Association between circulatory complement activation and hypertensive renal damage: a case-control study.

OBJECTIVE: The aim of this study was to investigate the potential importance of complement system activation, with particular emphasis on the complement alternative pathway (AP), in the pathogenesis of hypertensive renal damage. METHODS: Serum complement C3, complement Factor H (CFH) and AP activation were assessed in 66 participants with established essential hypertension with renal damage (RD). Fifty-nine patients with age- and sex-matched essential hypertension without renal damage (NRD) and 58 healthy participants (normal) were selected. RESULTS: Our study revealed that C3 and AP50 continuously increased from normal to NRD to RD (p < 0.05, respectively), while CFH was significantly lower than that in NRD and healthy participants (p < 0.05, respectively). After multifactorial logistic regression analysis corrected for confounders, elevated serum C3 (p = 0.001) and decreased CFH (p < 0.001) were found to be independent risk factors for hypertension in healthy participants; elevated serum C3 (p = 0.034), elevated AP50 (p < 0.001), decreased CFH (p < 0.001), increased age (p = 0.011) and increased BMI (p = 0.013) were found to be independent risk factors for the progression of hypertension to hypertensive renal damage; elevated serum C3 (p = 0.017), elevated AP50 (p = 0.023), decreased CFH (p = 0.005) and increased age (p = 0.041) were found to be independent risk factors for the development of hypertensive renal damage in healthy participants. CONCLUSION: Abnormal activation of complement, particularly complement AP, may be a risk factor for the development and progression of hypertensive renal damage.

Canagliflozin attenuates kidney injury, gut-derived toxins, and gut microbiota imbalance in high-salt diet-fed Dahl salt-sensitive rats.

PURPOSE: To investigate the effects of canagliflozin (20 mg/kg) on Dahl salt-sensitive (DSS) rat gut microbiota and salt-sensitive hypertension-induced kidney injury and further explore its possible mechanism. METHODS: Rats were fed a high-salt diet to induce hypertension and kidney injury, and physical and physiological indicators were measured afterwards. This study employed 16S rRNA sequencing technology and liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based metabolic profiling combined with advanced differential and association analyses to investigate the correlation between the microbiome and the metabolome in male DSS rats. RESULTS: A high-salt diet disrupted the balance of the intestinal flora and increased toxic metabolites (methyhistidines, creatinine, homocitrulline, and indoxyl sulfate), resulting in severe kidney damage. Canagliflozin contributed to reconstructing the intestinal flora of DSS rats by significantly increasing the abundance of Corynebacterium spp., Bifidobacterium spp., Facklamia spp., Lactobacillus spp., Ruminococcus spp., Blautia spp., Coprococcus spp., and Allobaculum spp. Moreover, the reconstruction of the intestinal microbiota led to significant changes in host amino acid metabolite concentrations. The concentration of uremic toxins, such as methyhistidines, creatinine, and homocitrulline, in the serum of rats was decreased by canagliflozin, which resulted in oxidative stress and renal injury alleviation. CONCLUSION: Canagliflozin may change the production of metabolites and reduce the level of uremic toxins in the blood circulation by reconstructing the intestinal flora of DSS rats fed a high-salt diet, ultimately alleviating oxidative stress and renal injury.

Management of nocturnal hypertension: An expert consensus document from Chinese Hypertension League.

Nocturnal hypertension is highly prevalent among Chinese and Asian populations, which is mainly attributed to high salt intake and high salt sensitivity. Nocturnal hypertension increases the risk of cardiovascular and all-cause mortality, independent of daytime blood pressure (BP). However, it can usually be detected by 24-h ambulatory BP monitoring, rather than routine office or home BP measurement, thus is often underdiagnosed in clinical practice. Currently, no specific guidance is available for the management of nocturnal hypertension in China or worldwide. Experts from the Chinese Hypertension League summarized the epidemiologic and pathophysiologic characteristics and clinical phenotype of nocturnal hypertension and provided consensus recommendations on optimal management of nocturnal hypertension, with the goal of maximally reducing the cardiovascular disease risks. In this consensus document, 24-h ABPM is recommended for screening and diagnosis of nocturnal hypertension, especially in the elderly, patients with diabetes, chronic kidney diseases, obstructive sleep apnea and other conditions prone to high nocturnal BP. Lifestyle modifications including salt intake restriction, exercise, weight loss, sleep improvement, and mental stress relief are recommended. Long-acting antihypertensive medications are preferred for nocturnal and 24-h BP control. Some newly developed agents, renal denervation, and other device-based therapy on nocturnal BP reduction are evaluated.

Canagliflozin and irbesartan ameliorate renal fibrosis via the TGF-ß1/Smad signaling pathway in Dahl salt-sensitive rats.

OBJECTIVES: This study assessed the antifibrotic effects of canagliflozin, with or without irbesartan, on renal injury in Dahl salt-sensitive (SS) rats fed a high-salt (HS) diet. METHODS: After the preconditioning stage, Dahl SS rats (n = 47) were divided into five experimental groups as follows: low-salt (LS, n = 7), HS (n = 10), HS with canagliflozin (n = 10), HS with irbesartan (n = 10), and HS with canagliflozin and irbesartan (n = 10). RESULTS: The HS diet increased systolic blood pressure (SBP), renal fibrosis, fibrotic protein expression, and transforming growth factor-ß1 (TGF-ß1)/Smad2/3 pathway protein expression compared with the findings in the LS group. Irbesartan reduced SBP and slowed the loss of renal function. Canagliflozin significantly reduced body weight and renal fibrosis and suppressed the TGF-ß1/Smad2/3 pathway. The combined therapy exerted better renoprotective effects on all outcome parameters. CONCLUSIONS: These results indicate that canagliflozin and irbesartan exert different effects on renal injury in SS hypertensive rats, and the combined regimen could have stronger effects than either monotherapy.

Canagliflozin Ameliorates Ventricular Remodeling through Apelin/Angiotensin-Converting Enzyme 2 Signaling in Heart Failure with Preserved Ejection Fraction Rats.

INTRODUCTION: The aim of this study was to investigate the effect of canagliflozin (CANA) on ventricular remodeling in patients with preserved ejection fraction (HFpEF) heart failure and to further investigate its possible molecular mechanisms. METHODS: A high-salt diet was used to induce the formation of HFpEF model in salt-sensitive rats. The rats were fed with CANA and irbesartan, respectively. The mice were divided into control group, model group, CANA group, irbesartan group, and combined drug group. After 12 weeks of feeding, the rats were evaluated by measuring the relevant indexes and echocardiography for cardiac function. Histological analysis was performed using Masson trichrome staining and immunohistochemical staining. RT-qPCR and Western blot were used to quantify the relevant genes and proteins. RESULTS: In this study, CANA exhibited diuresis, decreased blood pressure, weight loss, and increased food and water intake. Following a high-salt diet, Dahl salt-sensitive rats developed hypertension followed by left ventricular diastolic dysfunction, myocardial fibrosis, and left ventricular remodeling. Myocardial hypertrophy and fibrosis were reduced, and left ventricular diastolic function and ventricular remodeling improved after CANA treatment. The combination of CANA and irbesartan was superior to monotherapy in reducing blood pressure and improving cardiac insufficiency and left ventricular diastolic dysfunction in rats. CANA improves myocardial fibrosis, left ventricular diastolic dysfunction, and ventricular remodeling by upregulating apelin, activating angiotensin-converting enzyme 2 (ACE2), and increasing ACE2/Ang (1-7)/MASR axis levels. CONCLUSION: CANA improves myocardial fibrosis, left ventricular diastolic dysfunction, and ventricular remodeling in HFpEF rats through upregulation of apelin/ACE2 signaling.

MiR-21 attenuates FAS-mediated cardiomyocyte apoptosis by regulating HIPK3 expression.

MicroRNA-21 (miR-21) plays an anti-apoptotic role following ischemia-reperfusion (I/R) injury (IRI) in vivo; however, its underlying mechanism remains unclear. The present study explored the effects of miR-21 and homeodomain interacting protein kinase 3 (HIPK3) on cardiomyocyte apoptosis induced by hypoxia/reoxygenation (H/R) in vitro. To this end, the rat cardiomyocyte H9C2 cell line was exposed to H/R and the roles of miR-21 and HIPK3 in regulating cell viability and apoptosis were evaluated by cell counting kit-8 assay, terminal-deoxynucleotidyl-transferase-mediated dUTP nick end labeling, and flow cytometry. Immunofluorescence and Western blotting were performed to detect the expression/phosphorylation of apoptosis-related proteins. miR-21 expression was measured with quantitative real-time polymerase chain reaction. The putative interaction between miR-21 and HIPK3 was evaluated using the luciferase reporter assay. Our results showed that (i) miR-21 overexpression or HIPK3 down-regulation significantly attenuated H9C2 cells apoptosis after H/R, (ii) suppression of miR-21 expression promoted apoptosis, (iii) miR-21 overexpression inhibited HIPK3 expression, (iv) HIPK3 was the direct and main target of miR-21, (v) miR-21/HIPK3 formed part of a reciprocal, negative feedback loop, and (vi) HIPK3 down-regulation decreased FAS-mediated apoptosis by inhibiting the phosphorylation of FADD, which subsequently inhibited the expression of BAX and cleaved caspase-3 and increased the expression of BCL2. Our study indicates that miR-21 attenuates FAS-mediated cardiomyocyte apoptosis by regulating HIPK3 expression, which could eventually have important clinical implications for patients with acute myocardial infarction.

Canagliflozin ameliorates epithelial-mesenchymal transition in high-salt diet-induced hypertensive renal injury through restoration of sirtuin 3 expression and the reduction of oxidative stress.

Hypertensive nephropathy is characterized by long-term damage to renal tissues by chronic uncontrolled hypertension, and ultimately leads to the development of renal fibrosis. The epithelial-mesenchymal transition (EMT) potentially contributes to the promotion of renal fibrosis in chronic kidney disease (CKD). In this study, we investigated the potential roles of canagliflozin (Cana) on renal EMT and oxidative stress through its effects on sirtuin 3 (SIRT3) expression. High-salt diet (HSD)-induced Dahl salt-sensitive rats hypertensive renal injury led to decreased SIRT3 expression and an increase in EMT and oxidative stress. In contrast, Cana administration rescued SIRT3 expression, decreased both EMT and levels of oxidative stress, and ameliorated renal injury. Furthermore, we compared the antihypertensive and renoprotective properties of Cana when combined with irbesartan (Irb), a renin-angiotensin system (RAS) blocker. We concluded that administration of Cana in combination with Irb had a significantly greater effect in lowering systolic blood pressure when compared to Cana monotherapy. However, no statistical differences were observed between combined therapy and monotherapy groups with regards to the lowering of diastolic blood pressure and renoprotection. Utilizing the human renal proximal tubular epithelial cell line (HK-2), Angiotensin II (AngⅡ) induced HK-2 negatively regulated the expression of SIRT3, FOXO3a, catalase, and promoted EMT, all of which were reversed by Cana. Furthermore, SIRT3 silencing abolished Cana-mediated rescue of forkhead box O3a (FOXO3a) and catalase expression and Cana-mediated suppression of EMT in AngⅡ induced HK-2. Taken together, Cana acts as a renoprotective agent by suppressing EMT in the pathology of renal fibrosis via interaction with the SIRT3-FOXO3a pathway.

Asiaticoside attenuates oxygen-glucose deprivation/reoxygenation-caused injury of cardiomyocytes by inhibiting autophagy.

Asiaticoside is a natural triterpene compound derived from Centella asiatica, possessing confirmed cardioprotective property. However, the roles of asiaticoside in regulating oxygen-glucose deprivation/reoxygenation (OGD/R)-caused cardiomyocyte dysfunction remain largely obscure. Human cardiomyocyte AC16 cells were stimulated with OGD/R to mimic myocardial ischemia/reperfusion injury and treated with asiaticoside. Cytotoxicity was investigated by CCK-8 assay and lactate dehydrogenase (LDH) release analysis. Autophagy- and Wnt/ß-catenin signaling-related protein levels were measured via western blotting. Asiaticoside (0-20 µM) did not induce cardiomyocyte cytotoxicity. Asiaticoside (20 µM) mitigated OGD/R-induced autophagy, cytotoxicity, oxidative stress, and myocardial injury. Rapamycin, an autophagy inductor, reversed the influences of asiaticoside on autophagy, cytotoxicity, oxidative stress, and myocardial injury, whereas 3-methyadanine, an autophagy inhibitor, played an opposite effect. Asiaticoside (20 µM) attenuated OGD/R-induced Wnt/ß-catenin signaling inactivation, which was reversed after transfection with si-ß-catenin. Transfection with si-ß-catenin attenuated the influences of asiaticoside on autophagy, cytotoxicity, oxidative stress, and myocardial injury. In conclusion, asiaticoside protected against OGD/R-induced cardiomyocyte cytotoxicity, oxidative stress, and myocardial injury via blunting autophagy through activating the Wnt/ß-catenin signaling, indicating the therapeutic potential of asiaticoside in myocardial ischemia/reperfusion injury.

Canagliflozin Attenuates Hepatic Steatosis and Atherosclerosis Progression in Western Diet-Fed ApoE-Knockout Mice.

Purpose: To investigate the effect of canagliflozin (20 mg/kg) on hepatic steatosis and atherosclerosis, and further to explore its possible mechanism. Methods: Blood glucose, blood lipid, oxidative stress response and inflammatory cytokines were examined by intraperitoneal glucose tolerance test and ELISA assay. HE and Oil Red O staining were used to estimate the extent of hepatic steatosis and atherosclerosis. RNA-seq and qRT-PCR were used to further investigate the potential mechanism. The effects of canagliflozin on autophagy were detected using transmission electron microscopy and Western blotting. The endothelial function-related markers were determined by qRT-PCR. Results: Canagliflozin notably alleviated the elevation in blood glucose and insulin resistance in western diet-fed ApoE-/- mice. In ApoE-/-+Cana group, ApoE-/- mice had lower levels of TG, TC, LDL-C, TNF-α, IL-6, IL-1ß, and MCP-1. HE and Oil Red O staining presented that canagliflozin restrained the atherosclerotic plaque development and lipid accumulation. RNA-seq showed that 87 DEGs were relevant to improvement of hepatic steatosis and atherosclerosis by canagliflozin. Among them, CPS1, ASS1, ASL, ARG1, MATLA, GLS2, GOT1, SREBP1, Plin5, Retreg1, and C/EBPß were verified. KEGG enrichment analysis indicated that DEGs were mainly involved in amino acid metabolism. Besides, we observed that canagliflozin reduced the contents of aspartic acid and citrulline in liver. Western blotting showed that ASS1 and p-AMPK/AMPK was remarkably elevated after administration of canagliflozin. Correspondingly, canagliflozin down-regulated SREBP1, FAS, ACC1, HMGCR, p-mTOR/m-TOR, p-ULK1/ULK1 and p62, but up-regulated CPT1, Beclin 1 and LC3 II/LC3I. TEM showed that canagliflozin reduced the number of lipid droplets and increased the autophagosomes. Moreover, we found that canagliflozin elevated the aortic endothelial function-associated markers including ASS1, ASL and eNOS. Conclusion: Canagliflozin may attenuate hepatic steatosis by improving lipid metabolism, enhancing autophagy, and reducing inflammatory response through ASS1/AMPK pathway. Besides, canagliflozin further effectively improves the aortic endothelial function, thereby suppressing atherosclerosis development.

The relationship between serum miR-21 levels and left atrium dilation in elderly patients with essential hypertension.

BACKGROUND: MicroRNA-21 (miR-21) is related to hypertension and cardiac remodelling. Left atrium (LA) dilation is highly sensitive to small haemodynamic changes in the left ventricle (LV) that are induced by hypertension. This study aimed to elucidate the relationship between miR-21 expression and LA dilation in elderly patients with essential hypertension (EH). METHODS: In this cross-sectional study, one hundred elderly patients with EH were recruited for the study. According to their left atrium diameters (LADs), the patients were divided into the LA dilation group [42 patients (42%)] and the no-LA dilation group [58 patients (58%)]. The serum levels of miR-21 and chemical biomarkers used in the clinic, such as creatinine, blood urea nitrogen, uric acid, fasting blood glucose, total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), very-low-density lipoprotein cholesterol, Lp(a), apolipoprotein A1 (apoA1), and apolipoprotein B, were measured. All the patients underwent echocardiographic examination, and the LAD, interventricular septum (IVS), right atrium diameter (RAD), right ventricle diameter (RVD), left ventricular end-systolic diameter (LVESD), left ventricular end-systolic diameter (LVEDD) and left ventricular ejection fraction (LVEF) were measured. RESULTS: The levels of miR-21 [8.02 (5.21, 14.39) vs. 6.05 (3.81, 8.95), P = 0.011] and LVEF (67.02 ± 3.82 vs. 64.14 ± 4.43, P = 0.001) were higher in the LA dilation group. The levels of creatinine [70.40 (64.45, 80.15) vs. 63.9(60.1, 73.43)], P = 0.020] were higher in the no-LA dilation group. The levels of HDLC (r = - 0.209, P = 0.037), apoA1 (r = -0.269, P = 0.007) and RAD (r = 0.203, P = 0.043) were significantly correlated with miR-21 expression. The LAD was significantly correlated with the RAD (r = 0.287, P = 0.004), RVD (r = 0.450, P < 0.001), LVEDD (r = 0.248, P = 0.013) and LVEF (r = 0.232, P = 0.020). Multivariate logistic regression revealed that miR-21 significantly influenced LA dilation in elderly patients with EH (P < 0.05). CONCLUSIONS: Circulating serum levels of miR-21 are increased in elderly patients with EH with LA dilation. miR-21 levels are significantly correlated with LA dilation in elderly patients with EH, and miR-21 may be a factor related to the clinical pathophysiological occurrence of and treatment for the progression of hypertension-related early heart damage in EH patients.

Liquid biopsy using ascitic fluid and pleural effusion supernatants for genomic profiling in gastrointestinal and lung cancers.

BACKGROUND: Precision medicine highlights the importance of incorporating molecular genetic testing into standard clinical care. Next-generation sequencing can detect cancer-specific gene mutations, and molecular-targeted drugs can be designed to be effective for one or more specific gene mutations. For patients with special site metastases, it is particularly important to use appropriate samples for genetic profiling. This study aimed to determine whether genomic profiling using ASC and PE is effective in detecting genetic mutations. METHODS: Tissues, plasma, ascites (ASC) supernatants, and pleural effusion (PE) samples from gastrointestinal cancer patients with peritoneal metastasis and lung cancer patients with pleural metastasis were collected for comprehensive genomic profiling. The samples were subjected to next-generation sequencing using a panel of 59 or 1021 cancer-relevant genes panel. RESULTS: A total of 156 tissues, 188 plasma samples, 45 ASC supernatants, and 1 PE samples from 304 gastrointestinal cancer patients and 446 PE supernatants, 122 tissues, 389 plasma samples, and 45 PE sediments from 407 lung cancer patients were analyzed. The MSAF was significantly higher in ASC and PE supernatant than that in plasma ctDNA (50.00% vs. 3.00%, p < 0.0001 and 28.5% vs. 1.30%, p < 0.0001, respectively). The ASC supernatant had a higher actionable mutation rate and more actionable alterations than the plasma ctDNA in 26 paired samples. The PE supernatant had a higher total actionable mutation rate than plasma (80.3% vs. 48.4%, p < 0.05). The PE supernatant had a higher frequency of uncommon variations than the plasma regardless of distant organ metastasis. CONCLUSION: ASC and PE supernatants could be better alternative samples when tumor tissues are not available, especially in patients with only peritoneal or pleural metastases.

Intravoxel incoherent motion diffusion-weighted imaging for early assessment of combined anti-angiogenic/chemotherapy for colorectal cancer liver metastases.

Background: To explore the value of intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) in the early assessment of colorectal cancer liver metastases (CRLM). Methods: A total of 34 patients with pathologically confirmed unresectable CRLM were enrolled. All participants uniformly received capecitabine and oxaliplatin (CAPOX) plus bevacizumab chemotherapy as standard first-line treatment for advanced colorectal cancer (CRC). Participants underwent 1.5-T conventional magnetic resonance imaging (MRI) and IVIM-DWI sequence scans with 9 b values (0 to 1,000 s/mm2) before treatment and at 3 weeks of treatment, and conventional MRI scans were performed at 6 and 12 weeks after the initial treatment. The IVIM-DWI parameters in the tumor target area were extracted using image post-processing software, including perfusion fraction (f), true diffusion coefficient (D), and false diffusion coefficient (D*). The response assessment was based on the Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1 by measuring the longest tumor diameter on dynamic contrast-enhanced (DCE) T1-weighted images. Results: According to the RECIST v. 1.1 criteria, the 34 participants were divided into a response group (n=16) and a non-response group (n=18). In the response group, the f value was significantly lowered (P=0.001) and the D value was significantly increased after treatment (P=0.002). In the non-response group, the D value was increased slightly after treatment (P=0.039), and there was no significant difference in the f value and the D* value. In addition, the f value at baseline was significantly greater in the response group than in the non-response group (0.221±0.033 vs. 0.175±0.040; P=0.001). The receiver operating characteristic (ROC) curve analysis showed that the percentage change of the f value obtained the largest area under the curve (AUC =0.797), and the AUC obtained by the Fisher's linear discriminant analysis (FLDA) method (Δf & ΔD combination) was 0.819. Conclusions: The IVIM-DWI parameters (f values and D values) provided effective assessment of the therapeutic effect of CAPOX combined with bevacizumab in patients with CRLM at an early stage, and the f value of the pre-treatment tumor area was shown to be useful for predicting the treatment response of patients.

Canagliflozin mitigates ferroptosis and ameliorates heart failure in rats with preserved ejection fraction.

Recently, hypoglycemic drugs belonging to sodium-glucose cotransporter 2 inhibitors (SGLT2i) have generated significant interest due to their clear cardiovascular benefits for heart failure with preserved ejection fraction (HFpEF) since there are no effective drugs that may improve clinical outcomes for these patients over a prolonged period. But, the underlying mechanisms remain unclear, particularly its effects on ferroptosis, a newly defined mechanism of iron-dependent non-apoptotic cell death during heart failure (HF). Here, with proteomics, we demonstrated that ferroptosis might be a key mechanism in a rat model of high-salt diet-induced HFpEF, characterized by iron overloading and lipid peroxidation, which was blocked following treatment with canagliflozin. Data are available via ProteomeXchange with identifier PXD029031. The ferroptosis was evaluated with the levels of acyl-CoA synthetase long-chain family member 4, glutathione peroxidase 4, ferritin heavy chain 1, transferrin receptor, Ferroportin 1, iron, glutathione, malondialdehyde, and 4-hydroxy-trans-2-nonenal. These findings highlight the fact that targeting ferroptosis may serve as a cardioprotective strategy for HFpEF prevention and suggest that canagliflozin may exert its cardiovascular benefits partly via its mitigation of ferroptosis.

An Effective Sodium-Dependent Glucose Transporter 2 Inhibition, Canagliflozin, Prevents Development of Hypertensive Heart Failure in Dahl Salt-Sensitive Rats.

Background: The aim of the study was to investigate the protective effect of canagliflozin (CANA) on myocardial metabolism and heart under stress overload and to further explore its possible molecular mechanism. Methods: High-salt diet was used to induce heart failure with preserved ejection fraction (HFpEF), and then, the physical and physiological indicators were measured. The cardiac function was evaluated by echocardiography and related indicators. Masson trichrome staining, wheat germ agglutinin, and immunohistochemical staining were conducted for histology analysis. Meanwhile, oxidative stress and cardiac ATP production were also determined. PCR and Western blotting were used for quantitative detection of related genes and proteins. Comprehensive metabolomics and proteomics were employed for metabolic analysis and protein expression analysis. Results: In this study, CANA showed diuretic, hypotensive, weight loss, and increased intake of food and water. Dahl salt-sensitive (DSS) rats fed with a diet containing 8% NaCl AIN-76A developed left ventricular remodeling and diastolic dysfunction caused by hypertension. After CANA treatment, cardiac hypertrophy and fibrosis were reduced, and the left ventricular diastolic function was improved. Metabolomics and proteomics data confirmed that CANA reduced myocardial glucose metabolism and increased fatty acid metabolism and ketogenesis in DSS rats, normalizing myocardial metabolism and reducing the myocardial oxidative stress. Mechanistically, CANA upregulated p-adenosine 5'-monophosphate-activated protein kinase (p-AMPK) and sirtuin 1 (SIRT1) and significantly induced the expression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1a). Conclusion: CANA can improve myocardial hypertrophy, fibrosis, and left ventricular diastolic dysfunction induced by hypertension in DSS rats, possibly through the activation of the AMPK/SIRT1/PGC-1a pathway to regulate energy metabolism and oxidative stress.

Effects of selenylation modification on the antioxidative and immunoregulatory activities of polysaccharides from the pulp of Rose laevigata Michx fruit.

Selenylation modification has been widely utilized to improve the activity of polysaccharides and to develop novel sources of selenium (Se) supplements. A purified pulp polysaccharide of Rose laevigata Michx fruit (PPRLMF-2) was selenized into Se-PPRLMF-2 in this study. PPRLMF-2 + Se was formulated by Na2SeO3 according to the Se content of Se-PPRLMF-2. To investigate the effects of selenylation modification on the structure and functions of PPRLMF-2, the characteristics, antioxidative and immunoregulatory activities of PPRLMF-2 before and after selenylation were compared. The results showed that compared with PPRLMF-2, Se-PPRLMF-2 became an irregular fibrous network, and its Mw decreased and C-6 substitution predominated in 13C NMR spectra. Se-PPRLMF-2 significantly increased chemical antioxidant activity and reduced the oxidative damage of erythrocytes, which was not due to Se alone. Se-PPRLMF-2 significantly increased immunomodulatory activity on macrophages, which was related to Se alone. Se-PPRLMF-2 could be a good potential source of antioxidants, immune enhancers and dietary Se supplements.

Effects of different enantiomers of amlodipine on lipid profiles and vasomotor factors in atherosclerotic rabbits.

This research aimed to describe the functions of vascular endothelial cells (VECs) in protecting target organs and the anti-atherosclerotic effects of different enantiomers of amlodipine on a rabbit model of atherosclerosis. Thirty male New Zealand white rabbits were randomly allocated to four groups (nA = 9, nB = 7, nC = 7, and nD = 7 rabbits): rabbits in group-A (control group) were fed a high-fat diet, group-B rabbits were fed a high-fat diet plus 2.5 mg/kg/day S-amlodipine, group-C rabbits were fed a high-fat diet plus 2.5 mg/kg/day R-amlodipine, and group-D rabbits were fed a high-fat diet plus 5 mg/kg/day racemic amlodipine. Different enantiomers of amlodipine did not influence lipid profiles and serum level of eNOS in the rabbit atherosclerosis model but decreased ET-1 expression to some extent. The serum NO and iNOS levels in the drug intervention groups were significantly reduced. No significant differences in the rabbits' body weights were observed. At the 4th and 8th weeks, the serum lipid profiles significantly increased in high cholesterol diet groups. The serum ET-1 level was significantly increased in each group of rabbits at the 8th week. Both S-amlodipine and R-amlodipine may protect the endothelium by reducing the serum ET-1 level, downregulating iNOS expression.

Circulating miRNA-21 as a diagnostic biomarker in elderly patients with type 2 cardiorenal syndrome.

Circulating miRNAs have attracted attention as serum biomarkers for several diseases. In this study, we aimed to evaluate the diagnostic value of circulating miRNA-21 (miR-21) as a novel biomarker for elderly patients with type 2 cardiorenal syndrome (CRS-2). A total of 157 elderly patients with chronic heart failure (CHF) were recruited for the study. According to an estimated glomerular filtration rate (eGFR) cut-off of 60 ml/min/1.73 m2, 84 patients (53.5%) and 73 patients (46.5%) were assigned to the CRS group and the CHF group, respectively. Expression levels of serum miR-21 and biomarkers for CRS, such as kidney injury factor-1 (KIM-1), neutrophil gelatinase-related apolipoprotein (NGAL), cystatin C (Cys C), amino-terminal pro-B-type natriuretic peptide (NT-proBNP), N-acetyl-κ-D-glucosaminidase (NAG), and heart-type fatty acid-binding protein (H-FABP), were detected. Serum miR-21, KIM-1, NGAL, Cys C, NT-proBNP and H-FABP levels were significantly higher in the CRS group than in the CHF group (P < 0.01), whereas NAG expression was not significantly different between the two groups (P > 0.05). Cys C, H-FABP and eGFR correlated significantly with miR-21 expression, but correlations with miR-21 were not significant for NT-proBNP, NGAL, NAG and KIM-1. Moreover, multivariate logistic regression found that serum miR-21, increased serum Cys C, serum KIM-1, hyperlipidaemia and ejection fraction (EF) were independent influencing factors for CRS (P < 0.05). The AUC of miR-21 based on the receiver operating characteristic (ROC) curve was 0.749, with a sensitivity of 55.95% and a specificity of 84.93%. Furthermore, combining miR-21 with Cys C enhanced the AUC to 0.902, with a sensitivity of 88.1% and a specificity of 83.6% (P < 0.001). Our findings suggest that circulating miR-21 has medium diagnostic value in CRS-2. The combined assessment of miR-21 and Cys C has good clinical value in elderly patients with CRS-2.

No association between low-dose reserpine use and depression in older hypertensive patient: result of a multicenter, cross-sectional study.

BACKGROUND: Reserpine is currently used by millions of Chinese hypertensive patients, in spite of the continued concern of its depressogenic effect, even when used in low dose. This study aimed to investigate the association between low-dose reserpine use and depression in older Chinese hypertensive patient. METHODS: In this cross-sectional, case-control study, we recruited patient aged 60 years or over who had regularly taken one or two tables of "compound reserpine and triamterene tablets (CRTTs)" for more than one year (reserpine user) from 26 community health centers located in 10 provinces in China. For each patient who took CRTTs, we selected an age (within five years) and sex matched hypertensive patient who had never taken any drugs containing reserpine (non-reserpine user) as control. Depressive symptoms were evaluated using a Chinese depression scale adapted from the Zung Self-Rating Depression Scale. Demographic, clinical data and laboratory examination results within six months were collected. RESULTS: From August 2018 to December 2018, 787 reserpine user and 787 non-reserpine user were recruited. The mean age of all study subjects was 70.3 years, with about equal numbers of males and females. The mean depression score was 40.4 in reserpine users and 40.6 in non-reserpine users (P = 0.7). The majority of study subject had a depression score < 53 (87.6% in reserpine users and 88.2% in non-reserpine users, respectively). There were no significant differences in the prevalence of mild, moderate or severe depression in reserpine users and non-reserpine users. CONCLUSIONS: There is no association between low-dose reserpine use and depression in older hypertensive patient. The role of reserpine in the treatment and control of hypertension should be reconsidered; and further studies, especially randomized, controlled clinical trials to compare efficacy and safety of reserpine and other widely recommended anti-hypertensive agents are needed.