Relationship between Uric Acid to High Density Lipoprotein Cholesterol Ratio and Nonalcoholic Fatty Liver Disease in Nonoverweight/Obese Patients with Type 2 Diabetes.

Aims: To investigate the relationship between uric acid to high-density lipoprotein cholesterol ratio (UHR) levels and nonalcoholic fatty liver disease (NAFLD) in nonoverweight/obese patients with type 2 diabetes. Methods: A retrospective study was designed including a total of 343 inpatients with type 2 diabetes whose BMI<24 kg/m2. The population was divided into three groups as the UHR tertiles. Logistic regression analysis was performed to estimate odds ratios (ORs) of UHR for NAFLD. ROC curve analysis was used to estimate the diagnostic value of UHR for NAFLD. Results: The prevalence rat of NAFLD enhanced progressively from the tertile 1 to tertile 3 of UHR (30.70% vs. 56.52% vs. 73.68%). Logistic regression analysis showed that participants in the higher UHR groups, compared with those in the first tertile group, had higher occurrence risks for NAFLD. The positive association between UHR and NAFLD was independent of age, BMI, blood pressure, hepatic enzymes, and other components of metabolic disorders. ROC curve analysis showed that the area under curve (AUC), sensitivity, and specificity for UHR were 0.697, 0.761, and 0.553, respectively. Conclusions: In type 2 diabetic patients without overweight or obesity, UHR is significantly associated with NAFLD and can be used as a novel and useful predictor for NAFLD onset.

Temporal-spatial low shear stress induces heterogenous distribution of hematopoietic stem cell budding in zebrafish.

Hematopoietic stem/progenitor cells (HSPCs) originate from endothelial cells (ECs) localized on the ventral side of the dorsal aorta (DA), and hemodynamic parameters may suffer sharp changes in DA at HSPCs development stage for intersegmental vessel formation. However, the temporal-spatial shear stress parameters and biomechanics mechanisms of HSPC budding remain unknown. Here, we found that the hematopoietic endothelium (HE) in the aorta-gonad-mesonephros was heterogeneous; that is, HEs were mainly distributed at the ventral side of the vascular bifurcation in zebrafish embryos, which was found to show low shear stress (LSS) through numerical simulation analysis. Furthermore, HSPCs localized in the posterior somite of aorta-gonad-mesonephros with slow velocity. On the temporal scale, there was a slow velocity and LSS during HE budding from 36 h post-fertilization and decreased shear stress with drug expanded HSPC numbers. Mechanistically, matrix metalloproteinase (MMP) expression and macrophage chemotaxis were significantly increased in HEs by RNA-seq. After treatment with an MMP13 inhibitor, HSPCs were significantly reduced in both the aorta-gonad-mesonephros and caudal hematopoietic tissue in embryos. Our results show that HSPC budding is heterogeneous, and the mechanism is that physiological LSS controls the emergence of HSPCs by promoting the accumulation of macrophages and subsequent MMP expression.

Uptake of oxidative stress-mediated extracellular vesicles by vascular endothelial cells under low magnitude shear stress.

Extracellular vesicles (EVs) are increasingly used as delivery vehicles for drugs and bioactive molecules, which usually require intravascular administration. The endothelial cells covering the inner surface of blood vessels are susceptible to the shear stress of blood flow. Few studies demonstrate the interplay of red blood cell-derived EVs (RBCEVs) and endothelial cells. Thus, the phagocytosis of EVs by vascular endothelial cells during blood flow needs to be elucidated. In this study, red blood cell-derived extracellular vesicles (RBCEVs) were constructed to investigate endothelial cell phagocytosis in vitro and animal models. Results showed that low magnitude shear stress including low shear stress (LSS) and oscillatory shear stress (OSS) could promote the uptake of RBCEVs by endothelial cells in vitro. In addition, in zebrafish and mouse models, RBCEVs tend to be internalized by endothelial cells under LSS or OSS. Moreover, RBCEVs are easily engulfed by endothelial cells in atherosclerotic plaques exposed to LSS or OSS. In terms of mechanism, oxidative stress induced by LSS is part of the reason for the increased uptake of endothelial cells. Overall, this study shows that vascular endothelial cells can easily engulf EVs in areas of low magnitude shear stress, which will provide a theoretical basis for the development and utilization of EVs-based nano-drug delivery systems in vivo.

Functionalized nanoparticles with monocyte membranes and rapamycin achieve synergistic chemoimmunotherapy for reperfusion-induced injury in ischemic stroke.

BACKGROUND: Ischemic stroke is an acute and severe neurological disease, and reperfusion is an effective way to reverse brain damage after stroke. However, reperfusion causes secondary tissue damage induced by inflammatory responses, called ischemia/reperfusion (I/R) injury. Current therapeutic strategies that control inflammation to treat I/R are less than satisfactory. RESULTS: We report a kind of shield and sword nano-soldier functionalized nanoparticles (monocyte membranes-coated rapamycin nanoparticles, McM/RNPs) that can reduce inflammation and relieve I/R injury by blocking monocyte infiltration and inhibiting microglia proliferation. The fabricated McM/RNPs can actively target and bind to inflammatory endothelial cells, which inhibit the adhesion of monocytes to the endothelium, thus acting as a shield. Subsequently, McM/RNPs can penetrate the endothelium to reach the injury site, similar to a sword, and release the RAP drug to inhibit the proliferation of inflammatory cells. In a rat I/R injury model, McM/RNPs exhibited improved active homing to I/R injury areas and greatly ameliorated neuroscores and infarct volume. Importantly, in vivo animal studies revealed good safety for McM/RNPs treatment. CONCLUSION: The results demonstrated that the developed McM/RNPs may serve as an effective and safe nanovehicles for I/R injury therapy.

Serum uric acid is positively associated with the prevalence of nonalcoholic fatty liver in non-obese type 2 diabetes patients in a Chinese population.

AIMS: To investigate whether SUA is independently associated with NAFLD in non-obese type 2 diabetic patients in a Chinese population. METHODS: A cross-sectional study was carried out among 400 non-obese type 2 diabetic inpatients. Patients were stratified according to SUA levels and presence/absence of NAFLD. The clinical and laboratory features were collected retrospectively. Multivariate logistic regression analysis was conducted to estimate odds ratios of SUA for NAFLD. RESULTS: The levels of SUA were significantly higher in patients with NAFLD than those without NAFLD. SUA was positively associated with the risk factors of NAFLD such as BMI, serum insulin and lipids. The odds of NAFLD were increasingly higher from the second to the fourth quartile of SUA as compared to the lowest quartile. After adjustment for age, gender, BMI and other metabolic components, the odds of NAFLD remained significantly increased for quartile 4. CONCLUSIONS: SUA levels are strongly and independently associated with the prevalence of NAFLD. SUA may be used as a useful predictor to stratify the higher risks for NAFLD of non-obese type 2 diabetes patients.

Nanoparticles retard immune cells recruitment in vivo by inhibiting chemokine expression.

The large-scale utilization of nanotechnology depends on public and consumer confidence in the safety of this new technology. Studying the interaction of nanoparticles with immune cells plays a vital role in the safety assessment of nanomedicine. Although some researches have indicated that the immune cells undergo severe interfere after phagocytosis of nanoparticles, the impact on immune system of the whole body are still unclear. Here, we use immune cells labeled transgenic zebrafish to study the mechanisms of nanoparticles on zebrafish immune cells. We demonstrate that gold nanoparticles (Au NPs) phagocytized by immune cells can reduce and retard the sensitivity of immune response, resulting nanoparticle-induced bluntness in immune cell (NIBIC). RNA-seq and functional analysis reveal that NIBIC is mainly induced by the inhibiting expression of chemokine receptor 5 (CCR5). Furthermore, PVP-modified Au NPs can eliminate NIBIC by inhibiting the cell phagocytosis. Our results highlight the potential risk for Au NPs in vivo and further the understanding of the mechanism of the interaction between Au NPs and the immune response. We should consider this factor in future material design and pay more attention to the process of using nanomedicines on immune diseases.

SRGN, a new identified shear-stress-responsive gene in endothelial cells.

Endothelial cells (ECs) play an important role in the pathogenesis of cardiovascular disease, especially atherosclerosis (AS). The abnormal wall shear stress (WSS) which directly contacts with ECs is the key stimulating factor leading to AS. However, the underlying mechanism of ECs responding to WSS is still incompletely understood. This study aims to explore the novel mechano-sensitive genes and its potential mechanism in response to WSS in ECs by employing bioinformatics methods based on previously available high-throughput data from zebrafish embryos, both before and after blood flow formation. Six common differentially expressed genes (DEGs) (SRGN, SLC12A3, SLC25A4, PVALB1, ITGAE.2, zgc:198419) were selected out from two high-throughput datasets (GSE126617 and GSE20707) in the GEO database. Among them, SRGN was chosen for further verification through the in vitro shear stress loading experiments with human umbilical vein endothelial cells (HUVECs) and the in vivo partial ligation of carotid artery in mice. Our data indicated that low shear stress (LSS) could enhance the expression of SRGN via the PKA/CREB-dependent signaling pathway. The proportion of Ki67+ cells and the concentration of nitric oxide (NO) were high in SRGN high expression cells, suggesting that SRGN may be involved in the proliferation of HUVECs. Furthermore, in the partial ligation of the carotid artery mice model, we observed that the expression of SRGN was significantly increased in atherosclerotic plaques induced by abnormal shear stress. Taken together, this study demonstrated that SRGN is a key gene in the response of ECs to WSS and could be involved in AS.

Duodenal-Jejunal Exclusion Surgery Improves Type 2 Diabetes in a Rat Model Through Regulation of Early Glucose Metabolism.

OBJECTIVES: Metabolic surgery has been proven to be widely effective for the control of glucose and weight in patients with type 2 diabetes and obesity. However, the effects of bariatric surgery on nonobesity type 2 diabetes and its metabolism are still unclear. This study aimed to measure the effects of duodenal-jejunal exclusion on glycometabolism in nonobese rats with type 2 diabetes and to investigate its mechanisms. METHODS: Goto-Kakizaki rats and Sprague-Dawley rats were divided into duodenal-jejunal exclusion operation groups and sham operation groups, respectively. The glucose-relative parameters were measured before and after operation. Eight weeks postoperation, the levels of the key regulators of intestinal gluconeogenesis and the crucial proteins of hepatic insulin signalling were evaluated. RESULTS: Postoperatively, the concentrations of blood glucose declined, and the insulin sensitivity increased significantly in rats with diabetes. However, there was no obvious reduction in weight. Eight weeks postoperatively, the mRNA levels of glucose-6-phosphatase and phosphoenolpyruvate pyruvate kinase in the jejunum and the levels of insulin receptor substrate-2 and glucose transporter-2 in the liver were significantly increased compared with the rats that had undergone the sham operation. CONCLUSIONS: Duodenal-jejunal exclusion surgery is an effective procedure for improving glucose metabolism independent of weight loss in nonobese rats with diabetes. The molecular mechanisms might be associated with a series of processes, including intestinal gluconeogenesis and the hepatic insulin signaling pathway.

Lactic acid-mediated endothelial to mesenchymal transition through TGF-ß1 contributes to in-stent stenosis in poly-L-lactic acid stent.

Currently, bioresorbable stents made with biodegradable materials are attracting more and more attentions in cardiovascular tissue engineering. Especially, poly-L-lactic acid (PLLA) stent has been regarded as the most promising one due to excellent biodegradability until serious in-stent restenosis at late stage was reported. This imply that the PLLA stent has side effect in cell function, and it is rarely reported the effect of degradation product of PLLA on endothelial function. Here we reported that lactic acid (LA) not acidic pH induced endothelial-to-mesenchymal transition (EndMT) leading to vascular fibrosis which may contribute to in-stent stenosis after PLLA stent implantation. Furthermore, we found TGF-ß1 signaling was involved in boosting EndMT by LA. These results demonstrate a mechanism of in-stent stenosis induced by PLLA and indicate its utility for the future design of polymeric vascular scaffolds.

A study on the physiological and behavioral mechanisms underlying the differences in survival capacity between two cyprinid fish species.

The crucian carp (Carassius auratus) and common carp (Cyprinus carpio) are close relatives and coexist in most of their natural habitats but with different levels of abundance. The crucian carp is usually more abundant than the common carp in high predation-pressure habitats. To verify whether the crucian carp exhibits a significantly higher survival capacity combined with additional antipredator strategies than the common carp, we measured the morphology, behavioral traits, fast-start escape swimming performance and survival time under predation in both fish species. Additionally, the relationships between morphology, behavioral traits, locomotion and survival in both fish species were analyzed to determine which components can explain survival. We found that the crucian carp showed significantly higher survival times combined with greater body depth and fast-start escape performance than did the common carp, and the fast-start escape performance may be the main reason that the crucian carp showed a higher survival capacity. Additionally, the predator (Channa argus) chased the common carp more frequently when exposed to both species simultaneously. The higher survival capacity of the crucian carp and the preference of the predator for the common carp may be partial reasons that crucian carp were more abundant in habitats with high-predation pressure. Despite the differences among species, only the fast-start maximum velocity and exploration of the crucian carp were significantly related to survival time based on Pearson correlations. Overall, the relationships between the components measured in this study and survival in both fish species were quite weak or even lacking, which may be associated with the lack of predation experience in the fish specimens used.

The Relation between Serum Uric Acid and HbA1c Is Dependent upon Hyperinsulinemia in Patients with Newly Diagnosed Type 2 Diabetes Mellitus.

Objective. The aim of our study was to explore the dependent condition of the relationship between uric acid and blood glucose in type 2 diabetes. Research Design and Methods. We measured the HbA1c, serum uric acid, creatinine, lipids profiles, and so forth of 605 newly diagnosed type 2 diabetes patients, and oral glucose tolerance tests (OGTTs) were performed on each patient. The population was divided into high and low insulin groups. Multiple linear regression analyses were conducted to assess the relationship between uric acid and HbA1c. Results. Serum uric acid and HbA1c levels were low in newly diagnosed type 2 diabetes patients. However, we found no significant relationship between uric acid and HbA1c by regression analysis after adjusting total insulin. The concentration of uric acid was inversely correlated with HbA1c in the high insulin group, regardless of patient sex. However, no associations were found in low insulin group. Conclusions. The negative correlation between uric acid and HbA1c is conditional in newly diagnosed type 2 diabetes patients and is related to hyperinsulinemia. Therefore, uric acid is likely only useful as a biomarker of blood glucose in patients exhibiting hyperinsulinemia.

[From gene cloning to expressional analysis--practice and experience from educational reform of experimental gene engineering].

Experimental gene engineering is a laboratory course focusing on the molecular structure, expression pattern and biological function of genes. Providing our students with a solid knowledge base and correct ways to conduct research is very important for high-quality education of genetic engineering. Inspired by recent progresses in this field, we improved the experimental gene engineering course by adding more updated knowledge and technologies and emphasizing on the combination of teaching and research, with the aim of offering our students a good start in their scientific careers.