Pericytes protect rats and mice from sepsis-induced injuries by maintaining vascular reactivity and barrier function: implication of miRNAs and microvesicles.

BACKGROUND: Vascular hyporeactivity and leakage are key pathophysiologic features that produce multi-organ damage upon sepsis. We hypothesized that pericytes, a group of pluripotent cells that maintain vascular integrity and tension, are protective against sepsis via regulating vascular reactivity and permeability. METHODS: We conducted a series of in vivo experiments using wild-type (WT), platelet-derived growth factor receptor beta (PDGFR-ß)-Cre + mT/mG transgenic mice and Tie2-Cre + Cx43flox/flox mice to examine the relative contribution of pericytes in sepsis, either induced by cecal ligation and puncture (CLP) or lipopolysaccharide (LPS) challenge. In a separate set of experiments with Sprague-Dawley (SD) rats, pericytes were depleted using CP-673451, a selective PDGFR-ß inhibitor, at a dosage of 40 mg/(kg·d) for 7 consecutive days. Cultured pericytes, vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs) were used for mechanistic investigations. The effects of pericytes and pericyte-derived microvesicles (PCMVs) and candidate miRNAs on vascular reactivity and barrier function were also examined. RESULTS: CLP and LPS induced severe injury/loss of pericytes, vascular hyporeactivity and leakage (P < 0.05). Transplantation with exogenous pericytes protected vascular reactivity and barrier function via microvessel colonization (P < 0.05). Cx43 knockout in either pericytes or VECs reduced pericyte colonization in microvessels (P < 0.05). Additionally, PCMVs transferred miR-145 and miR-132 to VSMCs and VECs, respectively, exerting a protective effect on vascular reactivity and barrier function after sepsis (P < 0.05). miR-145 primarily improved the contractile response of VSMCs by activating the sphingosine kinase 2 (Sphk2)/sphingosine-1-phosphate receptor (S1PR)1/phosphorylation of myosin light chain 20 pathway, whereas miR-132 effectively improved the barrier function of VECs by activating the Sphk2/S1PR2/zonula occludens-1 and vascular endothelial-cadherin pathways. CONCLUSIONS: Pericytes are protective against sepsis through regulating vascular reactivity and barrier function. Possible mechanisms include both direct colonization of microvasculature and secretion of PCMVs.

Research advances in pericyte function and their roles in diseases.

Pericyte, a kind of pluripotent cell, may regulate the irrigation flow and permeability of microcirculation. Pericytes are similar to the smooth muscle cells, which express several kinds of contractile proteins and have contractility. The dysfunction of pericytes is related to many microvascular diseases, including hypoxia, hypertension, diabetic retinopathy, fibrosis, inflammation, Alzheimer's disease, multiple sclerosis, and tumor formation. For a long time, their existence and function have been neglected. The distribution, structure, biomarker, related signaling pathways as well as the roles of pericytes on vascular diseases will be introduced in this review.

[Study on the Structure and Nanomechanical Properties of Organic Montmorillonite Reinforced Urea-Formaldehyde Adhesive].

Montmorillonite (MMT) is a natural mineral that has great potential as reinforcing filler in wood adhesives. In order to study the reinforcing mechanism more clearly, organic MMT-reinforced urea-formaldehyde adhesive (UF-OMMT) was prepared to analyze its chemical properties and crystal structure with Fourier Transform Infrared Spectroscopy (FTIR) and X-Ray Diffraction (XRD). The nanomechanical properties of UF, UF-MMT and PF-OMMT adhesives in the interphase of wood-based composite were analyzed by nanoindentation (NI) and the macro-bonding strength of composite were also tested. The results of FTIR and XRD indicated that in the spectra of MMT modified by cetyltrimethyl ammonium bromide (CTAB), the new peaks appeared at 2 929 and 2 853 cm-1corresponding to C­H stretching vibrations of the organic intercalation agent (CTAB). The (001) diffraction peak of MMT was shifted to a lower angle and the lamellar repeat distance increases from 1.51 nm to 2.71 nm after organic modification. The ion exchange of the cations in montmorillonite with organic ammonium ions and the separating and disorder crystalline improved the compatibility of the modified clay with the polymers and the dispersion of the layers into the matrix. The good physical filling of MMT particles and the elastomer formed during the reaction could transfer and distribute loads between components more homogenously, therebycontributing to the improved mechanical properties of adhesives. As compared to the untreated UF, the reduced elastic modulus and hardness of UF-OMMT in the interphase increased by about 66.9% and 24.2%, respectively. At the macroscale, the bonding strength of plywood bonded with UF-OMMT increased by about 97% as compared to that of unmodified UF resin. The positive effects of montmorillonite on water and heat resistance can be attributed to the better barrier properties of the interphase.

[Protective effects of penehyclidine hydrochloride against acute renal injury induced by hemorrhagic shock and lipopolysaccharides in rats].

OBJECTIVE: To investigate the effect of penehyclidine hydrochloride (PHC) in a rat model of renal injury induced by hemorrhagic shock and lipopolysaccharides (LPS). METHODS: Forty-five healthy Wistar rats were randomized into sham operated group, model group, and 3 penehyclidine hydrochloride (PHC) dose (1, 2 and 3 mg/kg) groups (PHC1, PHC2, and PHC3 groups, respectively). The arterial blood samples were collected to determine the concentrations of serum tumor necrosis factor-α (TNF-α), interleukin-8 (IL-8), interleukin-1 (IL-1), urine creatinine (Cr) and blood urine nitrogen (BUN), and the renal tissues were collected to measure the expressions of ICAM-1 and nuclear factor-κB (NF-κB) and observe the pathological changes. RESULTS: TNF-α, IL-8, IL-1, Cr, BUN, ICAM-1 and NF-κB in the 3 PHC groups were significantly lower than those in the model group (P<0.05). TNF-α, IL-8, IL-1, Cr and BUN were significantly lower in PHC1 (P<0.05) than in the PHC2 and PHC3 groups, and ICAM-1 and NF-κB were similar between 3 PHC groups (P>0.05). Compared with the model group, the 3 PHC groups showed lessened pathological changes in the renal tubules. CONCLUSION: PHC has protective effects against renal injury induced by hemorrhagic-endotoxin shock in rats, and treatment with 1 mg/kg PHC produces the most significant protective effect.

NAT2 polymorphisms combining with smoking associated with breast cancer susceptibility: a meta-analysis.

To derive a more precise estimation of the relationship between the slow or rapid acetylation resulting from N-acetyltransferase 2 (NAT2) polymorphisms and breast cancer risk, a meta-analysis was performed. PubMed, Medline, Embase, and Web of Science were searched. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess strength of association. The pooled ORs were performed for slow versus rapid acetylation genotypes. A total of 26 studies including 9,215 cases and 10,443 controls were included in the meta-analysis. Overall, no significantly elevated breast cancer risk was associated with NAT2 slow genotypes when all studies were pooled into the meta-analysis (OR = 1.026, 95% CI = 0.968-1.087). In the subgroup analysis by ethnicity, increased risks were not found for either Caucasians (OR = 1.001, 95% CI = 0.938-1.068) or Asians (OR = 1.155, 95% CI = 0.886-1.506). When stratified by study design, statistically significantly elevated risk associated with NAT2 slow genotypes was only found among hospital-based studies (OR = 1.178, 95% CI = 1.037-1.339). In the subgroup analysis by menopausal status, no statistically significantly increased risk was found in either premenopausal (OR = 1.053, 95% CI = 0.886-1.252) or postmenopausal women (OR = 0.965, 95% CI = 0.844-1.104). When stratified by cumulative smoking exposure, in the subgroup of smokers with high pack-years, NAT2 slow genotypes were significantly associated with increased breast cancer risk (OR = 1.400, 95% CI = 1.099-1.784). In conclusion, this meta-analysis suggested that there is overall lack of association between NAT2 genotypes and breast cancer risk, however, NAT2 polymorphisms when combining with heavy smoking history may contribute to breast cancer susceptibility.