Immunogenicity-masking delivery of uricase against hyperuricemia and gout.

Improving the activity of uricase and lowering its immunogenicity remain significant challenges in the enzyme replacement management of hyperuricemia and related inflammatory diseases. Herein, an immunogenicity-masking strategy based on engineered red blood cells (RBCs) was developed for effective uricase delivery against both hyperuricemia and gout. The dynamic membrane of RBCs enabled high resistance to protease inactivation and hydrogen peroxide accumulation. Benefiting from these advantages, a single infusion of RBC-loaded uricase (Uri@RBC) performed prolonged blood circulation and sustained hyperuricemia management. Importantly, RBCs masked the immunogenicity of uricase, leading to the maintenance of UA-lowering performance after repeated infusion through reduced antibody-mediated macrophage clearance. In an acute gout model, Uri@RBC profoundly alleviated joint edema and inflammation with minimal systemic toxicity. This study supports the employment of immunogenicity-masking tools for efficient and safe enzyme delivery, and this strategy may be leveraged to improve the usefulness of enzyme replacement therapies for managing a wide range of inflammatory diseases.

Serum retinol-binding protein 4 is associated with the presence and severity of coronary artery disease in patients with subclinical hypothyroidism.

Subclinical hypothyroidism (SCH) plays a crucial role in the development and progression of coronary heart disease (CAD). Retinol-binding protein 4 (RBP4) is an adipokine correlated with cardiovascular diseases. Recent studies found that RBP4 levels are increased in patients with SCH. However, the relationship of RBP4 with CAD in SCH patients remains unclear. A total of 199 SCH patients (148 with CAD and 51 without CAD) and 102 healthy controls were enrolled in this study. Serum RBP4 was increased in SCH patients than controls. Moreover, serum RBP4 was higher in SCH patients with CAD. Although there was no significant difference of metabolic parameters between SCH patients with and without CAD, serum RBP4 was positively correlated with body mass index, total cholesterol, and low-density lipoprotein cholesterol, as well as thyroid stimulating hormone. Multivariable logistic regression analyses revealed elevated RBP4 was correlated with increased risk for CAD in SCH patients. Serum RBP4 levels were also increased as the number of stenosed vessels increased. Furthermore, increased RBP4 was positively correlated with the severity of CAD quantified by the Gensini score. Our findings demonstrate that serum RBP4 is associated with the presence and severity of CAD in patients with SCH.

Serum Metrnl is associated with the presence and severity of coronary artery disease.

Meteorin-like (Metrnl) is a novel adipokine that is highly expressed in white adipose tissue. Metrnl stimulates energy expenditure and improves glucose tolerance in rodents. However, whether Metrnl plays a role in coronary artery disease (CAD) remains to be elucidated. The present study aimed to investigate the association of serum Metrnl with CAD in Chinese patients. A total of 193 patients with CAD and 156 control subjects were enrolled in this study. Serum Metrnl concentration was measured by enzyme-linked immunosorbent assay. Anthropometric phenotypes, fasting glucose, serum lipids, and inflammatory cytokines were measured. Serum Metrnl was lower in CAD patients when compared to those controls (132.41 vs 173.17 pg/mL, P < 0.001). Serum Metrnl was negatively correlated with metabolic parameters, including body mass index, total cholesterol, and low-density lipoprotein cholesterol as well as inflammatory markers including high-sensitivity C-reactive protein, IL-1ß, and IL-11 even after adjustment for potential confounding variables (P < 0.05). In multivariable logistic regression analyses, compared to those in the highest tertile of serum Metrnl levels, subjects in the lowest tertile had the highest risks for CAD (adjusted OR = 2.63, 95% CI = 1.46-4.27, P = 0.001). After adjustment for potential confounding variables, serum Metrnl was also decreased as the number of stenosed vessels increased (P < 0.001). Furthermore, decreased Metrnl level was negatively correlated with the severity of CAD quantified by the Gensini score. This first case-control study shows significant associations of serum Metrnl with the presence and severity of CAD, suggesting Metrnl might be a new promising therapeutic target for CAD.

Knockdown the P2X3 receptor in the stellate ganglia of rats relieved the diabetic cardiac autonomic neuropathy.

Diabetic cardiac autonomic neuropathy (DCAN) is a common and serious complication of diabetes mellitus (DM), is manifested by nerve fiber injury in the sympathetic and parasympathetic nerve of the autonomic nervous system, and causes hypertension, cardiac arrhythmias, silent myocardial infarction, and sudden death. Our previous study observed that P2X3 receptor in superior cervical ganglia in rat was associated with sympathetic neuropathy caused by myocardial ischemia. However, whether the P2X3 receptor is involved in the diabetic cardiac autonomic neuropathy and the underlying mechanisms remain unclear. The aim of this research was explored the effect of P2X3 short hairpin RNA (shRNA) on information transmission of sympathetic nerve induced by DCAN. Sprague-Dawley (SD) male rats were randomly divided into four groups: Control, DM, DM treated with P2X3 shRNA and DM treated with scramble shRNA. Blood pressure, heart rate and heart rate variability were measured in each group. The expression of P2X3 in stellate ganglion (SG) was detected by immunohistochemistry, western blotting and QPCR. Results showed that P2X3 shRNA alleviated blood pressure and heart rate, improved heart rate variability, decreased the up-regulated expression levels of P2X3, interleukin-1beta and tumor necrosis factor alpha in stellate ganglion (SG) of diabetic rats. P2X3 shRNA also reduced the incremental concentration of serum epinephrine and the phosphorylation level of extracellular regulated protein kinases1/2 in diabetic rats. These results indicated that P2X3 shRNA could decrease sympathetic activity via inhibiting P2X3 receptor in the SG to alleviate DCAN.

Involvement of P2Y12 receptor of stellate ganglion in diabetic cardiovascular autonomic neuropathy.

Diabetes as a chronic epidemic disease with obvious symptom of hyperglycemia is seriously affecting human health globally due to the diverse diabetic complications. Diabetic cardiovascular autonomic neuropathy (DCAN) is a common complication of both type 1 and type 2 diabetes and incurs high morbidity and mortality. However, the underlying mechanism for DCAN is unclear. It is well known that purinergic signaling is involved in the regulation of cardiovascular function. In this study, we examined whether the P2Y12 receptor could mediate DCAN-induced sympathetic reflexes. Our results revealed that the abnormal changes of blood pressure, heart rate, heart rate variability, and sympathetic nerve discharge were improved in diabetic rats treated with P2Y12 short hairpin RNA (shRNA). Meanwhile, the expression of P2Y12 receptor, interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and connexin 43 (Cx43) in stellate ganglia (SG) was decreased in P2Y12 shRNA-treated diabetic rats. In addition, knocking down the P2Y12 receptor also inhibited the activation of p38 MARK in the SG of diabetic rats. Taken together, these findings demonstrated that P2Y12 receptor in the SG may participate in developing diabetic autonomic neuropathy, suggesting that the P2Y12 receptor could be a potential therapeutic target for the treatment of DCAN.