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Gamma-aminobutyric acid type A (GABA

Lipopolysaccharide (LPS) can induce bone loss by stimulating osteoclast formation. Colony-stimulating factor 1 receptor (CSF 1R) inhibitors have great potential for the treatment of rheumatoid arthritis and tumor-related bone erosion. However, its role in LPS-induced bone loss is still not clarified. In this study, we observed the effects of CSF 1R inhibitor, PLX3397, on LPS-induced bone damage in an animal model. The models were established by LPS administration in male Sprague-Dawley rats. PLX3397 (30 mg/kg body weight) was given by oral gavage. MicroCT analysis, biomechanical properties, biomarker assay, histological examination, and mRNA expression of osteoclast differentiation-related genes (Traf6, Fra1, c-fos and NFATc1) were performed on the 8th week. LPS induced bone loss was shown as the decrease in bone volume fraction and trabecular number and increase in trabecular separation (p

Mutant Huntingtin (mtHtt) causes neurodegeneration in Huntington's disease (HD) by evoking defects in the mitochondria, but the underlying mechanisms remains elusive. Our proteomic analysis identifies valosin-containing protein (VCP) as an mtHtt-binding protein on the mitochondria. Here we show that VCP is selectively translocated to the mitochondria, where it is bound to mtHtt in various HD models. Mitochondria-accumulated VCP elicits excessive mitophagy, causing neuronal cell death. Blocking mtHtt/VCP mitochondrial interaction with a peptide, HV-3, abolishes VCP translocation to the mitochondria, corrects excessive mitophagy and reduces cell death in HD mouse- and patient-derived cells and HD transgenic mouse brains. Treatment with HV-3 reduces behavioural and neuropathological phenotypes of HD in both fragment- and full-length mtHtt transgenic mice. Our findings demonstrate a causal role of mtHtt-induced VCP mitochondrial accumulation in HD pathogenesis and suggest that the peptide HV-3 might be a useful tool for developing new therapeutics to treat HD., Mitochondria defects caused by mutant huntingtin (mtHtt) have been implicated in Huntington's disease. Here authors show that VCP binds to mtHtt on the mitochondria, and that treatment with a peptide that disrupts this interaction reduces the cellular and behavioural deficits in mouse models of HD.

Grape seed procyanidin B2 (GSPB2) exerts a variety of potent protective pharmacological effects on diabetic complications. The renal protective effects of GSPB2 and the target protein mimecan regulated by GSPB2, discovered in a previous quantitative proteomic analysis, were assessed in mice with diabetic nephropathy Twenty-four db/db mice were divided into 2 groups of the vehicle-treated and GSPB2-treated (30 mg/kg/d) diabetic groups. All animals were observed for 10 weeks. Treatment with GSPB2 resulted in an improvement in body weight increase and serum levels of triglyceride, total cholesterol, advanced glycation end products, and urinary albumin excretion in comparison with the vehicle-treated diabetic mice (P.05), although these levels were still higher than those in the control group. Treatment with GSPB2 significantly reduced the extent of glomerular basement membranes thickening, mesangial expansion, and glomerular area as well. Mimecan protein expressions in diabetes mellitus were decreased approximately by 28% when compared with those in the control group (P.05), and restored remarkably after GSPB2 treatment (P.05). The expression of nuclear factor-κB (NF-κB) p65 in nuclear extracts, markedly higher in the diabetic mice than in the controls, was significantly suppressed by GSPB2. The findings of this study revealed that mimecan might become a new therapeutic target in the future and indicated that GSPB2 had beneficial effects not only on oxidative stress, but also on renal fibrosis, particularly in the diabetic kidney.

In the present study, we investigated the effect of classic PDE4 inhibitor rolipram and novel PDE4 inhibitor ZL-n-91 on LPS-induced acute lung injury (ALI) in mice and its mechanism. ALI was induced in ICR mice by instilling intratracheally with LPS, and mice were divided into seven groups: control (Saline), LPS group, ZL-n-91 (3 microg, 10 microg, and 30 microg kg(-1), ip), Rolipram (1.0 mg kg(-1), ip) and dexamethasone (0.5 mg kg(-1), ip). After the 6h of instilling intratracheally with LPS in mice, total leukocyte number, neutrophil number and protein content in BALF increased rapidly, a large number of neutrophil infiltration around the pulmonary vessel and airway, the lung wet weight/dry weight (w/d)ratio raised significantly. MPO activity, TNF-alpha level and cAMP-PDE, PDE4 activity in lung homogenate raised significantly. P(a)O(2), P(a)CO(2) and PH value in peripheral arterial blood also changed obviously, P(a)O(2) and PH value dropped slightly and P(a)CO(2) increased significantly in LPS group. ZL-n-91 (3 microg, 10 microg, 30 microg kg(-1)) dose-dependently reduced the total leukocyte number, neutrophil number and total protein content in BALF, MPO activity, TNF-alpha level and cAMP-PDE, PDE4 activity in lung homogenate, but the effect of ZL-n-91 in pathological changes and lung wet w/d ratio is slight; Rol and Dex significantly reduced lung wet w/d ratio and improved pathological changes, neutrophil around the pulmonary vessel and airway significantly reduced, symptoms of lung edema relieved; The PH value, P(a)O(2) and P(a)CO(2) in ZL-n-91 high dosage group and Rol group had changes, but there was no significant difference compared with LPS group or saline group; After the administration, the righting reflex recovery time significantly shorten in every group of ZL-n-91. the righting reflex recovery time of Rol group was similar with ZL-n-91 30 microg kg(-1) group, while Dex group was similar with saline group. The present study confirms that the inhibitory effect of ZL-n-91(30 microg kg(-1)) on the inflammatory reactivity, including inhibition of inflammatory cell and protein exudation, MPO and PDE4 activity, improvement of the blood gas, those effects were equivalent with rolipram 1 mg kg(-1), and suggested that ZL-n-91 was stronger than rolipram in PDE4 inhibition. So we speculated that ZL-n-91 may have stronger therapeutic potential for treatment of inflammatory disease than rolipram, meantime have stronger nervous system effect than rolipram.

This study aims to investigate the protective role of crocetin, a natural antioxidant, against cytotoxicity produced by exposure to norepinephrine (NE) in primary cultured rat cardiac myocytes. Reactive oxygen species (ROS) and Ca(2+) in cells were evaluated by fluorescence microplate reader using 6-carboxy-2',7'-dichlorofluorescein and fluoro-3-acetoxymethyl ester, respectively. Lipid peroxidation was quantified using thiobarbituric acid-reactive substances. The activities of superoxide dismutase (SOD) and contents of glutathione (GSH) were detected by xanthine/xanthime oxidase-mediated ferricytochrome c reduction assay, and recycling effection of glutathione disulfide with GSH reductase and NADPH, respectively. The apoptotic cells were assayed by fluorescein diacetate (FDA)-ethidium bromide (EB) two-staining method. Intracellular accumulation of ROS, Ca(2+), and products of lipid peroxidation resulting from NE were significantly reduced by crocetin. Preincubation of primary cultured rat cardiac myocytes with crocetin remarkably prevented the decrease in SOD activity and quantities of GSH induced by NE. The percentage of NE-induced apoptosis in the cells was decreased by FDA-EB two-staining assay after pretreated with crocetin. The results showed that crocetin may ameliorate NE-induced injury in cardiac myocytes by enhanced SOD activity and increased quantities of GSH, decreased lipid peroxidation and Ca(2+) in cells, and apoptosis death ratio that may represent the cellular mechanisms for its cardioprotective role.

This paper indicated that inactivatedBordetella pertussis(iBp) can enhance the lung airway hyperreactivity of the rats sensitized and challenged with OVA. The mechanisms were involved in the upregulation of cAMP-PDE activity and PDE4A, PDE4D, and PDE3 gene expression in the lungs. But only PDE4 activity was different between the OVA and OVA+iBp groups, and PDE4D expression was significantly increased in iBp rats alone. So, our data suggested that cosensitization with OVA and iBp affects lung airway reactivity by modulating the lung cAMP-PDE activity and PDE4D gene expression.

To investigate the effects of sapindus saponins on myocardial inflammation mediated by Ang II/ p38MAPK signal pathway and cardiac hypertrophy in spontaneously hypertensive rats. And also to explore the correlation of cardiac hypertrophy and inflammation.Thirty-two 16-week-old spontaneously hypertensive rats (SHR) were randomly divided into four groups, one with placebo as model group, one with captopril tablets (27 mg x kg(-1)) as positive control, one with low-dose sapindus saponins (27 mg x kg(-1)), one with high-dose (108 mg x kg(-1)). And another eight healthy Wistar-Kyoto strain (WKY) rats were used as the normal group. The animals were treated for eight weeks, and the indicators detected were as follows: (1) left ventricular mass index (LVMI); (2) the content of Ang II and hs-CRP in plasma were determined by ELISA; (3) the protein expression of AT1R and VEGF were determined by immunohistochemical method; (4) the protein expression of p-p38MAPK in myocardial cells was determined by Western blot.Sapindus saponins reduced LVMI, and blocked the expression level of Ang II, AT1R, p-p38MAPK, VEGF and hs-CRP in myocardial tissue. Vs the SHR model group, there were significant differences (P0.05 or P0.01).Our findings suggested that sapindus saponins could inhibited cardiac hypertrophy, the possible mechanisms may be related to the inhibition on inflammatory response mediated by Ang II/p38MAPK pathway.

To investigate the protective effects of Sapindus saponins in spontaneously hypertensive rats, and the possible cellular and molecular mechanisms. Thirty-two 16-week-old spontaneously hypertensive rats were randomly divided into four groups (8 in each group): model group (placebo), positive control group (27 mg/kg of Captopril Tablets), Sapindus saponins groups (27 mg/kg and 108 mg/kg, respectively). Another 8 healthy Wistar-Kyoto strain (WKY) rats were used as the normal group. The animals were treated for 8 weeks. Blood pressure of rats was determined by non-invasive blood pressure meter (BP-6). Furthermore, the contents of angiotensin II (Ang II) in plasma and myocardial tissue were determined by enzyme-linked immunosorbent assay (ELISA), the gene expression of receptor angiotensin type 1 (AT1R) in aorta was determined by quantitative realtime polymerase chain reaction (qRT-PCR). The protein expression of transforming growth factor-β1 (TGF-β1) and AT1R in heart was determined by immunohistochemical staining. The protein expression of p-phosphorylation of p38 mitogen-activated protein kinase (p-p38MAPK) was determined by Western blotting. The contents of interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF) in serum were determined by radioimmunoassay. And the histopathological and morphological changes of aorta and heart tissue samples were assessed semi-quantitatively by hematoxylin-eosin (HE) or Masson staining. Thirty minutes after single or continuous treatment, systolic blood pressure (SBP) was reduced significantly in Sapindus saponins groups. And the contents of AngII, IL-1, IL-6 and TNF-α in serum, the expression of AT1R mRNA, p-p38MAPK and TGF-β1 were significantly suppressed dose-dependently (P

OBJECTIVE To investigate the regulation on endothelial function of sapindus saponins in spontaneously hypertensive rats by studying the reactivity on different vasoconstrictor and dilator, and the content of the active substances. METHOD Forty 16-week-old spontaneously hypertensive rats were randomly divided into five groups, one with placebo as model group, one with captopril tablets (27 mg x kg(-1)) as positive control, one with low-dose sapindus saponins (27 mg x kg(-1)), one with medium-dose (54 mg x kg(-1)), one with high-dose (108 mg x kg(-1)). And another eight healthy Wistar-Kyoto strain (WKY) rats were used as the normal group. The animals were treated for eight weeks, and the indicators to be detected were as follows: (1) the response of thoracic aorta on different vasoconstrictors Ang II (1 x 10(-9) -1 x 10(-5) mol x L(-1)), PE (1 x 10(-8) 1 x 10(-4) mol x L(-1)), KCl (20 -120 mmol x L(-1)); (2) the endothelium-dependent or non-endothelium-dependent vasodilation response of thoracic aorta on Ach (1 x 10-(10)-1 x 10(-5) mol x L(-1)) or SNP (1 x 10(-8)-1 x 10(-3) mol x (L(-1); (3) the content of NO, 6-KPG1alpha, ET-1 and TXB2 in serum was determined by Elisa. RESULT In SHR model group, the response of thoracic aorta on Ang II, PE and KCl was increased, the endothelium-dependent vasodilation on Ach was reduced, but the effects on SNP was not obvious, the content of ET-1 and TXB2 was increased, and the content of NO and 6-KPG1alpha was reduced, Vs the normal control group, there were significant differences (P < 0.05 or P < 0.01); in the treatment groups, the response of thoracic aorta on Ang II, PE and KCl was reduced, the endothelium-dependent vasodilation of thoracic aorta on Ach was improved, the content of ET-1 and TXB2 was reduced, and the content of NO and 6-KPG1alpha was increased, Vs the SHR model group, there were significant differences (P < 0.05 or P < 0.01). CONCLUSION Our findings suggested that sapindus saponins protected the endothelial function in SHR, the mechanisms were relevant to the protection of endothelial function.

Chronic obstructive pulmonary disease (COPD) is defined as a disease state characterized by poorly reversible airflow limitation induced by cigarette smoking and/or other noxious particle and gases. Phosphodiesterase (PDE) 4 inhibitors are known to elevated cAMP concentrations in inflammatory cells, leading to inhibition of inflammatory response, relaxation of smooth muscle in the airway, and modulation of sensory nerves in the lung as well. To investigate whether Zl-n-91, a new selective PDE4 inhibitor, could decrease inflammation and improve lung function in a COPD-like rat model, male Sprague-Dawley rats are used to challenge with lipopolysaccharide (LPS) and cigarette smoking (CS) exposure to induce COPD-like animal model. Administration of Zl-n-91 at different dosages results in decreases of inflammatory cell in bronchoalveolar lavage fluid (BALF) as compared with vehicle treatment. Zl-n-91 at 0.03, 0.3 or 3mg/kg not only dose-dependently inhibited PDE4 activity, but also decreased MMP-9 level in lungs and improved dynamic compliance (C(dyn)) as compared with vehicle treatment. Therefore, Zl-n-91 could inhibit inflammatory responses in rats after cigarette smoking exposure and LPS challenge, and it could be of some therapeutic potential as an alternative medicine in treatment of pulmonary diseases such as COPD.

To investigate the cardio-protective effect of crocetin on primary culture of cardiac myocyte treated with noradrenaline.After adding crocetin, the primary culture of cardiac myocyte was injured by 1.0 micromol x L(-1) noradrenaline. The activity of lactic dehydrogenase (LDH), mitochondrion succinic dehydrogenase (MSDH) and ATPase were assayed. The mitochondrion membrane potential was detected by Rh123. The percentage of cardiac myocyte apoptosis was observed by flow cytometry.Crocetin significantly decreased the activity of LDH in culture supernatant, increased the activity of MSDH, ATPase (Na+-K+ ATPase, Ca2+ ATPase) and mitochondrion membrane potential.Crocetin could alleviate the disturbance of energy metabolism and decrease the percentage of apoptosis of cardiac myocyte treated with noradrenaline.