Arcuate NPY is involved in salt-induced hypertension via modulation of paraventricular vasopressin and brain-derived neurotrophic factor.

Chronic high salt intake is one of the leading causes of hypertension. Salt activates the release of the key neurotransmitters in the hypothalamus such as vasopressin to increase blood pressure, and neuropepetide Y (NPY) has been implicated in the modulation of vasopressin levels. NPY in the hypothalamic arcuate nucleus (Arc) is best known for its control in appetite and energy homeostasis, but it is unclear whether it is also involved in the development of salt-induced hypertension. Here, we demonstrate that wild-type mice given 2% NaCl salt water for 8 weeks developed hypertension which was associated with marked downregulation of NPY expression in the hypothalamic Arc as demonstrated in NPY-GFP reporter mice as well as by in situ hybridization analysis. Furthermore, salt intake activates neurons in the hypothalamic paraventricular nucleus (PVN) where mRNA expression of brain-derived neurotrophic factor (BDNF) and vasopressin was found to be upregulated, leading to elevated serum vasopressin levels. This finding suggests an inverse correlation between the Arc NPY level and expression of vasopressin and BDNF in the PVN. Specific restoration of NPY by injecting AAV-Cre recombinase into the Arc only of the NPY-targeted mutant mice carrying a loxP-flanked STOP cassette reversed effects of salt intake on vasopressin and BDNF expression, leading to a normalization of salt-dependent blood pressure. In summary, our study uncovers an important Arc NPY-originated neuronal circuitry that could sense and respond to peripheral electrolyte signals and thereby regulate hypertension via vasopressin and BDNF in the PVN.

Animal Model Analysis of Acute Pancreatitis Based on Clinical Syndrome Characteristics of Traditional Chinese and Western Medicine / 中国实验方剂学杂志

This study summarized and analyzed the modeling methods， modeling mechanisms， and advantages and disadvantages of existing animal models of acute pancreatitis （AP） with the purposes of replicating animal models more in line with the clinical syndrome characteristics of traditional Chinese medicine （TCM） and Western medicine， improving the basic research of AP， and promoting its in-depth research. Further， the clinical diagnostic criteria of TCM and Western medicine were drawn up， and the agreement was evaluated between animal models of AP and clinical syndrome characteristics of TCM and Western medicine. The results demonstrated that the AP model induced by choline-deficient ethionine-supplemented diet （CDE）-supplemented diet was highly consistent with the clinical syndromes of TCM and Western medicine， which was simple in operation and small in mortality. However， the modeling did not involve the pathogenic factors of TCM. Although many approaches have been proposed to establish animal models of AP so far， most of the models meet the diagnostic criteria of Western medicine but， lacking the manifestation of TCM symptoms， less agree with the clinical syndromes of TCM. At present， animal models of AP alone are mostly used to study the pharmacodynamics and mechanisms of Chinese and Western medicines， which fail to meet the requirements of syndrome differentiation and treatment in TCM theories. Only the animal models of AP which conform to the TCM syndrome characteristics and are basically consistent with clinical syndromes greatly contribute to the essence study of TCM syndromes and the development of innovative Chinese medicines. Therefore， establishing animal models that can simultaneously reflect the clinical syndrome characteristics of AP in both TCM and Western medicine and replicating more realistic， accurate and comprehensive animal models of AP are worthy of further research.

Transcription factor Tbx18 induces the differentiation of c-kit+ canine mesenchymal stem cells (cMSCs) into SAN-like pacemaker cells in a co-culture model in vitro.

Bone mesenchymal stem cells (MSCs), as well as cardiomyocytes, are derived from early mesoderm, becoming committed to their fate under the influence of different differentiation factors. We examined whether the overexpression of Tbx18 can induce the differentiation of c-kit+ cMSCs into a phenotype similar to that of native pacemaker cells and whether these transfected cells can couple to adjacent atrial cells with functional consequences. The c-kit+ cMSCs were first sorted, then transfected with different lentiviral vectors. Tbx18-c-kit+ cMSCs represented the experimental group, while EYFP-c-kit+ cMSCs and canine sinoatrial node (SAN) cells were used as controls. Within days of transfection, the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel HCN4 protein and gap junction protein Connexin 45 (Cx45) expression in Tbx18-c-kit+ cMSCs were 12-fold and 5.6-fold higher, respectively, than that in EYFP-c-kit+ cMSCs. After co-culture with canine atrial cells in vitro for three days, the funny currents (If) were recorded in the Tbx18-c-kit+ cMSCs, but not in EYFP-c-kit+ cMSCs. The trend of these If currents was highly similar to that of SAN cells, although the current density was smaller. The Tbx18-EYFP-c-kit+ cMSCs showed responsiveness to ß-adrenergic stimulation, and the intracellular cyclic adenosine monophosphate (cAMP) level was higher than that in EYFP-c-kit+ cMSCs. The Tbx18-EYFP-c-kit+ cMSCs delivered fluorescent dye to neighboring atrial cells via gap junctions, thus these cell pairs could communicate as a pacemaker unit. We propose that the overexpression of Tbx18 in c-kit+ cMSCs induces their differentiation to SAN-like pacemaker cells.

Elevated Type II Secretory Phospholipase A2 Increases the Risk of Early Atherosclerosis in Patients with Newly Diagnosed Metabolic Syndrome.

A critical association between type II secretory phospholipase A2 (sPLA2-IIa) and established atherosclerotic cardiovascular disease has been demonstrated. However, the contribution of sPLA2-IIa to early atherosclerosis remains unknown. This study investigated the association between early-stage atherosclerosis and sPLA2-IIa in metabolic syndrome (MetS) patients. One hundred and thirty-six MetS patients and 120 age- and gender-matched subjects without MetS were included. Serum sPLA2-IIa protein levels and activity were measured using commercial kits. Circulating endothelial activation molecules (vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), E-selectin, and P-selectin), and carotid intima-media thickness (cIMT), were measured as parameters of vascular endothelial dysfunction and early atherosclerosis. MetS patients exhibited significantly higher sPLA2-IIa protein and activity levels than the controls. Both correlated positively with fasting blood glucose and waist circumference in MetS patients. Additionally, MetS patients exhibited strikingly higher levels of endothelial activation molecules and increased cIMT than controls. These levels correlated positively with serum sPLA2-IIa protein levels and activity. Moreover, multivariate analysis showed that high sPLA2-IIa protein and activity levels were independent risk factors of early atherosclerosis in MetS patients. This study demonstrates an independent association between early-stage atherosclerosis and increased levels of sPLA2-IIa, implying that increased sPLA2-IIa may predict early-stage atherosclerosis in MetS patients.