USP18 Curbs the Progression of Metabolic Hypertension by Suppressing JAK/STAT Pathway.

Hypertension is a pathological state of the metabolic syndrome that increases the risk of cardiovascular disease. Managing hypertension is challenging, and we aimed to identify the pathogenic factors and discern therapeutic targets for metabolic hypertension (MHR). An MHR rat model was established with the combined treatment of a high-sugar, high-fat diet and ethanol. Histopathological observations were performed using hematoxylin-eosin and Sirius Red staining. Transcriptome sequencing was performed to screen differentially expressed genes. The role of ubiquitin-specific protease 18 (USP18) in the proliferation, apoptosis, and oxidative stress of HUVECs was explored using Cell Counting Kit-8, flow cytometry, and enzyme-linked immunosorbent assays. Moreover, USP18 downstream signaling pathways in MHR were screened, and the effects of USP18 on these signaling pathways were investigated by western blotting. In the MHR model, total cholesterol and low-density lipoprotein levels increased, while high-density lipoprotein levels decreased. Moreover, high vessel thickness and percentage of collagen were noted along with increased malondialdehyde, decreased superoxide dismutase and catalase levels. The staining results showed that the MHR model exhibited an irregular aortic intima and disordered smooth muscle cells. There were 78 differentially expressed genes in the MHR model, and seven hub genes, including USP18, were identified. USP18 overexpression facilitated proliferation and reduced apoptosis and oxidative stress in HUVECs treated with Ang in vitro. In addition, the JAK/STAT pathway was identified as a USP18 downstream signaling pathway, and USP18 overexpression inhibited the expression of JAK/STAT pathway-related proteins. Conclusively, USP18 restrained MHR progression by promoting cell proliferation, reversing apoptosis and oxidative stress, and suppressing the JAK/STAT pathway.

Beneficial effects of Panax notoginseng (Burkill) F. H. Chen flower saponins in rats with metabolic hypertension by inhibiting the activation of the renin-angiotensin-aldosterone system through complement 3.

BACKGROUND: Metabolic hypertension (MH) has become the most common type of hypertension in recent years due to unhealthy eating habits and lifestyles of people, such as over-eating alcohol, high fat, and sugar diets (ACHFSDs). Therefore, effective means to combat MH are needed. Previous studies have shown that Panax notoginseng (Burkill) F. H. Chen flower saponins (PNFS) can lower blood pressure in spontaneously hypertensive rats (SHR). However, whether it acts on MH and its mechanism of action remain unclear.  METHODS: The pharmacodynamic effects of PNFS were evaluated in rats with ACHFSDs-induced MH. The blood pressure, blood biochemical, grip strength, face temperature, vertigo time, and liver index were estimated. The histological changes in the liver and aorta were observed using hematoxylin and eosin staining. The levels of ET-1, TXB2, NO, PGI2, Renin, ACE, Ang II, and ALD in plasma were detected using ELISA. The levels of C3, KLF5, LXRα, and Renin in kidney tissues were measured using qRT-PCR.The expression levels of C3, KLF5, LXRα, and Renin in kidney tissues were examined using Western blotting. RESULTS: In the present study, PNFS was found to reduce blood pressure, face temperature, and vertigo time, increase grip strength and improve dyslipidemia in rats with MH. In addition, PNFS decreased the plasma levels of ET-1 and TXB2, elevated the levels of NO and PGI2, and improved pathological aortic injury. Meanwhile, PNFS decreased the plasma levels of Renin, ACE, Ang II, and ALD. QRT-PCR and Western bolt showed that PNFS downregulated C3, KLF5, LXRα, and Renin protein and mRNA expression in the kidneys of rats with MH. CONCLUSION: The finding of the present study suggested that PNFS could downregulate C3 and KLF-5 expression in rats with MH, thereby inhibiting the overactivation of the renin-angiotensin-aldosterone system, while improving vascular endothelial function and ultimately reducing blood pressure in rats with MH.

Polysaccharide, the Active Component of Dendrobium officinale, Ameliorates Metabolic Hypertension in Rats via Regulating Intestinal Flora-SCFAs-Vascular Axis.

Metabolic hypertension (MH) is the most common type of hypertension worldwide because of unhealthy lifestyles, such as excessive alcohol intake and high-sugar/high-fat diets (ACHSFDs), adopted by humans. Poor diets lead to a decrease in the synthesis of short-chain fatty acids (SCFAs), which are produced by intestinal flora and transferred by G protein-coupled receptors (GPCRs), resulting in impaired gastrointestinal function, disrupted metabolic processes, increased blood pressure (BP), and ultimately, MH. It is not clear whether Dendrobium officinale polysaccharide (DOPS) can mediate its effects by triggering the SCFAs-GPCR43/41 pathway. In this study, DOPS, with a content of 54.45 ± 4.23% and composition of mannose, glucose, and galacturonic acid at mass percentages of 61.28, 31.87, and 2.53%, was isolated from Dendrobium officinale. It was observed that DOPS, given to rats by intragastric administration after dissolution, could lower the BP and improve the abnormal lipid metabolic processes in ACHSFD-induced MH rats. Moreover, DOPS was found to increase the production, transportation, and utilization of SCFAs, while improving the intestinal flora and strengthening the intestinal barrier, as well as increasing the intestinal levels of SCFAs and the expression of GPCR43/41. Furthermore, DOPS improved vascular endothelial function by increasing the expression of GPCR41 and endothelial nitric oxide synthase in the aorta and the nitric oxide level in the serum. However, these effects were all reversed by antibiotic use. These findings indicate that DOPS is the active component of Dendrobium officinale, and it can reverse MH in rats by activating the intestinal SCFAs-GPCR43/41 pathway.

Refined-JinQi-JiangTang tablet ameliorates hypertension through activation of FGF21/FGFR1 axis in fructose-fed rats.

The aim of this study was to investigate the therapeutic effect of JQ-R on metabolic hypertension and its correlation with Fibroblast growth factor 21/Fibroblast growth factor receptors 1(FGF21/FGFR1) pathway. In this study, fructose-induced metabolic hypertension rats were used as hypertension models to detect the regulation effect of JQ-R on hypertension. The effects of JQ-R on blood glucose, blood lipids, serum insulin levels and other metabolic indicators of rats were also measured. The effects of JQ-R on FGF21/FGFR1 signaling pathway in model animals were detected by Real-time quantitative PCR and Western blotting. The results showed that JQ-R significantly reduce the blood pressure of model rats in a dose-dependent manner. Meanwhile, fasting insulin, fasting blood glucose, insulin resistance index, total cholesterol and triglyceride levels were significantly decreased, and glucose and lipid metabolism abnormalities were also significantly improved. JQ-R induces these changes along with FGFR1 phosphorylation, which was also detected in JQ-R treated FGF21 knockout mice. These results suggest that JQ-R can reduce blood pressure and improve glucose and lipid metabolism in fructose-induced hypertension rats. Activation of FGF21/FGFR1 signaling pathway to regulate downstream blood pressure and glucolipid metabolism-related pathways may be one of the important mechanisms of JQ-R in regulating blood pressure.

Aqueous extract of large cardamom inhibits vascular damage, oxidative stress, and metabolic changes in fructose-fed hypertensive rats.

PURPOSE: Since metabolic abnormalities such as elevated glucose level and imbalanced lipid profiles increase the risk for hypertension and cause endothelial dysfunction, we evaluated the effect of aqueous extract of large cardamom (AELC) on fructose-induced metabolic hypertension and oxidative stress. METHODS: The male Sprague-Dawley rats were divided into 6 groups with 5 rats in each group, and each group was fed with 10% fructose in drinking water for 8 weeks. Starting from week 5, animals were treated with 50, 100, and 200 mg/kg/day AELC or Losartan (10 mg/kg/day). Systolic, diastolic, and mean arterial blood pressure was measured once in every seven days using the tail-cuff method. Vascular function, plasma nitric oxide (NO), glucose, lipid profiles, serum biochemical, and anti-oxidant parameters were also evaluated. RESULTS: Rats fed with fructose showed higher blood pressure, serum cholesterol, and triglyceride levels, but decreased in the AELC or Losartan treatment group. Treatments with AELC prevented exaggerated plasma glucose and oxidative stress and restored the nitric oxide level in fructose-fed rats. Besides, it also reduced vascular proliferation and improved the relaxation response of acetylcholine in the aorta pre-contracted with phenylephrine. CONCLUSION: In summary, the obtained results suggest that AELC can prevent and reverse the high blood pressure induced by fructose, probably by restoring nitric oxide level and by improving altered metabolic parameters.

[Effect of Dendrobii officinalis superfine powder on overeating greasy-induced metabolic hypertension in rats].

Dendrobii officinalis, with a definite effect of nourishing Yin and clearing heat, has been a folk habit for drinking after being mixed with water. Because its superfine powder has the advantages of high dissolution and convenient drinking, we observed the effect of D. officinalis superfine powder on metabolic hypertension model rats and its possible mechanism in this experiment, which can be used as a reference for its clinical application for hypertension. The overeating greasy-induced metabolic hypertension model was established with high-fat, high-sugar and high-purine diet. These rats were orally administered with 400 mg·kg~(-1) and 200 mg·kg~(-1) of D. officinalis superfine powder for 20 consecutive weeks. During this period, blood pressure, blood lipid, blood glucose, insulin and other related indexes of glucose and lipid metabolism were monitored; the levels of lipopolysaccharide(LPS), C-reactive protein(CRP), interleukin 6(IL-6) and other inflammatory mediators were measured; the levels of nitric oxide(NO) and endothelin-1(ET-1) were detected, and the histomorphological and ultrastructural changes of aorta were observed. In addition, the expression of LPS/TLR4 pathway-related molecules in aorta was determined. The results showed that long-term administration of D. officinalis superfine powder significantly reduced the levels of systolic blood pressure(SBP), diastolic blood pressure(DBP) and mean arterial pressure(MBP) in metabolic hypertension model rats, decreased the levels of total cholesterol(TC), triglyceride(TG), low density lipoprotein cholesterol(LDL-c), glucose(Glu), and insulin(INS) levels in blood, increased the contents of high density lipoprotein cholesterol(HDL-c),decreased the LPS, CRP, IL-6 and ET-1 levels in blood and increased NO content. Furthermore, it improved the abnormality of aortic histomorphology and endothelial ultrastructure, and inhibited the protein expression of TLR4, myeloid differentiation factor(MyD88), IL-6, interleukin-1 ß(IL-1ß), and tumor necrosis factor-α(TNF-α) as well as mRNA expression of TNF-α and IL-1ß in aorta. In conclusion, D. officinalis superfine powder may improve the abnormal function and structure of blood vessels by inhibiting the activation of LPS/TLR4 pathway, thus playing a role against metabolic hypertension.

Effect of Dendrobii officinalis superfine powder on overeating greasy-induced metabolic hypertension in rats / 中国中药杂志

Dendrobii officinalis, with a definite effect of nourishing Yin and clearing heat, has been a folk habit for drinking after being mixed with water. Because its superfine powder has the advantages of high dissolution and convenient drinking, we observed the effect of D. officinalis superfine powder on metabolic hypertension model rats and its possible mechanism in this experiment, which can be used as a reference for its clinical application for hypertension. The overeating greasy-induced metabolic hypertension model was established with high-fat, high-sugar and high-purine diet. These rats were orally administered with 400 mg·kg~(-1) and 200 mg·kg~(-1) of D. officinalis superfine powder for 20 consecutive weeks. During this period, blood pressure, blood lipid, blood glucose, insulin and other related indexes of glucose and lipid metabolism were monitored; the levels of lipopolysaccharide(LPS), C-reactive protein(CRP), interleukin 6(IL-6) and other inflammatory mediators were measured; the levels of nitric oxide(NO) and endothelin-1(ET-1) were detected, and the histomorphological and ultrastructural changes of aorta were observed. In addition, the expression of LPS/TLR4 pathway-related molecules in aorta was determined. The results showed that long-term administration of D. officinalis superfine powder significantly reduced the levels of systolic blood pressure(SBP), diastolic blood pressure(DBP) and mean arterial pressure(MBP) in metabolic hypertension model rats, decreased the levels of total cholesterol(TC), triglyceride(TG), low density lipoprotein cholesterol(LDL-c), glucose(Glu), and insulin(INS) levels in blood, increased the contents of high density lipoprotein cholesterol(HDL-c),decreased the LPS, CRP, IL-6 and ET-1 levels in blood and increased NO content. Furthermore, it improved the abnormality of aortic histomorphology and endothelial ultrastructure, and inhibited the protein expression of TLR4, myeloid differentiation factor(MyD88), IL-6, interleukin-1 β(IL-1β), and tumor necrosis factor-α(TNF-α) as well as mRNA expression of TNF-α and IL-1β in aorta. In conclusion, D. officinalis superfine powder may improve the abnormal function and structure of blood vessels by inhibiting the activation of LPS/TLR4 pathway, thus playing a role against metabolic hypertension.

Systematic Understanding of the Mechanisms of Flos Chrysanthemi Indici-mediated Effects on Hypertension via Computational Target Fishing.

AIMS AND OBJECTIVE: Hypertension-induced stroke and coronary artery disease are significant causes of global morbidity and mortality. Metabolic hypertension has recently become the leading cause of hypertension. Flos Chrysanthemi Indici (CIF) has a long history as a treatment of hypertension as part of traditional Chinese medicine. However, its mechanisms of activity remain largely unknown. This study was aimed to uncover the potential anti-hypertensive mechanisms of CIF based on network pharmacology. MATERIALS AND METHODS: In this research, a systems pharmacology approach integrating the measurement of active compounds, target fishing, gene screening, Gene Ontology (GO) pathway analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) Orthology Based Annotation System (KOBAS) database analysis, and compound-target network construction were performed to explore the anti-hypertensive mechanisms of CIF. RESULTS: These studies revealed that 12 bioactive compounds in CIF had good druggability, 5 of which were flavonoids. After screening, 8 of those 12 bioactive compounds interacted with 118 hypertensionrelated target genes, which were mapped to 218 signal pathways. Network analysis showed that these targets were associated with improving insulin resistance, improving vascular function, inhibiting renninangiotensin- aldosterone system (RAAS), inhibiting the sympathetic nervous system (SNS) and regulating other physiological processes. CONCLUSION: In summary, CIF is predicted to target multiple proteins and pathways to form a network that exerts systematic pharmacological effects in order to regulate blood pressure and metabolic disorder.

[Effects and active substances of ethanol extract from Dendrobium officinale on metabolic hypertensive rats induced by comprehensive dietary].

Previous studies of Dendrobium officinale on anti-hypertension effect always focused only on the blood pressure,while polysaccharides of D. officinale( DOP) have been traditionally considered as one of the main effective substances. This study aimed to evaluate the effect of ethanol extract from D. officinale( DOE) on blood pressure,Glu and lipid profile in metabolic hypertensive rats induced by comprehensive dietary factors,and elucidate the composition of effective fractions from DOE. A metabolic hypertension model of rat induced by high-sugar,high-fat diet and alcohol drinking was adopted to evaluate the effect of DOE on hypertension and other metabolic disorders. Blood pressure,Glu and lipid profile were detected to find the features and differences of DOE and DOP on metabolic hypertension. Furthermore,DOE was separated with three different common solvents according to the polarity. Along with blood pressure,Glu,UA and lipid profile,hemorheology,oxidative index and aortas structure changes were adopted to evaluate the comprehensive effects of the most effective fractions on metabolic hypertension. Finally,HPLC-DAD-MS was adopted to identify the components of the most effective fraction. The SBP and Glu of models were decreased significantly after administration of DOE and DOP for 6 weeks,while TG in DOE groups also reduced dramatically. The DOE was separated with ether,n-butanol respectively and named NAF,NBF and NCF. SBP,TG,Glu,UA of model rats were decreased significantly after 4 weeks administration with NBF. The level of MDA in serum was down-regulated,while GSH-Px and T-AOC were up-regulated obviously after 12 weeks.And the blood viscosity also obviously decreased,with less collagen deposition of aortas by Masson's trichrome staining. NBF was mainly composed of phenols and flavone C-glycosides,whose aglycone was apigenin,and monosaccharide was connected to C-6 and C-8. Ethanol extract from D.officinale has an positive effect in alleviating hypertension and metabolic disorders in metabolic hypertension. Medium polarity fraction was the effective fraction of alcohol extraction from D. officinale,and mainly composed of phenols and flavone C-glycosides.

Chemerin stimulates aortic smooth muscle cell proliferation and migration via activation of autophagy in VSMCs of metabolic hypertension rats.

Vascular remodeling is a characteristic pathogenesis of hypertension and a main cause of abnormal construction and function of organs because of hypertension. Chemerin is a new adipokine that is elevated in states of obesity and metabolic syndrome (MS). However, the molecular mechanisms behind these pathological processes are not fully clarified. An animal model of metabolic hypertension was created to evaluate the role of metabolic chemerin in hypertension. In this study, the expression of chemerin/CMKLR-1 and autophagy in the arteries of metabolic hypertension rats undergoing vascular remodeling was investigated and the effect and mechanisms on the regulation of human aortic smooth muscle cells (HA-SMCs) were explored. The vascular remodeling in vivo was more serious in the metabolic hypertensive rat model, and the expression of chemerin and its receptor CMKLR1 were remarkably higher in the media layer of the thoracic aorta and the mesenteric artery in metabolic hypertension rats. In addition, there was an increased number of autophagosomes in SMCs and an up-regulation of the autophagy-related protein LC3 and beclin-1 levels in metabolic hypertension rats. In vitro, chemerin significantly stimulated HA-SMC proliferation and migration, as determined by MTT assay and scratch assay, respectively. Chemerin significantly increased LC3 and beclin-1 levels, as measured by western blot analysis, while this effect was inhibited by the autophagy inhibitor 3-MA. It is demonstrated that chemerin stimulates SMC proliferation and migration via autophagy, which may lead to vascular structural remodeling in metabolic hypertension.

Effects and active substances of ethanol extract from Dendrobium officinale on metabolic hypertensive rats induced by comprehensive dietary / 中国中药杂志

Previous studies of Dendrobium officinale on anti-hypertension effect always focused only on the blood pressure,while polysaccharides of D. officinale( DOP) have been traditionally considered as one of the main effective substances. This study aimed to evaluate the effect of ethanol extract from D. officinale( DOE) on blood pressure,Glu and lipid profile in metabolic hypertensive rats induced by comprehensive dietary factors,and elucidate the composition of effective fractions from DOE. A metabolic hypertension model of rat induced by high-sugar,high-fat diet and alcohol drinking was adopted to evaluate the effect of DOE on hypertension and other metabolic disorders. Blood pressure,Glu and lipid profile were detected to find the features and differences of DOE and DOP on metabolic hypertension. Furthermore,DOE was separated with three different common solvents according to the polarity. Along with blood pressure,Glu,UA and lipid profile,hemorheology,oxidative index and aortas structure changes were adopted to evaluate the comprehensive effects of the most effective fractions on metabolic hypertension. Finally,HPLC-DAD-MS was adopted to identify the components of the most effective fraction. The SBP and Glu of models were decreased significantly after administration of DOE and DOP for 6 weeks,while TG in DOE groups also reduced dramatically. The DOE was separated with ether,n-butanol respectively and named NAF,NBF and NCF. SBP,TG,Glu,UA of model rats were decreased significantly after 4 weeks administration with NBF. The level of MDA in serum was down-regulated,while GSH-Px and T-AOC were up-regulated obviously after 12 weeks.And the blood viscosity also obviously decreased,with less collagen deposition of aortas by Masson's trichrome staining. NBF was mainly composed of phenols and flavone C-glycosides,whose aglycone was apigenin,and monosaccharide was connected to C-6 and C-8. Ethanol extract from D.officinale has an positive effect in alleviating hypertension and metabolic disorders in metabolic hypertension. Medium polarity fraction was the effective fraction of alcohol extraction from D. officinale,and mainly composed of phenols and flavone C-glycosides.

Current situation and prospect of antihypertensive pharmacology of traditional Chinese medicine / 中国药理学与毒理学杂志

The incidence and its growth rate of hypertension are both very high. Its pathology and pathogenesis are complex and unclear,and it does serious harm to human health. Hypertension remains incurable. Chemical medicine has good effect on hypertension,but life-long application and multi-drug combination are required,with significant adverse reactions. Also,complications can′t be effectively alleviated. Traditional Chinese medicine (TCM)guided by traditional theories,can lower blood pressure,improve metabolic abnormalities and reduce complications. Its advantages or potentials have not been fully exploited and clinical application is inadequate. Metabolic hypertension has become the main form of hypertension,and its formation mechanism is mainly related to metabolic abnormalities and insulin resistance,metabolic inflammation and other pathology and pathogenesis. A better understanding of the current status of antihypertensive pharmacology of TCM,especially devel?opment and application of metabolic hypertension models is of great significance for TCM treatment of hypertension,and for exploration of new approaches to hypertension.