including PPAR-α, Tfam, ERR-γ, CPT1b, PDK4, and Nrf2. The effects of Selinexor on post-MI C57BL/6j mice were determined by echocardiography and qPCR. We found that Selinexor showed antihypertrophic effects but did not influence the ejection fraction of MI-mice. Interestingly, the antihypertrophic effects of Selinexor might be independent of NT-PGC-1α transportation

Mathematical modeling of the metastatic process

Mathematical modeling in cancer has been growing in popularity and impact since its inception in 1932. The first theoretical mathematical modeling in cancer research was focused on understanding tumor growth laws and has grown to include the competition between healthy and normal tissue, carcinogenesis, therapy and metastasis. It is the latter topic, metastasis, on which we will focus this short review, specifically discussing various computational and mathematical models of different portions of the metastatic process, including: the emergence of the metastatic phenotype, the timing and size distribution of metastases, the factors that influence the dormancy of micrometastases and patterns of spread from a given primary tumor.Comment: 24 pages, 6 figures, Revie

Mitofusin 2 Participates in Mitophagy and Mitochondrial Fusion Against Angiotensin II-Induced Cardiomyocyte Injury

BackgroundMitochondrial dynamics play a critical role in mitochondrial function. The mitofusin 2 (MFN2) gene encodes a mitochondrial membrane protein that participates in mitochondrial fusion to maintain and operate the mitochondrial network. Moreover, MFN2 is essential for mitophagy. In Ang II-induced cardiac remodeling, the combined effects of MFN2-mediated mitochondrial fusion and mitophagy are unclear. This study was designed to explore a novel strategy for preventing cardiomyocyte injury via modulation of mitochondrial dynamics.MethodsWe studied the function of MFN2 in mitochondrial fusion and mitophagy in Ang II-stimulated cardiomyocyte injury. Cardiomyocyte injury experiments, including reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP), and apoptosis rate of cardiomyocytes were performed. The mitochondrial morphology in cardiomyocytes was examined via transmission electron microscopy (TEM) and confocal microscopy. Autophagic levels in response to Ang II were examined by immunoblotting of autophagy-related proteins. Moreover, PINK1/MFN2/Parkin pathway-related proteins were examined.ResultsWith stimulation by Ang II, MFN2 expression was progressively reduced. MFN2 deficiency impaired mitochondrial quality, resulting in exacerbated mitochondrial damage induced by Ang II. The Ang II-induced increases in ROS production and apoptosis rate were alleviated by MFN2 overexpression. Moreover, MFN2 alleviated the Ang II-induced reduction in MMP. MFN2 promoted mitochondrial fusion, and MFN2 promoted Parkin translocation and phosphorylation, leading to mitochondrial autophagy. The effects of MFN2 overexpression were reversed by autophagy inhibitors.ConclusionMitofusin 2 promotes Parkin translocation and phosphorylation, leading to mitophagy to clear damaged mitochondria. However, the beneficial effects of MFN2 were reversed by autophagy inhibitors. Additionally, MFN2 participates in mitochondrial fusion to maintain mitochondrial quality. Thus, MFN2 participated in mitophagy and mitochondrial fusion against Ang II-induced cardiomyocyte injury

The structuring role of artificial structure on fish assemblages in a dammed river of the Pearl River in China

To address the fish use patterns of artificial structures mimicking floating macrophytes deployed in a impounded tributary of the Pearl River, China, field experiments were performed from December 2014 to June 2016 using multi-mesh gillnet. The fish assemblages using artificial structures differ in terms of species richness, abundance, body size, diversity indices, and ecological traits from fish assemblages on natural barren habitats of this river. Overall, fish abundance, species richness, Shannon diversity index, and functional richness were higher at the artificial structures than at the control sites, while fish length and functional evenness was greater at the control sites in comparison to artificial structures. The introduction of artificial structures did not result in statistically significant effects on fish biomass as artificial structures attracted more individuals with smaller size. Seasonal changes of chlorophyll-a and transparency may affect the efficiency of artificial structure in harboring fishes. This study revealed that artificial structures, as synthesized habitats, are effective in acting as a “fish attractor” and an alternative tool to provide new habitats for smaller individuals in a dammed river like the Youjiang River which is a structure-less ecosystem

Imatinib Mesylate Reduces Endoplasmic Reticulum Stress and Induces Remission of Diabetes in db/db Mice

OBJECTIVE—Imatinib has been reported to induce regression of type 2 diabetes in chronic leukemia patients. However, the mechanism of diabetes amelioration by imatinib is unknown, and it is uncertain whether imatinib has effects on type 2 diabetes itself without other confounding diseases like leukemia. We studied the effect of imatinib on diabetes in db/db mice and investigated possible mechanism's underlying improved glycemic control by imatinib