Pseudolaric Acid B Attenuates High Salt Intake-Induced Hypertensive Left Ventricular Remodeling by Modulating Monocyte/Macrophage Phenotypes.

BACKGROUND Studies in ApoE knockout mice have shown that pseudolaric acid B (PB) can act as an immunomodulatory drug and attenuate atherosclerosis progression by modulating monocyte/macrophage phenotypes. Our previous study demonstrated that high salt intake could shift the phenotype of monocytes/macrophages to an inflammatory phenotype, and that this shift was related to hypertension and hypertensive left ventricular (LV) remodeling. However, no comprehensive assessment of the effects of PB on hypertensive LV remodeling has been conducted. MATERIAL AND METHODS In this study, RAW264.7 macrophages cultured with different concentrations of NaCl were used to investigate the modulating effects of PB on macrophage phenotype. Furthermore, N-nitro-L-arginine methyl ester hypertensive mice were used to investigate the modulating effects of PB on monocyte phenotype. LV remodeling was investigated by echocardiography. LV morphologic staining (for cardiomyocyte hypertrophy and collagen deposition) was performed at the time of sacrifice. RESULTS The results showed that PB significantly improved the viability of RAW264.7 cells, suppressed their phagocytic and migration abilities, and inhibited their phenotypic shift to M1 macrophages. In addition, the blood pressure of PB-treated mice was significantly decreased relative to that of control mice. Furthermore, after PB treatment, the percentage of Ly6Chi monocytes was significantly decreased while that of Ly6Clo monocytes was apparently increased. Moreover, PB preserved LV function and alleviated myocardial fibrosis and cardiomyocyte hypertrophy as measured at the end of the experimental period. The transfer of monocytes from PB-treated mice to hypertensive mice achieved the same effects. CONCLUSIONS Together, these findings indicate that PB exerts its protective effects on hypertensive LV remodeling by modulating monocyte/macrophage phenotypes and warrants further investigation.

Xiaoyaosan Exerts Therapeutic Effects on the Colon of Chronic Restraint Stress Model Rats via the Regulation of Immunoinflammatory Activation Induced by the TLR4/NLRP3 Inflammasome Signaling Pathway.

Depression is the neurological manifestation most commonly associated with gastrointestinal diseases. The release of inflammatory cytokines mediated by TLR4/NLRP3 inflammasome signaling-induced immunoinflammatory activation may represent a common pathogenic process underlying the development of gastrointestinal diseases and depression. Clinical studies have indicated that Xiaoyaosan (XYS) can relieve depressive behavior by improving gastrointestinal symptoms. We previously demonstrated that XYS can reduce colonic inflammation in a rat model of chronic unpredictable mild stress; however, the precise anti-inflammatory mechanisms involved remain unclear. Here, we investigated whether XYS can ameliorate depressive behavior through regulating the TLR4/NLRP3 inflammasome signaling pathway, thereby inhibiting immunoinflammatory activation and reducing colonic proinflammatory cytokine levels. Fifty-two healthy male Sprague-Dawley rats were randomly divided into four groups (control, model, XYS, and fluoxetine). The latter three groups were subjected to 21 days of chronic restraint stress to generate a model of stress-induced depression. XYS and fluoxetine were administered intragastrically. Behavioral changes in the rats were assessed after 21 days. Serum and colon samples were collected, and the relative levels of the inflammation indicators IL-6, IL-1ß, and TNF-α were determined by ELISA. Pathological changes in colon tissue were assessed by hematoxylin and eosin staining. The levels of TLR4, MyD88, NF-κB-p65, TAK1, IRAK1, and TRAF6 were detected by immunohistochemistry, while the gene and protein expression levels of TLR4, MyD88, NF-κB-p65, TAK1, IRAK1, TRAF6, NLRP3, ASC, and caspase-1 were detected by quantitative polymerase chain reaction (qPCR) and Western blotting. The results indicated that XYS could improve the depressive-like behavior and the weight loss of rats with stress-induced depression. Furthermore, depressed rats treated with XYS exhibited decreased expression levels of TLR4, MyD88, NF-κB-p65, TAK1, IRAK1, TRAF6, NLRP3, ASC, and caspase-1 in colonic tissue; reduced colon and serum concentrations of the inflammatory factors IL-6, IL-1ß, and TNF-α; and lowered levels of colonic inflammation.

Experimental Study on the Effect of a Weifufang on Human Gastric Adenocarcinoma Cell Line BGC-823 Xenografts and PTEN Gene Expression in Nude Mice.

Background: This study aims at investigating the effect of the Weifufang, an effective prescription for the treatment of gastric cancer developed by the Traditional Chinese Medicine (TCM)/Combination of TCM and Western Medicine Department of the Hunan Cancer Hospital, on gastric cancer xenografts in nude mice and its effect on the PTEN gene; it also aims at exploring the possible tumor suppression mechanism. Methods: Nude mice with xenografts were treated with different concentrations of the Weifufang for 2 weeks, and changes in tumor volume were observed. The histopathology of the tumor was detected by hematoxylin and eosin staining; PTEN gene expression in tumor tissues was detected by immunohistochemistry (IHC) and western blot. Results: After 2 weeks of treatment, tumor inhibition rates in the 5-flourouracil (5-FU) group, and in the Weifufang low-, middle-, and high-dose groups were 30.67%, 19%, 49.52%, and 29.36%, respectively. The IOD of the PTEN gene was detected by IHC. The values in the water group, the 5-FU group, and the Weifufang low-, middle-, and high-dose groups were 0.013 ± 0.004, 0.085 ± 0.062, 0.041 ± 0.024, 0.128 ± 0.032, and 0.061 ± 0.052, respectively. Except for the 5-FU group, the differences between the gastric compound middle dose-group and the other groups were statistically significant (p < 0.05). Results of PTEN expression detection by western blot: The expression levels in the water group, 5-FU group, and the Weifufang low-, middle-, and high-dose groups were 0.2240 ± 0.0172, 0.4200 ± 0.0228, 0.2760 ± 0.0163, 0.3840 ± 0.0133, and 0.3040 ± 0.0211, respectively. Except for the 5-FU group, differences between the Weifufang middle-dose group and the other groups were statistically significant (p < 0.05). Conclusion: The Weifufang may inhibit the growth of gastric cancer xenografts by upregulating PTEN gene expression. The middle-dose group had the best effect.

Effects of allisartan isoproxil on blood pressure and target organ injury in patients with mild to moderate essential hypertension.

Evidence has shown that angiotensin II type 1 receptor antagonists have lower blood pressure and have target organ protective effects, but this is not the case for the drug allisartan isoproxil. The aim of this study was to evaluate the effects of allisartan isoproxil on blood pressure and target organ injury in patients with mild to moderate essential hypertension.In total, 80 essential hypertensive participants were randomly divided into an allisartan group and a nifedipine group (n = 40 per group), and their blood pressure was measured once per month for 6 months. A 2-dimensional echocardiogram was performed at baseline and at the end of the study. The serum levels of renal injury indexes, endothelial function markers, inflammatory factors, blood biochemical assays and urinary measurements were determined at baseline and at 6 months.At the end of the study, both systolic and diastolic blood pressure were significantly decreased in the allisartan group compared with baseline and showed the same antihypertensive effect as the nifedipine group. Meanwhile, the left ventricular remodeling, 24-hours levels of urinary microalbumin, endothelial dysfunction, and arterial stiffness were all significantly improved compared with that of the baseline and the nifedipine group (all P < .05).The present study showed that allisartan isoproxil had favorable blood pressure lowering and heart, renal, and endothelial protective effects in patients with mild to moderate essential hypertension.

Xiaoyaosan improves depressive-like behavior in rats with chronic immobilization stress through modulation of the gut microbiota.

Depression has become the leading cause of disability worldwide and a growing public health problem in China. In addition, intestinal flora may be associated with depression. This study investigated the effect of the decoction Xiaoyaosan (XYS) against depressive behavior through the regulation of intestinal flora. Fifty-two healthy male Sprague-Dawley rats were randomly divided into four groups (i.e., control, model, XYS, and fluoxetine). The latter three groups were subjected to 21 days of chronic restraint stress to produce the stress depression model. Rats in the XYS and fluoxetine groups received intragastric administration of XYS and fluoxetine, respectively. The behavioral changes of the rats were observed after 21 days. Stool specimens were sequenced using the 16S rDNA high-throughput method to detect the structure and changes in intestinal flora. There was no difference observed in alpha diversity among the groups. At the phylum level, XYS regulated the abundance of Bacteroidetes, Proteobacteria, Firmicutes, Chloroflexi, and Planctomycetes. At the genus level, XYS reduced the abundance of the Prevotellaceae_Ga6A1_group, Prevotellaceae_UCG-001, and Desulfovibrio. On the contrary, it increased the abundance of the Ruminococcaceae family to improve depression-like behavior. The mechanism involved in this process may be related to short-chain fatty acids, lipopolysaccharides, and intestinal inflammation.

SILAC-based proteomic analysis reveals that salidroside antagonizes cobalt chloride-induced hypoxic effects by restoring the tricarboxylic acid cycle in cardiomyocytes.

Hypoxic status alters the energy metabolism and induces cell injury in cardiomyocytes, and it further triggers the occurrence and development of cardiovascular diseases. Our previous studies have shown that salidroside (SAL) exhibits anti-hypoxic activity. However, the mechanisms remain obscure. In the present study, we successfully screened 92 different expression proteins in CoCl2-induced hypoxic conditions, 106 different expression proteins in the SAL-mediated anti-hypoxic group were compared with the hypoxic group using quantitative proteomics strategy, respectively. We confirmed that SAL showed a positive protective function involving the acetyl-CoA metabolic, tricarboxylic acid (TCA) cycle using bioinformatics analysis. We also demonstrated that SAL plays a critical role in restoring the TCA cycle and in protecting cardiomyocytes from oxidative injury via up-regulation expressions of PDHE1-B, ACO2, SUCLG1, SUCLG2 and down-regulation of MDH2. SAL also inhibited H9c2 cell apoptosis by inhibiting the activation of pro-apoptotic molecules caspase 3 and caspase 9 as well as activation of the anti-apoptotic molecular Bcl-2. Additionally, SAL also improved mitochondrial membrane potential (ΔΨm), reduced reactive oxygen species (ROS) and intercellular Ca(2+) concentration ([Ca(2+)]i) accumulation and inhibited the excessive consumption of ATP in H9c2 cells.

A novel Pseudolaric acid B derivative, Hexahydropseudolaric acid B, exterts an immunomodulatory effect in vitro/in vivo evaluation.

Identification of immunosuppressants from natural sources has a proven track record in immune mediated disorders. Pseudolaric acid B is a diterpenoid isolated from the roots of Pseudolarix amabilis, possessing potent immunomodulatory effect. However, the cytotoxicity limits its future clinical application. The purpose of this study was to investigate the immunosuppressive activity of Hexahydropseudolaric acid B, a Pseudolaric acid B derivative, on T cell-mediated immune response both in vitro and in vivo, and investigated its immunomodulatory effect to develop a more ascendant immunosuppressive agent. The results showed that Hexahydropseudolaric acid B could exert more preferable immunosuppressive activity and lower cytotoxicity than Pseudolaric acid B. Hexahydropseudolaric acid B significantly inhibited T cell proliferation activated by mitogen and alloantigen without obvious cytotoxicity in vitro. Furthermore, Hexahydropseudolaric acid B could ameliorate ear swelling in a mouse model of 2,4-dinitrofluorobenzene-induced delayed-type hypersensitivity in vivo. Mechanistic study revealed that Hexahydropseudolaric acid B could enhance regulatory T cells via promoting Foxp3 expression and TGF-ß level, accompanied by attenuating Akt activation, blocking p38MAPK/MK2-HSP27 signal cascades, and up-regulating PPAR-γ expression. Taken together, these results suggest that Hexahydropseudolaric acid B exerts more preferable immunosuppressive activity than its precursor Pseudolaric acid B by affecting multiple targets, which support the need for continued efforts to characterize the efficacy of HPAB as a promising and safe candidate to treat immune-related diseases.

New hopane triterpene from Dicranostigma leptopodum (Maxim) Fedde.

Phytochemical investigation of the whole plant of Dicranostigma leptopodum (Maxim) Fedde led to the isolation of a new hopane triterpene, dicranostigmone (1), and a known compound, erythrodiol-3-O-palmitate (2). The structure of the new compound (1) was elucidated by various spectroscopic methods including 2D NMR techniques (gCOSY, HMQC, HMBC, NOESY), HR-ESI-MS, and X-ray.

[Effect of capsule of Shenshuai Yangzhen on malnutrition rats with chronic renal failure by 5/6 nephrectomy].

OBJECTIVE: To investigate the effects of capsule of Shenshuai Yangzhen, a preparation of traditional Chinese medicine, on malnutrition rats with chronic renal failure (CRF). METHODS: SD rats received 5/6 nephrectomy for preparation of CRF models, and fed 4% casein at the same time. Observed when malnutrition began. Those consistents with malnutrition of CRF condition were randomized into model control group, Ketosteril group, Shenshuai Yangzhen group, and normal control group. After 4-weeks treatment as indicated, The blood parameters, like blood serum albumin (ALB), type-1 insulin like growth factor (IGF-1), total cholesterol (TC), triglyeride (TG), urea nitrogen (BUN), serum creatinine (Scr), haemoglobin (Hb), 24 hour urineprotein (24hUpr) and weight were determined. Nephrotic tissue was observed by microscope (included HE and PAS). RESULTS: Malnutrition situation in CRF rats began at the end of 10-weeks. After 4-weeks treatment, weight in Shenshuai Yangzhen group were higher significantly (P < 0.05). Compared with model control group, blood serum BUN (P < 0.05), SCr (P < 0. 05) and 24h Upr (P < 0.001) in Shenshuai Yangzhen group were significantly lower with substantially elevated blood serum ALB, Hb, IGF-1 (P < 0.01; P < 0.001; P < 0.001, respectively). Pathology of Shenshuai Yangzhen group was a meliorated significantly after treated. CONCLUSION: Capsule of Shenshuai Yangzhen has a possible therapic effect on improving malnutrition in rats with renal insufficiency.

[Effect of Shenshuai Yangzhen capsule on remnant renal tissue following 5/6 nephrectomy in malnutrition rats with chronic renal failure].

OBJECTIVE: To investigate effects of Shenshuai Yangzhen capsule, a preparation of traditional Chinese medicine, on remnant renal tissue following nephrectomy in malnutrition rats with chronic renal failure. METHODS: SD rats were subjected to 5/6 nephrectomy and fed 4% casein diet to induce chronic renal failure (CRF), and their blood urea nitrogen (BUN), serum creatinine (Scr), serum albumin (ALB), hemoglobin (Hb), 24-hour urineprotein (24-h Upro) and body weight were measured. Upon the onset of malnutrition, the rats were randomized into CRF control group (CC), ketosteril group (KT), and Shenshuai Yangzhen group (SSYZ), with also a normal control group (NC). After 4 weeks of treatment as indicated, the remnant nephrotic tissue was examined under optical and electron microscopes and by immunofluorescence assay. RESULTS: Malnutrition occurred in the CRF rats at the end of the 10th weeks after the operation. Compared with those in CC group, the plasma BUN, SCr and 24-h Upro levels in SSYZ group were significantly lower with substantially elevated plasma ALB and Hb. The pathological changes of SSYZ group was significantly improved after treatment with Shenshuai Yangzhen capsule. CONCLUSION: Shenshuai Yangzhen capsule can improve malnutrition and reduce renal damage in rats with renal insufficiency.

Enhancement of endogenous defenses against ROS by supra-nutritional level of selenium is more safe and effective than antioxidant supplementation in reducing hypertensive target organ damage.

Hypertension-induced target organ damage (TOD), is one of the leading causes of morbidity and mortality. Reactive oxygen species (ROS) play an important role in the pathogenesis and development of hypertension. It has been suggested that hypertension-induced TOD is related to the level of oxidative stress, but is in part independent of the level of blood pressure. Therefore, in addition to anti-hypertensive drug therapy, novel strategies against ROS, will provide additional benefits to patient with hypertension. Vitamin E has long been supplemented as an effective antioxidant. However, the potential hazardous effects of vitamin E supplementation as antioxidant revealed by recent studies make its clinical and routine use prudent. Therefore, novel approaches capable of enhancing endogenous system to defend against ROS are required. Here, we propose that enhancement of intrinsic defenses against ROS by supra-nutritional level of selenium is more safe and effective than antioxidant supplementation in reducing hypertensive target organ damage, owing to its role in activating and constitution of native vital proteins and/or enzymes against oxidative stress, and the fact that scarcity of selenium can not be supplemented by normal food, and potentially extra benefits by supra-normal intake.

[Effects of Shenshuai Yangzhen capsule on lipid metabolism disorder in rats with chronic renal failure].

OBJECTIVE: To investigate the therapeutic effect of Shenshuai Yangzhen capsule, a preparation of traditional Chinese medicine, on lipid metabolism disorder in rats with chronic renal failure (CRF) and explore its mechanism. METHODS: Fifty male SD rats received 5/6 nephrectomy for preparation of CRF models and were randomized into CRF group, gemfibrozil group, high-, moderate- and low-dose Shenshuai Yangzhen groups, and normal control group. After 4-week treatment as indicated, myocardial lipoprotein lipase messenger RNA (LPL mRNA) level were measured by RT-PCR in rats with surgically induced renal failure (two-stage subtotal nephrectomy). The blood lipid parameters in CRF rats were also determined. RESULTS: Compared with those in the CRF group, the plasma total cholesterol, triglyceride, low-density lipoprotein cholesterol and very-low-density lipoprotein cholesterol concentrations in the treatment groups were significantly lower with substantially elevated plasma high-density lipoprotein cholesterol and LPL gene expression. No significant differences were noted between different dose groups of Shenshuai Yangzhen. CONCLUSION: Shenshuai Yangzhen capsule can regulate blood lipid levels in rats with renal insufficiency possibly by enhancing LPL gene expression.