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Sleep loss can induce or aggravate the development of cardiovascular and cerebrovascular diseases. However, the molecular mechanism underlying this phenomenon is poorly understood. The present study was designed to investigate the effects of REM sleep deprivation on blood pressure in rats and the underlying mechanisms of these effects. After SpragueDawley rats were subjected to REM sleep deprivation for 5 days, their blood pressures and endothelial function were measured. In addition, one group of rats was given continuous access to L-arginine supplementation (2% in distilled water) for the 5 days before and the 5 days of REM sleep deprivation to reverse sleep deprivation-induced pathological changes. The results showed that REM sleep deprivation decreased body weight, increased blood pressure, and impaired endothelial function of the aortas in middle-aged rats but not young rats. Moreover, nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) concentrations as well as endothelial NO synthase (eNOS) phosphorylation in the aorta were decreased by REM sleep deprivation. Supplementation with L-arginine could protect against REM sleep deprivation-induced hypertension, endothelial dysfunction, and damage to the eNOS/NO/cGMP signaling pathway. The results of the present study suggested that REM sleep deprivation caused endothelial dysfunction and hypertension in middle-aged rats via the eNOS/NO/cGMP pathway and that these pathological changes could be inhibited via Larginine supplementation. The present study provides a new strategy to inhibit the signaling pathways involved in insomnia-induced or insomnia-enhanced cardiovascular diseases.

Background Adrenocorticotrophic hormone (ACTH)-treatment rat model has been utilized as a widely accepted model of treatment-resistant depression. Metabolomic signatures represent the pathophysiological phenotype of diseases. Recent studies in gut microbiota and metabolomics analysis revealed the dramatic role of microbiome in psychoneurological system diseases, but still, the mechanisms underlying gut microbiome–host interaction remain unclear. Methods Male Wistar rats were s.c . injection of ACTH fragment 1–24 for 14 days to induce treatment-resistant depression. Depression-related behavioral tests, analysis of serum monoamine neurotransmitters and hypothalamic–pituitary–adrenal (HPA) axis-related hormones were determined for assessment of ACTH-induced depression rat model. A gas chromatography-time-of-flight mass spectrometer based urinary metabolomic signatures integrated 16S rRNA sequence analysis based gut microbial profiling was performed, as well as Spearman’s correlation coefficient analysis was used to manifest the covariation between the differential urinary metabolites and gut microbiota of genus level. Results Chronic injection of ACTH-induced depression-like phenotype (increased immobility time in forced swimming test and tail suspension test) was accompanied by peripheral serotonin down-regulation and HPA axis overactivation (ACTH and corticosterone up-regulation). Urinary metabolomics analysis indicated that pyruvic acid, l -threonine, mannitol, d -gluconic acid, 4-hydroxybenzoic acid, d -arabitol, myo-inositol and ascorbic acid levels were reduced in ACTH-treated rats’ urine, while hippurate level was elevated. In addition, microbial community profiling revealed bacterial enrichment (e.g. Ruminococcus , Klebsiella ) and reduction (e.g. Akkermansia , Lactobacillus ) in the ACTH-induced depression rat model. Correlation analysis showed that Akkermansia and Lactobacillus were closely relevant to metabolites myo-inositol and hippurate, which were included in host inositol phosphate metabolism, and phenylalanine, tyrosine and tryptophan biosynthesis. Conclusions Depression rat model induced by ACTH is associated with disturbance of pyruvate metabolism, ascorbate and aldarate metabolism, inositol phosphate metabolism, glycine, serine and threonine metabolism, and glycolysis or gluconeogenesis, as well as changes in microbial community structure. Gut microbiota may participate in the mediation of systemic metabolomic changes in ACTH-induced depression model. Therefore, integrated metabolomic signatures and gut microbial community profiling would provide a basis for further studies on the pathogenesis of depression. Elect...

Hypertensive renal damage generally occurs during the middle and late stages of hypertension, which is typically characterized by proteinuria and renal inflammation. Captopril, an angiotensin-converting enzyme (ACE) inhibitor, has been widely used for therapy of arterial hypertension and cardiovascular diseases. However, the protective effects of captopril on hypertension-induced organ damage remain elusive. The present study was designed to explore the renoprotective action of captopril in spontaneously hypertensive rats (SHR). The 6-week-old male SHR and age-matched Wistar-Kyoto rats were randomized into long-term captopril-treated (34 mg/kg) and vehicle-treated groups. The results showed that in SHR there was obvious renal injury characterized by the increased levels of urine albumin, total protein, serum creatinine, blood urea nitrogen, renal inflammation manifested by the increased mRNA and protein expression of inflammatory factors including tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and inducible nitric oxide synthase, and enhanced nuclear factor-κB (NF-κB) activation. Captopril treatment could lower blood pressure, improve renal injury, and suppress renal inflammation and NF-κB activation in SHR rats. In conclusion, captopril ameliorates renal injury and inflammation in SHR possibly via inactivation of NF-κB signaling.

The endothelium contributes to the maintenance of vasodilator tone by releasing nitric oxide (NO), prostacyclin (PGI2), and endothelium-derived hyperpolarizing factor (EDHF). In hypertension, endothelium-dependent relaxation is attenuated (a phenomenon referred to as endothelial dysfunction) and contributes to the increased peripheral resistance. However, which vasodilator among NO, PGI2, and EDHF is impaired in hypertension remains largely unknown. The present study was designed to study the exact contribution of NO, PGI2, and EDHF to vascular reactivity in conduit and resistance artery, under physiological and pathological conditions. The aorta and the second-order mesenteric artery from spontaneous hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats were used to measure the vasorelaxation with myograph technology, in the presence or absence of different inhibitors. The results showed that the endothelium-dependent vasodilatation in the conduit artery was mediated mainly by NO, whereas the resistant artery by NO, PGI2, and EDHF together. In hypertension, both NO-mediated relaxation in the conduit artery and NO-, PGI2-, and EDHF-mediated dilation in the resistant artery were markedly impaired. Furthermore, the endothelium-dependent and the endothelium-independent vasorelaxation in conduit artery was attenuated more pronouncedly than that in the resistant artery from hypertensive rats, suggesting that the conduit artery is more vulnerable to hypertensive condition. In conclusion, vasodilators including NO, PGI2, and EDHF contribute distinctively to endothelium-dependent relaxation in conduit and resistance artery under physiological and pathological conditions.

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Korean mondshood root polysaccharides (KMPS) isolated from the root of Aconitum coreanum (Lévl.) Rapaics have shown anti-inflammatory activity, which is strongly influenced by their chemical structures and chain conformations. However, the mechanisms of the anti-inflammatory effect by these polysaccharides have yet to be elucidated. A RG-II polysaccharide (KMPS-2E, Mw 84.8 kDa) was isolated from KMPS and its chemical structure was characterized by FT-IR and NMR spectroscopy, gas chromatography–mass spectrometry and high-performance liquid chromatography. The backbone of KMPS-2E consisted of units of [→6) -β-D-Galp (1→3)-β-L-Rhap-(1→4)-β-D-GalpA-(1→3)-β-D-Galp-(1→] with the side chain →5)-β-D-Arap (1→3, 5)-β-D-Arap (1→ attached to the backbone through O-4 of (1→3,4)-L-Rhap. T-β-D-Galp is attached to the backbone through O-6 of (1→3,6)-β-D-Galp residues and T-β-D-Ara is connected to the end group of each chain. The anti-inflammatory effects of KMPS-2E and the underlying mechanisms using lipopolysaccharide (LPS) - stimulated RAW 264.7 macrophages and carrageenan-induced hind paw edema were investigated. KMPS-2E (50, 100 and 200 µg/mL) inhibits iNOS, TLR4, phospho-NF-κB–p65 expression, phosphor-IKK, phosphor-IκB-α expression as well as the degradation of IκB-α and the gene expression of inflammatory cytokines (TNF-α, IL-1β, iNOS and IL-6) mediated by the NF-κB signal pathways in macrophages. KMPS-2E also inhibited LPS-induced activation of NF-κB as assayed by electrophorectic mobility shift assay (EMSA) in a dose-dependent manner and it reduced NF-κB DNA binding affinity by 62.1% at 200µg/mL. In rats, KMPS-2E (200 mg/kg) can significantly inhibit carrageenan-induced paw edema as ibuprofen (200 mg/kg) within 3 h after a single oral dose. The results indicate that KMPS-2E is a promising herb-derived drug against acute inflammation.

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