p-Cresyl sulfate (PCS) is a risk factor of cardiovascular disease in patients with chronic kidney disease. Here we tested whether serum PCS levels were related to the rate and evolution of carotid atherosclerosis in hemodialysis patients and identified a potential mechanism. A total of 200 hemodialysis patients were categorized as with or without carotid atherosclerotic plaque and followed for 5 years. Serum PCS levels were found to be higher in patients with than without carotid atherosclerotic plaque and positively correlated with increased total plaque area during follow-up. Multiple logistic regression and mixed effects model analyses showed that serum PCS levels were independently associated with the incidence and progression of carotid atherosclerotic plaque. PCS induced inflammatory factor and adhesion molecule expression in endothelial cells and macrophages. In addition, PCS triggered monocyte-endothelial cell interaction in vitro and in vivo through increased production of reactive oxygen species. Compared with controls, increase of PCS levels produced by gavage promoted atherogenesis in 5/6-nephrectomized apoE-/- mice; a process attenuated by NADPH oxidase inhibitors. Thus, increased serum PCS levels are associated with the occurrence and progression of carotid atherosclerosis in hemodialysis patients and promote atherogenesis through increased reactive oxygen species production.

Recent studies have reported that subclinical hypothyroidism (SCH) is associated with atherosclerosis (AS). Thyroid hormone is maintained at normal levels in patients with SCH, whereas TSH is increased. However, the pathogenesis of AS in association with SCH is only partially understood. In addition, endothelial dysfunction plays an important role in the development of AS. The purpose of the present research was to study the direct effect of TSH on human umbilical vein endothelial cells (HUVECs). The expression of some genes associated with endothelial dysfunction after treatment with TSH was evaluated by real-time PCR and western blotting respectively. At first, we showed that the TSH receptor (TSHR) is expressed in HUVECs. We also provide evidence indicating that TSH treatment promotes tumor necrosis factor a-induced endothelial cells interactions by upregulating the expression of the adhesion molecules intercellular adhesion molecule-1. Furthermore, the expression of endothelial nitric oxide synthase (eNOS) and prostacyclin (PGI 2 ) was significantly attenuated following treatment with TSH in dose-and time-dependent manner. Conversely, the results indicated that TSH upregulated endothelin-1 (ET1) mRNA and protein expression in HUVECs, similar effects were observed for plasminogen activator inhibitor-1 (PAI1) after treatment with various concentrations of TSH. Taken together, these results demonstrate that elevated TSH can promote endothelial dysfunction by altering gene expression in HUVECs.

It is thought that carbamylated modification plays a crucial role in the development and progression of cardiovascular disease (CVD) in patients with end-stage renal disease (ESRD). However, information on the biological effects of carbamylated high-density lipoprotein (C-HDL) in ESRD is poor. The present study investigated the carbamylation level of HDL in ESRD and the effects of C-HDL on endothelial repair properties. HDL was isolated from healthy control subjects (n = 22) and patients with ESRD (n = 30). The carbamylation level of HDL was detected using ELISA. Isolated C-HDL for use in tissue culture experiments was carbamylated in vitro to a similar extent to that observed in ESRD. Human arterial endothelial cells were treated with C-HDL or native HDL to assess their migration, proliferation, and angiogenesis properties. HDL-associated paraoxonase 1 activity was also determined by spectrophotometry assay. Compared with healthy control subjects, the carbamylation level of HDL in ESRD patients was increased and positively correlated with blood urea concentration. In vitro, C-HDL significantly inhibited migration, angiogenesis, and proliferation in endothelial cells. Mechanistic studies revealed that HDL-associated paraoxonase 1 activity was decreased and negatively correlated with the carbamylation level of HDL in ESRD patients. In addition, C-HDL suppressed the expression of VEGF receptor 2 and scavenger receptor class B type I signaling pathways in endothelial cells. In conclusion, the present study identified a significantly increased carbamylation level of HDL in ESRD. Furthermore, C-HDL inhibited endothelial cell repair functions.

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Background: loss of the interdental papillae leads to the formation of a black triangle, which compromises smile esthetics and contributes to food impaction and plaque accumulation. The aim of this study was to evaluate the efficacy of the injection of hyaluronic acid (HA) and compare it to that of physiological saline solution in the restoration of deficient gingival papillae in vivo and in vitro.Methods: Twenty-four patients with 68 deficient gingival papillae were recruited for this clinical trial with a split-mouth design. The deficient gingival papillae on one side of the anterior maxilla were injected with HA, and those on the other side were injected with physiological saline solution. The heights of the gingival papillae and the areas of the black triangles were measured from clinical photographs obtained before and 6 and 12 months after treatment. Additionally, the proliferation and migration of gingival fibroblasts were evaluated after HA and physiological saline treatment by an in vitro study.Results: the results revealed that the injection of HA yielded 0.198 and 0.28 mm gingival papilla increasement at 6 and 12 months, respectively, relative to the baseline (P<0.05). However, deficient gingival papillae also grew by 0.278 mm at 12 months in the group that received physiological saline solution (P<0.05).The injection of HA significantly improved deficient gingival papillae 6 months earlier than the injection of physiological saline solution. HA also significantly accelerated the proliferation and migration of gingival fibroblasts in vitro.Conclusions: The present study confirms that the injection of HA could increase the height of gingival papillae for improving gingival papilla defects. However, the effect is not superior to that of physiological saline solution. This trial was registered in the Chinese Clinical Trial Registry (ChiCTR-ONC-17011781)

Subclinical hypothyroidism (SCH) was reported to be associated with atherosclerosis (AS) in recent studies. Thyroid hormone levels are normal in patients with SCH, but the levels of thyroid-stimulating hormone (TSH) are increased. Thyroid-stimulating hormone receptor (TSHR) in extra-thyroidal tissues plays a pathophysiological role in these conditions. Our previous results demonstrated that TSHR was functional in hepatocytes and revealed elevated total cholesterol levels in the serum, which were an independent risk factor for AS. TSHR is expressed in vascular smooth muscle cells (VSMCs), and VSMC proliferation plays an important role in the development of AS. Cell proliferation was measured by the MTT assay. Intracellular cyclic AMP (cAMP) was measured using a cAMP ELISA kit. Cells were analyzed using a flow cytometer to determine the cell-cycle phase of each cell. For the purpose of detecting cyclin A and cyclin D, immunohistochemical staining and western blots were performed. Real-time PCR was used to assess the VSMC phenotypes. TSH increased cell progression into the G2/M phases and induced VSMC proliferation; thus, functional TSHR was present on VSMCs. Furthermore, the expression of cyclin D1 and cyclin A was increased. In addition, the results indicated that VSMCs undergo a phenotypic transformation from a contractile state to a synthetic state after treatment with different concentrations of TSH. Elevated TSH can promote VSMC proliferation through the cAMP-dependent pathway.

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BackgroundThe aim of this study was to construct crosslinked polylysine‐hyaluronic acid microspheres (pl‐HAM) ladened with gingival mesenchymal stem cells (GMSCs) and explore its biologic behavior in soft tissue regeneration.MethodsThe effects of the crosslinked pl‐HAM on the biocompatibility and the recruitment of L‐929 cells and GMSCs were detected in vitro. Moreover, the regeneration of subcutaneous collagen tissue, angiogenesis and the endogenous stem cells recruitment were investigated in vivo. We also detected the cell developing capability of pl‐HAMs.ResultsThe crosslinked pl‐HAMs appeared to be completely spherical‐shaped particles and had good biocompatibility. L‐929 cells and GMSCs grew around the pl‐HAMs and increased gradually. Cell migration experiments showed that pl‐HAMs combined with GMSCs could promote the migration of vascular endothelial cells significantly. Meanwhile, the green fluorescent protein‐GMSCs in the pl‐HAM group still remain in the soft tissue regeneration area 2 weeks after surgery. The results of in vivo studies showed that denser collagen deposition and more angiogenesis‐related indicator CD31 expression in the pl‐HAMs+ GMSCs + GeL group compared with the pl‐HAMs + GeL group. Immunofluorescence showed that CD44, CD90, CD73 co‐staining positive cells surrounded the microspheres in both pl‐HAMs + GeL group and pl‐HAM + GMSCs + GeL group.ConclusionsThe crosslinked pl‐HAM ladened with GMSCs system could provide a suitable microenvironment for collagen tissue regeneration, angiogenesis and endogenous stem cells recruitment, which may be an alternative to autogenous soft tissue grafts for minimally invasive treatments for periodontal soft tissue defects in the future.