The Efficacy and Safety of a Qiliqiangxin Capsule Combined with Sacubitril/Valsartan in the Treatment of Chronic Heart Failure: A Systematic Review and Meta-Analysis.

Background: Qiliqiangxin (QLQX) capsules are a commonly used proprietary Chinese medicine for the adjuvant treatment of chronic heart failure (CHF) in China. In recent years, several randomized controlled trials (RCTs) have reported on the efficacy and safety of QLQX combined with sacubitril/valsartan for CHF. Objective: The purpose of this study was to systematically analyze the clinical efficacy and safety of QLQX combined with sacubitril/valsartan in the management of CHF and to provide clinicians as well as scientists with optimal evidence-based medical evidence. Methods: We searched RCTs to evaluate the efficacy and safety of QLQX combined with sacubitril/valsartan in the treatment of CHF in the Wanfang Database, China National Knowledge Infrastructure, China Science and Technology Journal Database, PubMed, Embase, and Cochrane Library databases from their inception until January 8, 2022. RCTs on QLQX in combination with sacubitril/valsartan for CHF were included. The outcome measures considered were total effective rate, left ventricular ejection fraction (LVEF), left ventricular end-diastolic dimension (LVEDD), 6-minute walking distance (6-MWD), and adverse events. The quality of the included RCTs was assessed thereafter using the Cochrane risk of bias tool. RevMan 5.3 software was used to conduct the meta-analysis. Results: The meta-analysis included 17 trials involving 1427 CHF patients. The results indicated that with sacubitril/valsartan administration combined with QLQX treatment, the total effective rate (relative risk (RR) = 1.24; 95% confidence interval (CI) (1.17, 1.31); p < 0.01), LVEF (mean difference (MD) = 6.20; 95% CI (5.36, 7.05; p < 0.01)), and 6-MWD (MD = 55.87; 95% CI (40.66, 71.09); p < 0.01) of CHF patients were significantly increased, and the LVEDD value of CHF patients was noted to be significantly reduced (MD = -3.98; 95% CI (-4.47, -3.48); p < 0.01). Moreover, there was no increase in the number of adverse events during treatment (RR = 0.67; 95% CI (0.33, 1.34); p < 0.01). Conclusions: This study indicated that in CHF patients, on the basis of sacubitril/valsartan treatment, combination with QLQX can potentially enhance the total effective rate, improve LVEF and 6-MWD, and reduce LVEDD values, with good safety. However, considering the poor quality of the included studies, a multicenter, randomized, double-blind controlled study is needed for further confirmation.

Acupuncture for premature ventricular complexes without ischemic or structural heart diseases: A systematic review and meta-analysis of clinical and pre-clinical evidence.

Background: With increasing evidence suggesting potential benefits, acupuncture is often applied to the treatment of premature ventricular complexes (PVCs), particularly in symptomatic patients who fail or are unsuitable for medications or refuse catheter ablation. However, the existing clinical evidence is inconsistent. Objectives: This review aims to systematically evaluate the effectiveness and safety of acupuncture therapies for PVCs without ischemic or structural heart diseases, when it is compared with sham/placebo acupuncture or usual care, or used as an add-on therapy to routine care; and to summarize existing pre-clinical research evidence supporting the effects of acupuncture therapies for this clinical condition. Methods: Four English-language databases, four Chinese-language databases and seven clinical registries were searched from their inceptions to May 21, 2021 and updated to November 01, 2022. Trials comparing acupuncture with sham acupuncture or evaluating the add-on effects of acupuncture were included. Primary outcomes are the number of premature ventricular beats (PVBs) and effective rate defined as "the proportion of participants with over 50% decrease in the number of PVBs from baseline to the end of treatment measured by 24-h Holter". Results: A total of 479 records were identified with nine trials involving 847 participants included in this review. Meta-analysis on two sham-control trials with low risk of bias for all domains suggested that acupuncture could significantly reduce the number of PVBs (RR 3.83, 95% CI [2.19, 6.7], I 2 = 0%). Moreover, the combination of acupuncture and standard treatment was superior to standard treatment alone in reducing the burden of PVBs (RR 1.21, 95% CI [1.08, 1.36], I 2 = 0%). Though no treatment protocol consensus was announced, body acupuncture on point PC6, HT7, DU10, DU11, and ST36 with duration of needle retention ranging from 15 to 30 min for a 4-week treatment period is broadly used by the included trials. For experimental evidence, five studies explored the mechanisms of acupuncture for PVCs were eventually included into analysis and PC6 was the most frequently studied acupuncture point. Moreover, a reduction of electrical activity of sympathetic nerves in experimental animals undergoing electro-acupuncture was observed by four of these studies. Conclusion: Sham-controlled RCT evidence with moderate-level certainty suggested that acupuncture could be a therapeutic option to reduce the burden of PVBs in patients without ischemic or structural heart diseases. Further clinical studies using validated and reliable outcome measurement instruments and bench research to unveil the mechanisms of acupuncture stimulation and point-specific effects for PVCs are needed. Systematic review registration: [https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=262132], identifier [CRD42021262132].

Influence of warm acupuncture on gut microbiota and metabolites in rats with insomnia induced by PCPA.

BACKGROUND: Insomnia is the most common of the sleep disorders. Current pharmacotherapy treatment options are usually associated with adverse effects and withdrawal phenomena. Therapeutic alternatives with a more favorable safety profile for patients are needed. Mongolian medical warm acupuncture (MMWA) is an emerging therapeutic option for treating insomnia. However, the underlying mechanisms responsible for the anti-insomnia efficacy of the MMWA remain unclear. This study aims to investigate the effect of the MMWA on the alterations of the gut microbiota and serum metabolome in rats with insomnia. RESULTS: We found that the relative abundances of gut bacteria and the concentrations of several serum metabolites were obviously altered in PCPA-induced insomnia rats. The MMWA treatment exerted an anti-insomnia effect. In addition, the dysbiosis of the gut microbiota and the serum metabolites were ameliorated by the MMWA. Correlation analysis between the gut microbiota and metabolites suggested that the levels of Amide c18, Benzoyl chloride, Cytosine, and N, n-dimethylarginine were positively correlated with the relative abundance of Clostridium XlVa and Blautia, which characterized the insomnia rats. KEGG enrichment analysis identified the cAMP signaling pathway involving anti-insomnia effect of the MMWA. Moreover, the MMWA intervention significantly increased contents of butyrate in feces, while effectively inhibited the expression level of GAT-1 in brain tissues. CONCLUSION: This study reveals that the MMWA intervention might have a major impact on the modulation of host gut microbiota and metabolites, which in turn have a crucial role in the regulation of the host's signaling pathways associated with insomnia. The present study could provide useful ideas for the study of the intervention mechanisms of the MMWA in insomnia rat models.

Protective Effects of Hydrogen-Rich Water Against Cartilage Damage in a Rat Model of Osteoarthritis by Inhibiting Oxidative Stress, Matrix Catabolism, and Apoptosis.

BACKGROUND The aim of this study was to investigate the mechanisms underlying the potential effects of hydrogen-rich water (HW) on articular cartilage in a rat osteoarthritis (OA) model. MATERIAL AND METHODS A rat model of OA was established using the modified Hulth method, and rats were forced to exercise for 30 min every day 1 week after surgery for 7 weeks. Mankin's method was used to score the severity of OA. The animals were assigned into the OA group, OA+HW group, and sham operation group. After 8 weeks, the animals in the OA group had a Mankin score >8 points, and HW was administered into the knee joint. After 2 weeks of treatment, articular cartilage was obtained for pathological examination, consisting of hematoxylin and eosin, toluidine blue, and Hoechst staining, as well as quantitative real-time PCR and Western blot analyses. This combination of pharmacological and molecular biological analyses was performed to examine the mechanism underlying the protective effect of HW on articular cartilage. RESULTS The antioxidant effects of HW suppressed oxidative damage, which may have aided the inhibition of ECM-degrading enzymes (MMP3, MMP13, ADAMT4, and ADAMT5), the upregulation of Col II and aggrecan expression, and the downregulation of COX-2, iNOS, and NO expression. The results of HE staining indicated intra-articular treatment of HW attenuated cartilage degradation. However, Hoechst staining in the OA group indicated the nuclei of the fragmented chondrocytes were condensed compared to the sham operation group, and this effect was inhibited by HW. CONCLUSIONS HW showed a protective effect against the progression of OA in an animal model, which may have been mediated by its anti-oxidant and anti-apoptotic activities.

Chronic infusion of berberine into the hypothalamic paraventricular nucleus attenuates hypertension and sympathoexcitation via the ROS/Erk1/2/iNOS pathway.

BACKGROUND: Berberine (BBR), a Chinese traditional herbal medicine, has many pharmacologic benefits such as anti-inflammation and anti-oxidation. It is widely used in clinical treatment of cardiovascular diseases such as hypertension. However, the mechanism of how BBR attenuates hypertension through affecting central neural system is not clear. PURPOSE: This study was designed to determine whether chronic infusion of BBR into the hypothalamic paraventricular nucleus (PVN) attenuates hypertension and sympathoexcitation via the ROS/Erk1/2/iNOS pathway. METHODS: Two-kidney, one-clip (2K1C) renovascular hypertensive rats were randomly assigned and treated with bilateral PVN infusion of BBR (2µg/h) or vehicle (artificial cerebrospinal fluid) via osmotic minipumps for 28 days. RESULTS: 2K1C rats showed higher mean arterial pressure (MAP) and PVN Fra-like activity, plasma levels of norepinephrine (NE), PVN levels of NOX2, NOX4, Erk1/2 and iNOS, and lower PVN levels of copper/zinc superoxide dismutase (Cu/Zn-SOD). Chronic infusion of BBR reduced MAP, PVN Fra-like activity and plasma levels of NE, reduced NOX2, NOX4, Erk1/2, iNOS and induced Cu/Zn-SOD in the PVN. CONCLUSIONS: These results suggest that BBR attenuates hypertension and sympathoexcitation via the ROS/Erk1/2/iNOS pathway in 2K1C renovascular hypertensive rats.

Antihypertensive effects of Tartary buckwheat flavonoids by improvement of vascular insulin sensitivity in spontaneously hypertensive rats.

Vascular insulin resistance and oxidative stress contribute to endothelial dysfunction and hypertension. The present study investigated whether chronic treatment with purified Tartary buckwheat flavonoids fraction (TBF) prevents the development of hypertension via improving vascular insulin sensitivity and reducing oxidative stress. Six-week-old male spontaneously hypertensive rats (SHRs) and their normotensive Wistar-Kyoto (WKY) control rats were subjected to different dosages of TBF for 8 weeks. Blood pressure, mesenteric arteriolar vasorelaxation, superoxide anion (O2-) generation, NAD(P)H oxidase activity, and insulin-stimulated Akt/endothelial nitric oxide synthase (eNOS) activation and nitric oxide (NO) production were determined. The SHRs had higher systolic blood pressure, systemic insulin resistance, and impaired vasodilator actions of insulin and the insulin signaling pathway in mesenteric arterioles when compared with the WKY rats. TBF treatment at a dosage of 100 mg kg-1 day-1 significantly reduced systolic blood pressure and increased vasodilator response to insulin in the SHRs. Additionally, TBF treatment significantly reduced phosphorylation of insulin receptor substrate 1 (IRS-1) at serine 307 and increased insulin-stimulated Akt/eNOS activation in the SHRs. Furthermore, TBF treatment reduced the overproduction of basal O2- in association with a reduction of NAD(P)H oxidase activity in mesenteric arterioles of the SHRs. Finally, quercetin was identified as the predominant active component of TBF in attenuating the development of hypertension with regard to reducing vascular oxidative stress, regulating the vascular insulin signaling pathway and restoring vasodilator response to insulin in the SHRs. In conclusion, TBF possesses protective effects against hypertension through attenuating vascular insulin resistance and oxidative stress.

Interleukin-18 Down-Regulates Multidrug Resistance-Associated Protein 2 Expression through Farnesoid X Receptor Associated with Nuclear Factor Kappa B and Yin Yang 1 in Human Hepatoma HepG2 Cells.

Multidrug resistance-associated protein 2 (MRP2) plays an important role in bile acid metabolism by transporting toxic organic anion conjugates, including conjugated bilirubin, glutathione, sulfate, and multifarious drugs. MRP2 expression is reduced in cholestatic patients and rodents. However, the molecular mechanism of MRP2 down-regulation remains elusive. In this report, we treated human hepatoma HepG2 cells with interleukin-18 (IL-18) and measured the expression of MRP2, nuclear factor kappa B (NF-κB), farnesoid X receptor (FXR), and the transcription factor Yin Yang 1 (YY1) by quantitative real-time quantitative polymerase chain reaction (PCR) and western blotting. We found that expression of MRP2 was repressed by IL-18 at both the mRNA and protein levels in a dose- and time-dependent manner. Furthermore, the activated NF-κB pathway increased YY1 and reduced FXR. These changes were all attenuated in HepG2 cells with knockdown of the NF-κB subunit, p65. The reduced expression of FXR and MRP2 in HepG2 cells that had been caused by IL-18 treatment was also attenuated by YY1 knockdown. We further observed significantly elevated IL-18, NF-κB, and YY1 expression and decreased FXR and MRP2 expression in bile duct-ligated Sprague Dawley rat livers. Chromatin immunoprecipitation assays also showed that FXR bound to the promoter region in MRP2 was less abundant in liver extracts from bile duct-ligated rats than sham-operated rats. Our findings indicate that IL-18 down-regulates MRP2 expression through the nuclear receptor FXR in HepG2 cells, and may be mediated by NF-κB and YY1.

Swertianlarin, an Herbal Agent Derived from Swertia mussotii Franch, Attenuates Liver Injury, Inflammation, and Cholestasis in Common Bile Duct-Ligated Rats.

Swertianlarin is an herbal agent abundantly distributed in Swertia mussotii Franch, a Chinese traditional herb used for treatment of jaundice. To study the therapeutic effect of swertianlarin on cholestasis, liver injury, serum proinflammatory cytokines, and bile salt concentrations were measured by comparing rats treated with swertianlarin 100 mg/kg/d or saline for 3, 7, or 14 days after bile duct ligation (BDL). Serum alanine aminotransferase (ATL) and aspartate aminotransferase (AST) levels were significantly decreased in BDL rats treated with swertianlarin for 14 days (P < 0.05). The reduced liver injury in BDL rats by swertianlarin treatment for 14 days was further confirmed by liver histopathology. Levels of serum tumor necrosis factor alpha (TNFα) were decreased by swertianlarin in BDL rats for 3 and 7 days (P < 0.05). Moreover, reductions in serum interleukins IL-1ß and IL-6 levels were also observed in BDL rats treated with swertianlarin (P < 0.05). In addition, most of serum toxic bile salt concentrations (e.g., chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA)) in cholestatic rats were decreased by swertianlarin (P < 0.05). In conclusion, the data suggest that swertianlarin derived from Swertia mussotii Franch attenuates liver injury, inflammation, and cholestasis in bile duct-ligated rats.

Swertianlarin, isolated from Swertia mussotii Franch, increases detoxification enzymes and efflux transporters expression in rats.

Swertianlarin, isolated from Swertia mussotii Franch and Enicostemma axillare, has hepatoprotective effects against cholestasis in rat models of hepatotoxicity. However, the underlying molecular mechanism is not clear. We then treated rats with swertianlarin for 7 d and then measured serum liver injury markers, lipids, and bile salts, as well as the expression of bile acid synthesis and detoxification enzymes (e.g. Cyp7a1 and Cyp3a), membrane influx and efflux transporters (e.g. Ntcp and Mrp3), nuclear receptors (e.g. Pxr and Fxr/Shp) and transcriptional factors (e.g. Nrf2 and Hnf3ß) in the liver. We found a significant induction of the expression of the basolateral efflux transporters Mrp3 and Mrp4 and canalicular transporter Mdr1 in rats treated with swertianlarin, compared with the controls (1.9-fold and 2.2-fold, P < 0.005, and 3.4-fold, P < 0.05, respectively). The expression of detoxification enzymes Cyp3a, Ugt2b, Sult2a1 and Gsta1 in rats treated with swertianlarin was significantly higher than that in controls (3.7-fold, 2.8-fold, 2.1-fold, and 1.7-fold, respectively, all P < 0.05). Expression of the synthetic enzyme, Cyp8b1, was higher in rats treated with swertianlarin than that in controls (1.8-fold at mRNA level and 3.4-flod at protein level, P < 0.05). Elevated serum levels of the conjugated bile acids, taurocholic acid and taurodeoxycholic acid, and a reduction in levels of serum ALP, unconjugated bile acid αMCA, and TG were observed (all P < 0.05). In conclusion, swertianlarin significantly up-regulates hepatic bile acid detoxification enzymes and efflux transporters in rats, which can increase the water solubility of hydrophobic bile acids and elimination of conjugated bile acids.

Vardenafil ameliorates calcium mobilization in pulmonary artery smooth muscle cells from hypoxic pulmonary hypertensive mice.

BACKGROUND AND AIMS: Vardenafil has been found to be potent in pulmonary hypertension; however, the underlying mechanisms remain poorly understood. To address this issue, we investigated the underlying mechanisms of vardenafil in the contribution of Ca(2+) signaling and mobilization in modifying vasoconstriction of pulmonary arteries in hypoxic mice. METHODS: Hemodynamic measurements and morphological studies were performed. Muscle tension was measured by PowerLab system. I(Ca,L) was recorded using a perforated patch-clamp technique. [Ca(2+)](i) was measured using a fluorescence imaging system. RESULTS: Vardenafil greatly inhibited RVSP increases, RV hypertrophy and ameliorated pulmonary artery remodeling in response to chronic hypoxia. Membrane depolarization following 50 mM high K(+)-caused muscle contraction significantly decreased from 101.7 ± 10.1 in the hypoxia group to 81.8 ± 5.0 mg in hypoxia plus vardenafil arteries. Fifty mM high K(+)-elicited increase [Ca(2+)](i) was markedly decreased from 610.6 ± 71.8 in hypoxia cells to 400.3 ± 47.2 nM in hypoxia plus vardenafil cells. Application of vardenafil greatly inhibited the density of I(Ca,L) by 37.7% compared with that in the hypoxia group. Administration of 1 µM phenylephrine to stimulate α(1)-adrenergic receptor resulted in a smaller increase in [Ca(2+)](i) in hypoxia plus vardenafil cells than that in hypoxia cells. One hundred µM ATP-mediated increase in [Ca(2+)](i) was also inhibited in vardenafil-hypoxia group (from 625.8 ± 62.3 to 390.9 ± 38.1 nM), suggesting that internal calcium reserves contribute to neurotransmitter-induced Ca(2+) release from the SR through IP(3)Rs in PASMCs. CONCLUSIONS: Vardenafil may effectively block Ca(2+) influx through L-type Ca(2+) channel and inhibit the Ca(2+) release from SR through IP(3)Rs, thus enhancing its vasorelaxation of pulmonary arteries under hypoxia conditions.

Comparison of operator radiation exposure during coronary sinus catheter placement via the femoral or jugular vein approach.

AIMS: To evaluate and compare operator radiation exposure during the catheter placement in the coronary sinus via the femoral vein with a steerable catheter or the jugular vein with a fixed curve catheter. METHODS AND RESULTS: A total of 156 patients undergoing electrophysiological study or radiofrequency catheter ablation were prospectively assigned in a random fashion to either the femoral vein access (FVA) with a steerable curve deca-polar catheter (n= 80) or the jugular vein access (JVA) with a fixed curve deca-polar catheter (n = 76). All the catheterization procedures were performed by the same operator who had extensive experience in both accesses. Operator radiation exposure was measured with an electronic radiation dosimeter attached to the breast pocket of the operator on the outside of the lead apron and estimates of the ambient dose equivalent were derived. The operator radiation exposure was reduced significantly by using the FVA compared with the JVA (1.8 ± 1.3 vs. 8.6 ± 6.5 µSv; P < 0.001). The fluoroscopy time (62.7 ± 45.8 vs. 61.9 ± 46.5 s; P = NS) and dose-area product (3.2 ± 2.3 vs. 3.1 ± 2.1 Gy cm(2); P = NS) were not statistically different. CONCLUSION: Operator radiation exposure can be significantly reduced by using the FVA approach with a steerable curve catheter compared with the JVA approach with a fixed curve catheter, without increasing the fluoroscopy time and dose-area product.