Knockout of interleukin-17A diminishes ventricular arrhythmia susceptibility in diabetic mice via inhibiting NF-κB-mediated electrical remodeling.

Interleukin-17A (IL-17), a potent proinflammatory cytokine, has been shown to participate in cardiac electrical disorders. Diabetes mellitus is an independent risk factor for ventricular arrhythmia. In this study, we investigated the role of IL-17 in ventricular arrhythmia of diabetic mice. Diabetes was induced in both wild-type and IL-17 knockout mice by intraperitoneal injection of streptozotocin (STZ). High-frequency electrical stimuli were delivered into the right ventricle to induce ventricular arrhythmias. We showed that the occurrence rate of ventricular tachycardia was significantly increased in diabetic mice, which was attenuated by IL-17 knockout. We conducted optical mapping on perfused mouse hearts and found that cardiac conduction velocity (CV) was significantly decreased, and action potential duration (APD) was prolonged in diabetic mice, which were mitigated by IL-17 knockout. We performed whole-cell patch clamp recordings from isolated ventricular myocytes, and found that the densities of Ito, INa and ICa,L were reduced, the APDs at 50% and 90% repolarization were increased, and early afterdepolarization (EAD) was markedly increased in diabetic mice. These alterations were alleviated by the knockout of IL-17. Moreover, knockout of IL-17 alleviated the downregulation of Nav1.5 (the pore forming subunit of INa), Cav1.2 (the main component subunit of ICa,L) and KChIP2 (potassium voltage-gated channel interacting protein 2, the regulatory subunit of Ito) in the hearts of diabetic mice. The expression of NF-κB was significantly upregulated in the hearts of diabetic mice, which was suppressed by IL-17 knockout. In neonatal mouse ventricular myocytes, knockdown of NF-κB significantly increased the expression of Nav1.5, Cav1.2 and KChIP2. These results imply that IL-17 may represent a potential target for the development of agents against diabetes-related ventricular arrhythmias.

Introducing Tb4+ in (Ce0.09/Eu0.96)Tb0.92Mo1.1O6.93 Metal Oxide at Room Temperature and Its Use in Amyloid Defibrillation.

Tunable optical properties in nanomaterials enable a variety of applications in multidisciplinary areas. These properties are directly related to several different factors such as solvent conditions, synthesis methods, and most significantly, the oxidation states of metals participating in the absorption or emission properties. Lanthanide metals containing ABO3 perovskites are among such nanomaterials that can be tuned to a great extent by only modifying the charged states on the metals in the composition. We report a green synthesis method through sonication to synthesize ABO3 perovskites to incorporate Tb4+ into the perovskite composition at room temperature. The optical properties of the nanomaterial show emission in the entire ultraviolet-visible-near-infrared spectral regions through charge transfer between europium and terbium. The combination of cerium (C), molybdenum (M), europium (E), and terbium (T) results in a sheet-like CMET perovskite obeying hexagonal geometry. The nanomaterial is highly stable in an aqueous medium, showing finely suspended Tyndall effect due to particle size <300 nm. Owing to their wide range of emission behavior, surface charge, and aqueous stability, CMET perovskites were used to study the defibrillation of hen egg-white lysozyme (HEWL) as an amyloid model protein. The intrinsic property of the nanomaterial assists in the interaction of the fibrils with the perovskite and the emission range becomes the reporter of the defibrillation. Infrared spectroscopy shows the change in the material properties during the defibrillation. A preliminary test on the varying concentration of HEWL incubated with CMET perovskites shows linear behavior with R2 = 0.9841. The tunable emission characteristic and aqueous stability of the perovskite material make it suitable for future biological applications.

Interleukin-17 upregulation participates in the pathogenesis of heart failure in mice via NF-κB-dependent suppression of SERCA2a and Cav1.2 expression.

Interleukin-17 (IL-17), also called IL-17A, is an important regulator of cardiac diseases, but its role in calcium-related cardiac dysfunction remains to be explored. Thus, we investigated the influence of IL-17 on calcium handling process and its contribution to the development of heart failure. Mice were subjected to transaortic constriction (TAC) to induce heart failure. In these mice, the levels of IL-17 in the plasma and cardiac tissue were significantly increased compared with the sham group. In 77 heart failure patients, the plasma level of IL-17 was significantly higher than 49 non-failing subjects, and was negatively correlated with cardiac ejection fraction and fractional shortening. In IL-17 knockout mice, the shortening of isolated ventricular myocytes was increased compared with that in wild-type mice, which was accompanied by significantly increased amplitude of calcium transient and the upregulation of SERCA2a and Cav1.2. In cultured neonatal cardiac myocytes, treatment of with IL-17 (0.1, 1 ng/mL) concentration-dependently suppressed the amplitude of calcium transient and reduced the expression of SERCA2a and Cav1.2. Furthermore, IL-17 treatment increased the expression of the NF-κB subunits p50 and p65, whereas knockdown of p50 reversed the inhibitory effects of IL-17 on SERCA2a and Cav1.2 expression. In mice with TAC-induced mouse heart, IL-17 knockout restored the expression of SERCA2a and Cav1.2, increased the amplitude of calcium transient and cell shortening, and in turn improved cardiac function. In addition, IL-17 knockout attenuated cardiac hypertrophy with inhibition of calcium-related signaling pathway. In conclusion, upregulation of IL-17 impairs cardiac function through NF-κB-mediated disturbance of calcium handling and cardiac remodeling. Inhibition of IL-17 represents a potential therapeutic strategy for the treatment of heart failure.

A retrospective analysis of hyponatremia during terlipressin treatment in patients with esophageal or gastric variceal bleeding due to portal hypertension.

BACKGROUND AND AIM: To explore the risk factors of hyponatremia caused by terlipressin. METHODS: Forty-four patients with acute variceal bleeding treated with terlipressin from December 2016 to December 2018 were analyzed. RESULTS: During the treatment, serum sodium levels decreased from 137.78 to 126.59 mmol/L (P < 0.05), with an average decrease of 11.19 mmol/L. The serum sodium level decreased by less than 5 mmol/L in 12 patients (27.27%), by 5-10 mmol/L in 13 patients (27.27%), and by more than 10 mmol/L in 19 patients (43.18%). The difference in baseline serum sodium levels was statistically significant (P < 0.05), and the differences in baseline total bilirubin levels, Child-Pugh scores, and model for end-stage liver disease scores were also significant. Logistic regression analysis suggested that the initial sodium level was an independent risk factor for the decrease in the serum sodium concentration caused by terlipressin. CONCLUSION: The incidence of hyponatremia is not low during treatment with terlipressin; a higher baseline serum sodium level is a risk factor for hyponatremia during treatment with terlipressin, and the mechanism may be related to endogenous vasopressin preconditioning.

Changes in thyroid function in patients with liver failure and their clinical significance: A clinical study of non-thyroidal illness syndrome in patients with liver failure.

BACKGROUND: Non-thyroidal illness syndrome (NTIS) develops in a large proportion of critically ill patients and is associated with high risk for death. We aimed to investigate the correlation between NTIS and liver failure, and the short-term mortality of patients with these conditions. METHODS: The clinical data of 87 patients with liver failure were collected retrospectively, 73 of them were randomly selected for an observational study and to establish prognostic models, and 14 for model validation. Another 73 sex- and age-matched patients with mild chronic hepatitis were randomly selected as a control group. Serum free triiodothyronine (FT3), free thyroxine (FT4), and thyroid-stimulating hormone (TSH) were measured. The clinical characteristics of patients with liver failure and NTIS were analyzed. The follow-up of patients lasted for 3 months. Additionally, the values for predicting short-term mortality of model for end-stage liver disease (MELD), Child-Turcotte-Pugh (CTP), chronic liver failure-sequential organ failure assessment (CLIF-SOFA) scores, FT3-MELD model, and FT3 were evaluated. RESULTS: The observation group had significantly lower FT3 (2.79 ± 0.71 vs. 4.43 ± 0.75 pmol/L, P < 0.001) and TSH [0.618 (0.186-1.185) vs. 1.800 (1.570-2.590) mIU/L, P < 0.001], and higher FT4 (19.51 ± 6.26 vs. 14.47 ± 2.19 pmol/L, P <0.001) than the control group. NTIS was diagnosed in 49 of the patients with liver failure (67.12%). In the observation group, patients with NTIS had a higher mortality rate than those without (63.27% vs. 25.00%, P = 0.002). Across the whole cohort, the 3-month mortality was 50.68%. The international normalized ratios (INR) were 2.40 ± 1.41 in survivors and 3.53 ± 1.81 in deaths (P = 0.004), the creatinine (Cr) concentrations were 73.27 ± 36.94 µmol/L and 117.08 ± 87.98 µmol/L (P = 0.008), the FT3 concentrations were 3.13 ± 0.59 pmol/L and 2.47 ± 0.68 pmol/L (P < 0.001), the MELD scores were 22.19 ± 6.64 and 29.57 ± 7.99 (P < 0.001), the CTP scores were 10.67 ± 1.53 and 11.78 ± 1.25 (P = 0.001), and the CLIF-SOFA scores were 8.42 ± 1.68 and 10.16 ± 2.03 (P < 0.001), respectively. FT3 was negatively correlated with MELD score (r = -0.430, P < 0.001). An FT3-MELD model was established by subjecting FT3 concentration and MELD score to logistic regression analysis using the following formula: Logit(P) = -1.337 × FT3+0.114 × MELD+0.880. The area under the receiver operating characteristic (ROC) curve was 0.827 and the optimal cut-off value was 0.4523. The corresponding sensitivity and specificity were 67.6% and 91.7%. The areas under the ROC curve for FT3 concentration, MELD score, CTP score, and CLIF-SOFA score were 0.809, 0.779, 0.699, and 0.737, respectively. CONCLUSIONS: Patients with liver failure often develop NTIS. FT3-MELD score perform better than CTP and CLIF-SOFA scores in predicting mortality in patients with liver failure. Thus, the FT3-MELD model could be of great value for the evaluation of the short-term mortality of such patients.

Phase IIb trial of in vivo electroporation mediated dual-plasmid hepatitis B virus DNA vaccine in chronic hepatitis B patients under lamivudine therapy.

AIM: To assess the efficacy and safety of in vivo electroporation (EP)-mediated dual-plasmid hepatitis B virus (HBV) DNA vaccine vs placebo for sequential combination therapy with lamivudine (LAM) in patients with chronic hepatitis B. METHODS: Two hundred and twenty-five patients were randomized to receive either LAM + vaccine (vaccine group, n = 109) or LAM + placebo (control group, n = 116). LAM treatment lasted 72 wk. Patients received the DNA vaccine or placebo by intramuscular injection mediated by EP at weeks 12 (start of treatment with vaccine or placebo, SOT), 16, 24, and 36 (end of treatment with vaccine or placebo, EOT). RESULTS: In the modified intent-to-treat population, more patients had a decrease in HBV DNA > 2 log10 IU/mL in the vaccine group at week 12 after EOT compared with the control group. A trend toward a difference in the number of patients with undetectable HBV DNA at week 28 after EOT was obtained. Adverse events were similar. In the dynamic per-protocol set, which excluded adefovir (ADV) add-on cases at each time point instantly after ADV administration due to LAM antiviral failure, more patients had a decrease in HBV DNA > 2 log10 IU/mL in the vaccine group at week 12 and 28 after EOT compared with the control group. More patients with undetectable HBV DNA at week 28 after EOT in the vaccine group were also observed. Among patients with a viral load < 1000 copies/mL at week 12, more patients achieved HBeAg seroconversion in the vaccine group than among controls at week 36 after EOT, as well as less virological breakthrough and YMDD mutations. CONCLUSION: The primary endpoint was not achieved using the HBV DNA vaccine. The HBV DNA vaccine could only be beneficial in subjects that have achieved initial virological response under LAM chemotherapy.

A preliminary study on the efficacy and influencing factors of interferon for the treatment of genotype 1 chronic hepatitis C with different dosage forms.

BACKGROUND AND OBJECTIVE: Nowadays, interferon alfa-2b is still in widespread use for the treatment of chronic hepatitis C in China. In this study, peginterferon alfa-2a plus ribavirin was compared with interferon alfa-2b plus ribavirin for the initial treatment of genotype 1 chronic hepatitis C. MATERIALS AND METHODS: Overall, 168 patients with genotype 1 chronic hepatitis C were assigned peginterferon alfa-2a (135-180 µg subcutaneously/week) plus ribavirin (800-1200 mg/day orally) or interferon alfa-2b (300-500 million units, once every other day) plus ribavirin (800-1200 mg/day). According to HCV RNA levels at weeks 4 and 12, patients were reallocated to receive different interferon dosage forms or different courses of treatment. The primary endpoint was a sustained virological response (SVR). RESULTS: A total of 160 patients completed the entire study and eight cases were lost to follow-up. The SVR rates in patients treated with peginterferon alfa-2a plus ribavirin for 24 and 48 weeks were 67.9% (53/78) and 73.6% (14/19), respectively, whereas in patients treated with interferon alfa-2b plus ribavirin for 24 and 48 weeks the SVR rates were 52.4% (43/82) and 40% (8/20), respectively. The SVR rates in the groups with a rapid virological response (RVR) and without RVR were 68.8 and 16.9%, respectively. The SVR rates in the groups with an early virological response (EVR) and in the groups without EVR were 88.1 and 10.5%, respectively. CONCLUSION: Peginterferon alfa-2a plus ribavirin was more effective than interferon alfa-2b plus ribavirin, with similar safety. RVR can predict a greater chance of SVR. The duration of treatment should be shortened for patients with RVR. Treatment for patients without EVR should be discontinued.

[Clinical study on effect of Shenmai Injection in treating congestive heart failure].

OBJECTIVE: To observe the therapeutic effect of Shenmai Injection (SI) in treating congestive heart failure (CHF). METHODS: The changes in cAMP, cGMP, serum cardiac troponin T (cTnT, a specific marker reflecting myocardial injury), creatine kinase (CK) and creatine kinase isoenzyme (CK-MB) were simultaneously monitored in 62 chronic CHF patients, distributed in the two groups, the routine treatment group and the routine treatment + SI group, by randomized grouping method, and the therapeutic effect of the two groups was compared. RESULTS: The plasma cAMP/cGMP ratio increased in early stage and decreased in late stage of the course of CHF. The serum cTnT level was progressively increased along with heart function deterioration. After treated with SI for 2 weeks, the CHF patients' hemodynamics got stable and heart function obviously improved. No serious adverse reaction was found in the therapeutic course. CONCLUSION: The level of serum cTnT might be taken as a reliable biochemical parameter to predict the prognosis of CHF patients. SI is an effective and safe agent in treating CHF.