Visual Analysis of Nutrient Deficiency and Treatment Protocols in Bariatric Surgery Based on VOSviewer.

Objective: To analyze the global literature on nutritional deficiencies in bariatric surgery (BS) since January 1, 1985, and to discuss the current status of research, research hotspots, and new development trend and treatment of nutritional deficiency in bariatric surgery. It provides ideas and basis for promoting the development of bariatric surgery and new alternative therapy or treatment protocols. Methods: The Web of Science (WOS) database core collection was used as the data source, and VOSviewer 1.6.17 software was used to search the literature on the topic of "nutritional deficiencies in bariatric surgery." The number of published literature, the distribution of authors, institutions, and countries, keyword cooccurrences, and journal cocitations were visualized and analyzed. Results: A total of 1015 relevant publications was obtained after searching and screening, and the overall trend of literature published was on the rise. The most published countries, institutions, and authors were USA, University of Sao Paulo, Ramalho, Andrea; Obesity Surgery has been the most frequently cited journal (7943 citations), and the top 10 journals had high impact factors. Keyword cooccurrence analysis showed that "bariatric surgery" and "nutritional deficiencies" are the hot topics of research in this field. Conclusion: There is an urgent need for bariatric surgery issuing institutions and authors to strengthen cross-institutional, cross-team, and multicenter and multidisciplinary cooperation, to promote and facilitate the exchange and cooperation in the field of bariatric surgery between developed countries in Europe and America and developing countries in Asia, Africa, and Latin America, to draw the attention of developing countries to the health problems caused by obesity, and to encourage and support the development of developing countries in this field. Bariatric surgery, obesity, weight loss, Y-type gastric bypass, gastric bypass, and nutritional deficiency are the hot research topics in the field of nutritional deficiency in bariatric surgery, and metabolic surgery, single anastomosis gastric bypass, micronutrient supplementation, micronutrient deficiency, intestinal microbiology, and guidelines are the new trends in this field.

Acacetin suppresses the electrocardiographic and arrhythmic manifestations of the J wave syndromes.

BACKGROUND: J wave syndromes (JWS), including Brugada (BrS) and early repolarization syndromes (ERS), are associated with increased risk for life-threatening ventricular arrhythmias. Pharmacologic approaches to therapy are currently very limited. Here, we evaluate the effects of the natural flavone acacetin. METHODS: The effects of acacetin on action potential (AP) morphology and transient outward current (Ito) were first studied in isolated canine RV epicardial myocytes using whole-cell patch clamp techniques. Acacetin's effects on transmembrane APs, unipolar electrograms and transmural ECGs were then studied in isolated coronary-perfused canine RV and LV wedge preparations as well as in whole-heart, Langendorff-perfused preparations from which we recorded a 12 lead ECG and unipolar electrograms. Using floating glass microelectrodes we also recorded transmembrane APs from the RVOT of the whole-heart model. The Ito agonist NS5806, sodium channel blocker ajmaline, calcium channel blocker verapamil or hypothermia (32°C) were used to pharmacologically mimic the genetic defects and conditions associated with JWS, thus eliciting prominent J waves and provoking VT/VF. RESULTS: Acacetin (5-10 µM) reduced Ito density, AP notch and J wave area and totally suppressed the electrocardiographic and arrhythmic manifestation of both BrS and ERS, regardless of the experimental model used. In wedge and whole-heart models of JWS, increasing Ito with NS5806, decreasing INa or ICa (with ajmaline or verapamil) or hypothermia all resulted in accentuation of epicardial AP notch and ECG J waves, resulting in characteristic BrS and ERS phenotypes. Phase 2-reentrant extrasystoles originating from the RVOT triggered VT/VF. The J waves in leads V1 and V2 were never associated with a delay of RVOT activation and always coincided with the appearance of the AP notch recorded from RVOT epicardium. All repolarization defects giving rise to VT/VF in the BrS and ERS models were reversed by acacetin, resulting in total suppression of VT/VF. CONCLUSIONS: We present experimental models of BrS and ERS capable of recapitulating all of the ECG and arrhythmic manifestations of the JWS. Our findings provide definitive support for the repolarization but not the depolarization hypothesis proposed to underlie BrS and point to acacetin as a promising new pharmacologic treatment for JWS.

Water-soluble acacetin prodrug confers significant cardioprotection against ischemia/reperfusion injury.

The morbidity and mortality of patients with ischemic cardiomyopathy resulted from ischemia/reperfusion injury are very high. The present study investigates whether our previously synthesized water-soluble phosphate prodrug of acacetin was cardioprotective against ischemia/reperfusion injury in an in vivo rat model. We found that intravenous administration of acacetin prodrug (10 mg/kg) decreased the ventricular arrhythmia score and duration, reduced ventricular fibrillation and infarct size, and improved the impaired heart function induced by myocardial ischemia/reperfusion injury in anesthetized rats. The cardioprotective effects were further confirmed with the parent compound acacetin in an ex vivo rat regional ischemia/reperfusion heart model. Molecular mechanism analysis revealed that acacetin prevented the ischemia/reperfusion-induced reduction of the anti-oxidative proteins SOD-2 and thioredoxin, suppressed the release of inflammation cytokines TLR4, IL-6 and TNFα, and decreased myocyte apoptosis induced by ischemia/reperfusion. Our results demonstrate the novel evidence that acacetin prodrug confer significant in vivo cardioprotective effect against ischemia/reperfusion injury by preventing the reduction of endogenous anti-oxidants and the release of inflammatory cytokines, thereby inhibiting cardiomyocytes apoptosis, which suggests that the water-soluble acacetin prodrug is likely useful in the future as a new drug candidate for treating patients with acute coronary syndrome.

Synthesis of a highly water-soluble acacetin prodrug for treating experimental atrial fibrillation in beagle dogs.

We previously reported that duodenal administration of the natural flavone acacetin can effectively prevent the induction of experimental atrial fibrillation (AF) in canines; however, it may not be used intravenously to terminate AF due to its poor water-solubility. The present study was to design a water-soluble prodrug of acacetin and investigate its anti-AF effect in beagle dogs. Acacetin prodrug was synthesized by a three-step procedure. Aqueous solubility, bioconversion and anti-AF efficacy of acacetin prodrug were determined with different methodologies. Our results demonstrated that the synthesized phosphate sodium salt of acacetin prodrug had a remarkable increase of aqueous solubility in H2O and clinically acceptable solution (5% glucose or 0.9% NaCl). The acacetin prodrug was effectively converted into acacetin in ex vivo rat plasma and liver microsome, and in vivo beagle dogs. Intravenous infusion of acacetin prodrug (3, 6 and 12 mg/kg) terminated experimental AF without increasing ECG QTc interval in beagle dogs. The intravenous LD50 of acacetin prodrug was 721 mg/kg in mice. Our preclinical study indicates that the synthesized acacetin prodrug is highly water-soluble and safe; it effectively terminates experimental AF in beagle dogs and therefore may be a promising drug candidate for clinical trial to treat patients with acute AF.

Screening and rational design of hepatitis C virus entry inhibitory peptides derived from GB virus A NS5A.

Chronic infection by hepatitis C virus (HCV) is a cause of the global burden of liver diseases. HCV entry into hepatocytes is a complicated and multistep process that represents a promising target for antiviral intervention. The recently reported amphipathic α-helical virucidal peptide (C5A) from the HCV NS5A protein suggests a new category of antiviral drug candidates. In this study, to identify C5A-like HCV inhibitors, synthetic peptides derived from the C5A-corresponding NS5 protein region of selected Flaviviridae viruses were evaluated for their anti-HCV activities. A peptide from GB virus A (GBV-A), but not other flaviviruses, demonstrated an inhibitory effect on HCV infection. Through a series of sequence optimizations and modifications of the peptide helicity and hydrophobicity, we obtained a peptide designated GBVA10-9 with highly potent anti-HCV activity. GBVA10-9 suppressed infection with both cell culture-derived and pseudotyped HCV in vitro, and the 50% cell culture inhibitory concentration ranged from 20 nM to 160 nM, depending on the genotypic origin of the envelope proteins. GBVA10-9 had no detectable effects on either HCV attachment to Huh7.5.1 cells or viral RNA replication. No virucidal activity was found with GBVA10-9, suggesting an action mechanism distinct from that of C5A. The inhibitory effect of GBVA10-9 appeared to occur at the postbinding step during viral entry. Taken together, the results with GBVA10-9 demonstrated a potent activity for blocking HCV entry that might be used in combination with other antivirals directly targeting virus-encoded enzymes. Furthermore, GBVA10-9 also provides a novel tool to dissect the detailed mechanisms of HCV entry.

Allitridi inhibits multiple cardiac potassium channels expressed in HEK 293 cells.

Allitridi (diallyl trisulfide) is an active compound (volatile oil) from garlic. The previous studies reported that allitridi had anti-arrhythmic effect. The potential ionic mechanisms are, however, not understood. The present study was designed to determine the effects of allitridi on cardiac potassium channels expressed in HEK 293 cells using a whole-cell patch voltage-clamp technique and mutagenesis. It was found that allitridi inhibited hKv4.3 channels (IC(50) = 11.4 µM) by binding to the open channel, shifting availability potential to hyperpolarization, and accelerating closed-state inactivation of the channel. The hKv4.3 mutants T366A, T367A, V392A, and I395A showed a reduced response to allitridi with IC(50)s of 35.5 µM, 44.7 µM, 23.7 µM, and 42.4 µM. In addition, allitridi decreased hKv1.5, hERG, hKCNQ1/hKCNE1 channels stably expressed in HEK 293 cells with IC(50)s of 40.2 µM, 19.6 µM and 17.7 µM. However, it slightly inhibited hKir2.1 current (100 µM, inhibited by 9.8% at -120 mV). Our results demonstrate for the first time that allitridi preferably blocks hKv4.3 current by binding to the open channel at T366 and T367 of P-loop helix, and at V392 and I395 of S6 domain. It has a weak inhibition of hKv1.5, hERG, and hKCNQ1/hKCNE1 currents. These effects may account for its anti-arrhythmic effect observed in experimental animal models.

Tanshinone IIA: a new activator of human cardiac KCNQ1/KCNE1 (I(Ks)) potassium channels.

Tanshinone IIA, one of the main active components from Chinese herb Danshen, is widely used to treat cardiovascular diseases including arrhythmia in Asian countries especially in China. However, the mechanisms underlying its anti-arrythmia effects are not clear. In this study we investigate the effects of tanshinone IIA on human KCNQ1/KCNE1 potassium channels (I(Ks)), human ether-a-go-go-related gene potassium channels (hERG), Kv1.5 potassium channels, inward rectifier potassium channels (I(K1)) expressed in HEK 293 cells using patch clamp technique. Tanshinone IIA potently and reversibly enhanced the amplitude of I(Ks) in a concentration dependent manner with an EC(50) of 64.5 microM, accelerated the activation rate of I(Ks) channels, decelerated their deactivation and shifted the voltage dependence of I(Ks) activation to negative direction. Isoproteronol, a stimulator of beta-adrenergic receptor, at 1 microM and sodium nitroprusside (SNP), a NO donor, at 1 mM, had no significant effects on the enhancement of I(Ks) by 30 microM tanshinone IIA. N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H89), a selective protein kinase A inhibitor, at 0.1 microM and 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ), a selective nitric oxide-sensitive guanylyl cyclase inhibitor, at 10 microM, also had no significant effects on the enhancement of I(Ks) by 30 microM tanshinone IIA. Tanshinone IIA did not affect expressed hERG channels, Kv1.5 channels and I(K1) channels. These results indicate that tanshinone IIA directly and specifically activate human cardiac KCNQ1/KCNE1 potassium channels (I(Ks)) in HEK 293 cell through affecting the channels' kinetics.

Acacetin, a natural flavone, selectively inhibits human atrial repolarization potassium currents and prevents atrial fibrillation in dogs.

BACKGROUND: The development of atrium-selective antiarrhythmic agents is a current strategy for inhibiting atrial fibrillation (AF). The present study investigated whether the natural flavone acacetin from the traditional Chinese medicine Xuelianhua would be an atrium-selective anti-AF agent. METHODS AND RESULTS: The effects of acacetin on human atrial ultrarapid delayed rectifier K(+) current (I(Kur)) and other cardiac ionic currents were studied with a whole-cell patch technique. Acacetin suppressed I(Kur) and the transient outward K(+) current (IC(50) 3.2 and 9.2 mumol/L, respectively) and prolonged action potential duration in human atrial myocytes. The compound blocked the acetylcholine-activated K(+) current; however, it had no effect on the Na(+) current, L-type Ca(2+) current, or inward-rectifier K(+) current in guinea pig cardiac myocytes. Although acacetin caused a weak reduction in the hERG and hKCNQ1/hKCNE1 channels stably expressed in HEK 293 cells, it did not prolong the corrected QT interval in rabbit hearts. In anesthetized dogs, acacetin (5 mg/kg) prolonged the atrial effective refractory period in both the right and left atria 1 to 4 hours after intraduodenal administration without prolongation of the corrected QT interval, whereas sotalol at 5 mg/kg prolonged both the atrial effective refractory period and the corrected QT interval. Acacetin prevented AF induction at doses of 2.5 mg/kg (50%), 5 mg/kg (85.7%), and 10 mg/kg (85.7%). Sotalol 5 mg/kg also prevented AF induction (60%). CONCLUSIONS: The present study demonstrates that the natural compound acacetin is an atrium-selective agent that prolongs the atrial effective refractory period without prolonging the corrected QT interval and effectively prevents AF in anesthetized dogs after intraduodenal administration. These results indicate that oral acacetin is a promising atrium-selective agent for the treatment of AF.

Regulation of voltage-gated cardiac sodium current by epidermal growth factor receptor kinase in guinea pig ventricular myocytes.

Voltage-gated cardiac fast sodium channel current (I(Na)) plays a critical role in the initiation and propagation of the myocardial action potential, and regulation of cardiac I(Na) by protein tyrosine kinases (PTKs) is not well documented, though it is known that ion channels are among the targets of PTKs. The present study was therefore designed to investigate whether/how cardiac I(Na) was modulated by PTKs in guinea pig ventricular myocytes using whole-cell patch clamp and immunoprecipitation and Western blotting approaches. It was found that cardiac I(Na) was enhanced by epidermal growth factor (EGF), and the effect was antagonized by the selective epidermal growth factor receptor (EGFR) kinase inhibitor tyrphostin AG556 while potentiated by orthovanadate (a protein tyrosine phosphatase (PTP) inhibitor). In addition, AG556 inhibited, while orthovanadate increased I(Na), and the inhibition of I(Na) by AG556 was antagonized by orthovanadate. Immunoprecipitation and Western blotting analysis demonstrated that tyrosine phosphorylation level of cardiac sodium channels was enhanced by EGF or orthovanadate, and reduced by AG556. The AG556-induced reduction of phosphorylation level was significantly reversed by orthovanadate. Our results demonstrate the novel information that EGFR kinase enhances, and PTPs reduce native cardiac I(Na) in guinea pig ventricular myocytes.

Ionic current abnormalities associated with prolonged action potentials in cardiomyocytes from diseased human right ventricles.

OBJECTIVES: This study was designed to determine whether ionic currents in right ventricular myocytes from explanted human transplant recipient hearts are related to right ventricular histopathology and function. BACKGROUND: Cardiac action potential duration (APD) is prolonged in ventricular tissues/cells from patients with heart failure, but the ionic mechanisms are not well documented. METHODS: Membrane currents and transmembrane action potentials in myocytes from right ventricular epicardium of explanted human hearts were recorded using whole-cell patch clamp technique. Data from cells from right ventricles with severe histologic and functional abnormalities (abnormal histology group [AH]) and from right ventricles with preserved histology and function (relatively normal histology group [RNH]) were compared. RESULTS: We found that APD at 50% (APD(50)) and 90% repolarization (APD(90)) were significantly longer in AH cells than in RNH cells. Early afterdepolarizations (EADs) were observed in 20% of AH cells and none of the RNH cells. Inwardly rectifying K(+) current (I(K1)) was decreased (both inward and outward components). Both transient outward K(+) current (I(to1)) and slowly delayed rectifier K(+) current (I(Ks)) were down-regulated in AH cells. L-type Ca(2+) (I(Ca.L)) was not altered in AH cells. CONCLUSIONS: I(K1), I(to1), and I(Ks) are down-regulated in AH cells of human heart failure. This down-regulation contributes to APD prolongation that favors the occurrence of arrhythmogenic EADs and suggests a link between human cardiac histopathologic/functional abnormalities and arrhythmogenic ionic remodeling.