The Role of the Gut Microbiota in Coronary Heart Disease.

PURPOSE OF REVIEW: This review focuses on recent evidence examining the role gut microbiota play in coronary heart disease. It also provides a succinct overview of current and future therapies targeting the gut microbiota for coronary heart disease risk reduction. RECENT FINDINGS: A consensus has been reached that differences exist in the gut microbiotas of patients with coronary heart disease. Studies have shown that the gut microbiota is associated with obesity, diabetes, dyslipidemia, and hypertension, which are risk factors for coronary heart disease. The gut microbiota is involved in mediating basic metabolic processes, such as cholesterol metabolism, uric acid metabolism, oxidative stress, and inflammatory reactions, through its metabolites, which can induce the development of atherosclerosis and coronary heart disease. Interfering with the composition of gut microbiota, supplementing probiotics, and fecal donation are active areas of research to potentially prevent and treat coronary heart disease. Gut microbiota are causally associated with coronary heart disease. We analyzed the gut microbiota's effects on risk factors for coronary heart disease and studied the effects of gut microbiota metabolites on coronary heart disease. Gut microbiota is a potential target for preventing and treating coronary heart disease.

Paenibacillus luteus sp. nov., isolated from soil.

A novel Gram-stain-positive, strictly aerobic, motile, spore-forming and rod-shaped bacterial strain, designated R-3T, was isolated from a soil sample obtained from the shore of Lake Panyang, Sichuan Province, PR China. Strain R-3T hydrolysed starch and casein. It could not assimilate d-glucose as a carbon source, or produce acid from d-glucose and l-arabinose. Phylogenetic, phenotypic, chemotaxonomic and molecular studies were performed on the new isolate. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain R-3T was a member of the genus Paenibacillus, exhibiting the highest sequence similarity to Paenibacillus sinopodophylli TEGR-3T (98.4 %). The organism grew at 4-38 °C (optimum, 28-30 °C), at pH 6.0-10.0 (pH 7.0-7.5) and with 0-2.5 % (w/v) NaCl (1 %). The predominant menaquinone was MK-7. Anteiso-C15 : 0 (60.7 %) and C16 : 0 (15.5 %) were the major fatty acids. The cellular polar lipids contained diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, three unidentified aminophospholipids and one unidentified phospholipid. The DNA G+C content of strain R-3T was determined to be 47.0 mol%. The DNA-DNA relatedness between strain R-3T and P. sinopodophylli TEGR-3T was 21.2 %. Based on the results obtained in this study, strain R-3T is considered to represent a novel species of the genus Paenibacillus, for which the name Paenibacillusluteus sp. nov. is proposed. The type strain is R-3T (=CGMCC 1.16135T=KCTC 33912T).

Overexpression of microRNA-138 alleviates human coronary artery endothelial cell injury and inflammatory response by inhibiting the PI3K/Akt/eNOS pathway.

This study aimed to investigate the role of miR-138 in human coronary artery endothelial cell (HCAEC) injury and inflammatory response and the involvement of the PI3K/Akt/eNOS signalling pathway. Oxidized low-density lipoprotein (OX-LDL)-induced HCAEC injury models were established and assigned to blank, miR-138 mimic, miR-138 inhibitor, LY294002 (an inhibitor of the PI3K/Akt/eNOS pathway), miR-138 inhibitor + LY294002 and negative control (NC) groups. qRT-PCR and Western blotting were performed to detect the miR-138, PI3K, Akt and eNOS levels and the protein expressions of PI3K, Akt, eNOS, p-Akt, p-eNOS, Bcl-2, Bax and caspase-3. ELISAs were employed to measure the expressions of TNF-α, IL-4, IL-6, IL-8, IL-10 and nitric oxide (NO) and the activities of lactate dehydrogenase (LDH) and eNOS. MTT and flow cytometry were performed to assess the proliferation and apoptosis of HCAECs. Compared to the blank group, PI3K, Akt and eNOS were down-regulated in the miR-138 mimic and LY294002 groups but were up-regulated in the miR-138 inhibitor group. The miR-138 mimic and LY294002 groups showed decreased concentrations of TNF-α, IL-6, IL-8 and NO and reduced activities of LDH and eNOS, while opposite trends were observed in the miR-138 inhibitor group. The concentrations of IL-4 and IL-10 increased in the miR-138 mimic and LY294002 groups but decreased in the miR-138 inhibitor group. The miR-138 mimic and LY294002 groups had significantly decreased cell proliferation and increased cell apoptosis compared to the blank group. These findings indicate that up-regulation of miR-138 alleviates HCAEC injury and inflammatory response by inhibiting the PI3K/Akt/eNOS signalling pathway.

Paenibacillus albidus sp. nov., isolated from grassland soil.

A novel bacterial strain, designed Q4-3T, was isolated from a soil sample obtained from Qilian grassland, Qinghai, China. Phylogenetic, phenotypic, chemotaxonomic and molecular analyses were performed on the new isolate. Cells were Gram-stain-positive, facultatively anaerobic, spore-forming, motile rods with peritrichous flagella. Phylogenetic analysis based on 16S rRNA gene sequences placed strain Q4-3T in the genus Paenibacillus, and its closest relatives were Paenibacillus odorifer JCM 21743T, Paenibacillus typhae DSM 25190T, Paenibacillus borealis DSM 13188T and Paenibacillus etheri DSM 29760T with 16S rRNA gene sequence similarities of 98.12, 97.89, 97.63 and 97.6 %, respectively. The isolate grew at 4-37 °C (optimum 28-30 °C), at pH 6.0-10.0 (optimum pH 7.5) and with 0-3 %(w/v) NaCl (optimum 1 %). The DNA of strain Q4-3T was determined to be 48.6 mol%. The predominant menaquinone was MK-7 and the diamino acid in the cell-wall peptidoglycan was found to be meso-diaminopimelic acid. Anteiso-C15 : 0 (55.5 %), iso-C16 : 0 (14.5 %) and C16 : 0 (13.3 %) were the major fatty acids. The polar lipids contained diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, three unidentified aminophospholipids and one unidentified lipid. Based on these results, strain Q4-3T is considered to represent a novel of the genus Paenibacillus, for which the name Paenibacillusalbidus nov. is proposed. The type strain is Q4-3T (=CGMCC 1.16134T=KCTC 33911T).

Streptomyces fuscichromogenes sp. nov., an actinomycete from soil.

A novel actinomycete, designated strain m16T, was isolated from a soil sample collected from the tropical rain forest of Xishuangbanna, a prefecture in Yunnan Province, south-west China, and characterized by using polyphasic taxomomy. Cells were aerobic and Gram-reaction-positive, and spore chains were observed to be of the helical type, with elliptical spores and smooth spore surfaces. The novel strain grew over a temperature range of 15-35 °C, at pH 5.0-11.0 and in the presence of 0-3 % (w/v) NaCl. The DNA G+C content of strain m16T was 70.0 mol%. The main fatty acids were iso-C16 : 0 (29.3 %), iso-C15: 0 (15.4 %) and anteiso-C15:0 (14.6 %), and the predominant menaquinones were MK-9(H6), MK-9(H8) and MK-9(H4). Comparative 16S rRNA gene sequence analysis showed that strain m16T was most closely related to Streptomyces jiujiangensis KCTC 29262T (98.7 %), Streptomyces panaciradicis KACC 17632T (98.7 %), Streptomyces rhizophilus NBRC 108885T (98.5 %), Streptomyces shenzhenensis DSM 42034T (98.4 %), Streptomyces graminisoli JR-19T (98.4 %) and Streptomyces gramineus JR-43T (98.3 %). Phylogenetic, chemotaxonomic and phenotypic analyses indicated that strain m16T represents a novel species within the genus Streptomyces, for which the name Streptomyces fuscichromogenes is proposed. The type strain is m16T (=CGMCC 4.7110T=KCTC 29195T).

Mesenchymal Stem Cells Deliver Exogenous MicroRNA-let7c via Exosomes to Attenuate Renal Fibrosis.

The advancement of microRNA (miRNA) therapies has been hampered by difficulties in delivering miRNA to the injured kidney in a robust and sustainable manner. Using bioluminescence imaging in mice with unilateral ureteral obstruction (UUO), we report that mesenchymal stem cells (MSCs), engineered to overexpress miRNA-let7c (miR-let7c-MSCs), selectively homed to damaged kidneys and upregulated miR-let7c gene expression, compared with nontargeting control (NTC)-MSCs. miR-let7c-MSC therapy attenuated kidney injury and significantly downregulated collagen IVα1, metalloproteinase-9, transforming growth factor (TGF)-ß1, and TGF-ß type 1 receptor (TGF-ßR1) in UUO kidneys, compared with controls. In vitro analysis confirmed that the transfer of miR-let7c from miR-let7c-MSCs occurred via secreted exosomal uptake, visualized in NRK52E cells using cyc3-labeled pre-miRNA-transfected MSCs with/without the exosomal inhibitor, GW4869. The upregulated expression of fibrotic genes in NRK52E cells induced by TGF-ß1 was repressed following the addition of isolated exosomes or indirect coculture of miR-let7c-MSCs, compared with NTC-MSCs. Furthermore, the cotransfection of NRK52E cells using the 3'UTR of TGF-ßR1 confirmed that miR-let7c attenuates TGF-ß1-driven TGF-ßR1 gene expression. Taken together, the effective antifibrotic function of engineered MSCs is able to selectively transfer miR-let7c to damaged kidney cells and will pave the way for the use of MSCs for therapeutic delivery of miRNA targeted at kidney disease.

Halomonas lutescens sp. nov., a halophilic bacterium isolated from a lake sediment.

A novel, Gram-stain-negative, facultatively anaerobic, halophilic bacterium, designated strain Q1UT, was isolated from a sediment sample collected from Qinghai Lake, PR China. The cells of the strain were short rod-shaped (0.2-0.3×0.6-2.5 µm) and non-motile. Strain Q1UT formed yellowish colonies and grew at temperatures of 2-37 °C (optimum 30-33 °C), at pH 6.0-9.0 (optimum pH 7.0) and in the presence of 0-20 % (w/v) NaCl (optimum 7.5 %). The major cellular fatty acids were C18 : 1ω7c (58.6 %), C16 : 1ω7c and/or C16 : 1ω6c (14.8 %) and C16 : 0 (10.1 %). The polar lipids were identified as diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, unknown phospholipid and unknown lipids. The genomic DNA G+C content was 61.5 mol%, and the predominant respiratory ubiquinone Q-9. Based on phylogenetic analysis of the 16S rRNA gene sequences and concatenated 16S rRNA, gyrB and rpoD gene sequences, the isolate was found to belong to the genus Halomonas in the class Gammaproteobacteria. The most closely related species were Halomonas venusta DSM 4743T (98.3 % 16S rRNA sequence similarity), Halomonas songnenensis DSM 25870T (98.2 %) and Halomonas hydrothermalis DSM 15725T (98.2 %). DNA-DNA relatedness values between strain Q1UT and the type strains of eight other species of the genus Halomonas ranged from 21.3 % to 10.1 %. On the basis of phenotypic, phylogenetic and chemotaxonomic analyses, and DNA-DNA hybridization relatedness values, strain Q1UT is considered to represent a novel species of the genus Halomonas; the name Halomonas lutescens sp. nov. is proposed. The type strain is Q1UT (=CGMCC 1.15122T=KCTC 42517T).

Major depressive disorder and aneurysm: A genetic study of association and causality.

BACKGROUND: Association between depression and aneurysm has been implicated but the specific role of depression in aneurysm remains unclear. We aimed to comprehensively characterize the relation of major depressive disorder (MDD) with aneurysm by subtype. METHODS: Harnessing summary statistics from genome-wide association studies (Ncase/Ncontrol = 7603/317,899 for aortic aneurysm; 7321/317,899 for thoracic aortic aneurysm; 3201/317,899 for abdominal aortic aneurysm; 1788/317,899 for cerebral aneurysm; and 246,363/561,190 for major depressive disorder), we estimated the genetic correlation between MDD and each of four aneurysm subtypes via LD Score Regression and tested the causality via various estimators under the bi-directional Mendelian randomization (MR) framework. RESULTS: Positive genetic correlation of statistical significance, ranging between 0.15 (with thoracic aortic aneurysm, P = 0.005) and 0.25 (with abdominal aortic aneurysm, P = 0.001), was consistently observed for MDD with each aneurysm subtype. In the MR analysis of MDD as an exposure, genetic liability to MDD causally increased the risk of cerebral (odds ratio: 1.71; 95 % confidence interval: 1.26-2.34) but not aortic aneurysm. Replication analysis of an independent dataset (Ncase/Ncontrol = 6242/59,418) corroborated this signal. In contrast, causal effect was not evident for any neurysm subtype on susceptibility to MDD. LIMITATIONS: Aneurysm could have been underdiagnosed if asymptomatic, leading to an underestimated causal impact on MDD. Non-linearity of the causal effect was not tested due to the lack of individual-level data. CONCLUSIONS: Depression and aneurysm may share common pathomechanisms. Screening depressed population and improving the clinical management for depression may benefit the primary prevention of cerebral aneurysm.

Design a dual-response two-photon fluorescent probe for simultaneous imaging of mitochondrial viscosity and peroxynitrite in a thrombosis model.

BACKGROUND: Venous thromboembolism is a sudden cardiovascular disease that can lead to death, and its pathologic development is closely related to vascular viscosity and inflammation. However, direct evidence from in vivo is really scarce. The key limitation is that the combined probes cannot detect multiple markers simultaneously, which may lead to unreliable results. Therefore, to develop a single probe that can simultaneously monitor the variations of viscosity in the vascular microenvironment as well as inflammation level during venous thrombosis. RESULTS: A dual-responsive two-photon fluorescent probe, Cou-ONOO, was designed and synthesized. Cou-ONOO provides a visualization tool for monitoring the viscosity of the vascular as well as the inflammatory marker ONOO‾ during thromboembolism via dual-channel simultaneous imaging. As a single probe that can recognize dual targets, Cou-ONOO effectively avoids the problems from unreliable results caused by complex synthesis and differences in intracellular localization, diffusion, and metabolism of different dyes as using combinatorial probes. Using Cou-ONOO, simultaneous imaging the variations of viscosity and ONOO‾at the cellular and tissue levels was successfully performed. In addition, Cou-ONOO also successfully visualized and tracked the viscosity of the vascular microenvironment and ONOO‾ during venous embolism in mice. SIGNIFICANCE: Experimental results show that both viscosity and inflammation are abnormally overexpressed in the microenvironment at the thrombus site during venous thrombosis. An intuitive visualization tool to elucidate the variations of viscosity as well as inflammation level in the vascular microenvironment during thrombosis was provided, which will facilitate a better clinical understanding of the pathological process of thrombosis.

Associating brain imaging phenotypes and genetic risk factors via a hypergraph based netNMF method.

Abstract: Alzheimer's disease (AD) is a severe neurodegenerative disease for which there is currently no effective treatment. Mild cognitive impairment (MCI) is an early disease that may progress to AD. The effective diagnosis of AD and MCI in the early stage has important clinical significance. Methods: To this end, this paper proposed a hypergraph-based netNMF (HG-netNMF) algorithm for integrating structural magnetic resonance imaging (sMRI) of AD and MCI with corresponding gene expression profiles. Results: Hypergraph regularization assumes that regions of interest (ROIs) and genes were located on a non-linear low-dimensional manifold and can capture the inherent prevalence of two modalities of data and mined high-order correlation features of the two data. Further, this paper used the HG-netNMF algorithm to construct a brain structure connection network and a protein interaction network (PPI) with potential role relationships, mine the risk (ROI) and key genes of both, and conduct a series of bioinformatics analyses. Conclusion: Finally, this paper used the risk ROI and key genes of the AD and MCI groups to construct diagnostic models. The AUC of the AD group and MCI group were 0.8 and 0.797, respectively.

PCSK9, a novel immune and ferroptosis related gene in abdominal aortic aneurysm neck.

The gene expression profile of abdominal aortic aneurysm (AAA) neck is not fully understood. The etiology of AAA is considered to be related to atherosclerosis and the inflammatory response, involving congenital, genetic, metabolic, and other factors. The level of proprotein convertase subtilisin/kexin type 9 (PCSK9) is related to those of cholesterol, oxidized low-density lipoprotein, and triglycerides. PCSK9 inhibitors have significant effects on lowering LDL-cholesterol, reversing atherosclerotic plaques, and reducing the risk of cardiovascular events and have been approved by several lipid-lowering guidelines. This work was aimed to investigate the potential role of PCSK9 in the neck of AAA. We extracted the expression dataset (GSE47472) containing 14 AAA patients and 8 donors and single-cell RNAseq (scRNA-seq) data (GSE164678) of CaCl2-induced (AAA) samples from the Gene Expression Omnibus dataset. Through bioinformatics methods, we found that PCSK9 was up-regulated in the proximal neck of human AAA. In AAA, PCSK9 was mainly expressed in fibroblasts. Additionally, immune check-point PDCD1LG2 was also expressed higher in AAA neck than donor, while CTLA4, PDCD1, and SIGLEC15 were down-regulated in AAA neck. The expression of PCSK was correlated with PDCD1LG2, LAG3, and CTLA4 in AAA neck. Additionally, some ferroptosis-related genes were also down-regulated in AAA neck. PCSK9 was also correlated with ferroptosis-related genes in AAA neck. In conclusion, PCSK9 was highly expressed in AAA neck, and may exert its role through interacting with immune check-points and ferroptosis-related genes.

Engineering T cell receptor fusion proteins using nonviral CRISPR/Cas9 genome editing for cancer immunotherapy.

Manufacture of chimeric antigen receptor (CAR)-T cells usually involves the use of viral delivery systems to achieve high transgene expression. However, it can be costly and may result in random integration of the CAR into the genome, creating several disadvantages including variation in transgene expression, functional gene silencing and potential oncogenic transformation. Here, we optimized the method of nonviral, CRISPR/Cas9 genome editing using large donor DNA delivery, knocked-in an anti-tumor single chain variable fragment (scFv) into the N-terminus of CD3ε and efficiently generated fusion protein (FP) T cells. These cells displayed FP integration within the TCR/CD3 complex, lower variability in gene expression compared to CAR-T cells and good cell expansion after transfection. CD3ε FP T cells were predominantly CD8+ effector memory T cells, and exhibited anti-tumor activity in vitro and in vivo. Dual targeting FP T cells were also generated through the incorporation of scFvs into other CD3 subunits and CD28. Compared to viral-based methods, this method serves as an alternative and versatile way of generating T cells with tumor-targeting receptors for cancer immunotherapy.

In vitro investigation of renal epithelial injury suggests that primary cilium length is regulated by hypoxia-inducible mechanisms.

Primary cilia are non-motile sensory organelles that project from cells in many tissues. The role of renal primary cilium-based signalling in regulating epithelial cell proliferation and differentiation is highlighted by studies showing that defects of the cilium lead to epithelial de-differentiation, over proliferation and polycystic kidney disease. Recent studies show that renal primary cilia may also play a role in controlling epithelial differentiation during renal repair. After injury, renal cilium length increases dramatically and then undergoes a normalization that coincides with structural and functional repair in both human patients and mouse models of renal injury. These changes in cilium length are likely to modulate cilium-based signalling, but the injury-related factors that influence renal primary cilium length have yet to be determined. Here, we investigated the effect of three factors commonly associated with renal injury on renal cilium length in an in vitro setting. MDCK (Madin Darby canine kidney) cell cultures bearing primary cilia were treated with BSA to simulate albuminuria, cobalt chloride to simulate hypoxia and the inflammation-related cytokine tumour necrosis factor α. Primary cilium length was only increased in cultures treated with cobalt chloride. Our results suggest a role for hypoxia and the induction of HIF-1α (hypoxia-inducible factor 1α) in increasing renal primary cilium length following renal injury.

Engineered CAR-T cells targeting TAG-72 and CD47 in ovarian cancer.

Chimeric antigen receptor (CAR) T cells have revolutionized blood cancer immunotherapy; however, their efficacy against solid tumors has been limited. A common mechanism of tumor escape from single target therapies is downregulation or mutational loss of the nominal epitope. Targeting multiple antigens may thus improve the effectiveness of CAR immunotherapies. We generated dual CAR-T cells targeting two tumor antigens: TAG-72 (tumor-associated glycoprotein 72) and CD47. TAG-72 is a pan-adenocarcinoma oncofetal antigen, highly expressed in ovarian cancers, with increased expression linked to disease progression. CD47 is ubiquitously overexpressed in multiple tumor types, including ovarian cancer; it is a macrophage "don't eat me" signal. However, CD47 is also expressed on many normal cells. To avoid this component of the dual CAR-T cells killing healthy tissue, we designed a truncated CD47 CAR devoid of intracellular signaling domains. The CD47 CAR facilitates binding to CD47+ cells, increasing the prospect of TAG-72+ cell elimination via the TAG-72 CAR. Furthermore, we could reduce the damage to normal tissue by monomerizing the CD47 CAR. Our results indicate that the co-expression of the TAG-72 CAR and the CD47-truncated monomer CAR on T cells could be an effective, dual CAR-T cell strategy for ovarian cancer, also applicable to other adenocarcinomas.

SCUBE1, a novel developmental gene involved in renal regeneration and repair.

BACKGROUND: We have identified that a novel developmental gene and protein, SCUBE1, is expressed in endothelial cells and may play an important role in kidney regeneration. METHODS: The temporal and spatial expression of SCUBE1 was determined in a mouse model of ischaemia-reperfusion (IR) injury at 3 days and 1, 3 and 6 weeks post-injury by immunofluorescence microscopy. In vitro analysis was used to examine SCUBE1 signalling in endothelial cells under conditions of cell stress using quantitative real-time polymerase chain reaction and immunofluorescence labelling. The media from cultured endothelial cells following SCUBE1 small interfering RNA (siRNA) transfection was used to assess the proliferation capacity of epithelial cells. RESULTS: Immunofluorescence confocal microscopy demonstrated that the SCUBE1 protein was localized to CD31-positive endothelial cells in IR kidneys during the resolution of tissue damage (3 weeks), but not in control animals. The peak expression of SCUBE1 following 3 weeks of IR injury was confirmed by reverse transcription-polymerase chain reaction. SCUBE1 mRNA and protein expression were detected in cultured endothelial cells under hypoxic conditions or serum starving. Furthermore, there was a significant decrease in epithelial cell proliferation following the addition of a supernatant derived from cultured endothelial cells following SCUBE1 siRNA gene silencing compared to control media. CONCLUSIONS: Our results indicate that SCUBE1 may be involved in the regulation of tubular cell proliferation and re-epithelialization during the resolution of kidney injury.

Renal primary cilia lengthen after acute tubular necrosis.

Renal primary cilia are sensory antennas required for the maintenance of normal epithelial differentiation and proliferation in the kidney, but they also have a potential role in epithelial differentiation during renal injury and repair. In mice, tubular damage causes an increase in the length of renal cilia, which may modify their sensory sensitivity during repair. Here, we investigated whether the alteration of renal cilium length during renal injury is clinically relevant. Using biopsies of human renal transplants that suffered acute tubular necrosis during transplantation, we compared the length of renal primary cilia with renal function. Serial biopsies showed that acute tubular necrosis resulted in more than a doubling of cilium length throughout the nephron and collecting duct approximately 1 wk after injury. Allografts displayed a trend toward normalization of cilium length in later biopsies, and this correlated with functional recovery. A mouse model of renal ischemia-reperfusion confirmed the increase and subsequent regression of cilium length during renal repair, displaying complete normalization of cilium length within 6 wk of injury. These findings demonstrate that the length of renal cilia is a clinically relevant indicator of renal injury and repair.

Negative pressure wound therapy promotes wound healing by suppressing macrophage inflammation in diabetic ulcers.

Aim: This work aims to explore the biological role of negative pressure wound therapy (NPWT) in the treatment of diabetic ulcer. Materials & methods: Full-thickness skin defects were created in diabetic (db/db) and non diabetic (db/m) mice to create wound models. The mice were received NPWT or rapamycin injection. Mouse macrophage cells (Raw264.7) were treated with lipopolysaccharide to induce inflammatory response, and then received negative pressure treatment. We observed the wound healing of mice and examined gene and protein expression and CD68+ macrophage levels. Results: NPWT notably enhanced the wound closure ratio, and inhibited the LC3-II/LC3-I ratio and Beclin-1 expression in diabetes mellitus (DM) mice. NPWT decreased CD68+ macrophage levels in wound tissues of DM mice. The influence conferred by NPWT was abolished by rapamycin treatment. Negative pressure repressed the LC3-II/LC3-I ratio and the expression of Beclin-1, TNF-α, IL-6 and IL-1ß in the Raw264.7 cells. Conclusion: NPWT promotes wound healing by suppressing autophagy and macrophage inflammation in DM.

Resveratrol attenuates inflammation in the rat heart subjected to ischemia-reperfusion: Role of the TLR4/NF-κB signaling pathway.

It has been previously reported that Toll­like receptor 4 (TLR4)/NF­κB signaling mediates early inflammation during myocardial ischemia and reperfusion. It has additionally been suggested that resveratrol produces cardioprotective and anti­inflammatory effects. The aim of the present study was to investigate whether resveratrol could modulate TLR4/NF­κB signaling, reduce neutrophil accumulation and TNF­α induction in an ischemia/reperfusion injured rat heart model. Rats were randomly exposed to a sham operation, myocardial ischemia and reperfusion (MI/R), MI/R + resveratrol or MI/R + resveratrol + L­NAME. The data showed that following MI/R, the expression of myocardial TLR4 and NF­κB increased significantly in the area of induced ischemia. As compared with MI/R, resveratrol significantly attenuated the expression of TLR4 and NF­κB and reduced the levels of myeloperoxidase, serum and myocardial TNF­α production, myocardial infarct size and myocardial apoptosis induced by MI/R. All the effects of resveratrol were abolished upon application of L­NAME, a nitric oxide (NO) synthase inhibitor. These data provide evidence that resveratrol inhibits TLR4/NF­κB signaling in the rat heart subjected to MI/R, and the anti­inflammatory effect of resveratrol is associated with NO production.

Association of polymorphisms of the receptor for advanced glycation end products gene and susceptibility to sporadic abdominal aortic aneurysm.

Accumulating evidence has suggested that receptor for advanced glycation end products (RAGE) is involved in the development and progression of human abdominal aortic aneurysms (AAAs). However, the association between RAGE gene polymorphisms and AAA has not yet been determined. The present study was aimed at analyzing the potential association between the RAGE gene polymorphisms and AAAs. A cohort of 381 patients and 436 age-matched healthy controls were genotyped to detect the three RAGE polymorphisms (-374 T/A, -429 T/C, and G82S) using SNaPshot. Our study demonstrated a significant difference in the genotype and allele frequencies of the RAGE G82S polymorphism between the AAA patients and the controls. Further stratification by gender and smoking status revealed that the presence of the RAGE 82S allele confers a higher risk for developing AAA in men and smokers. Moreover, AAA patients with the variant 82S allele of RAGE presented with reduced serum soluble RAGE (sRAGE) production, and this decrease was more significant in men and smokers with AAA. Our study provides preliminary evidence that the 82S allele of RAGE is a risk factor for AAA. This new piece of knowledge regarding RAGE may be clinically important for the prevention and therapy of AAAs.