Anti-inflammatory effect of a novel piperazino-enaminone delivered by liposomes in a mouse model of hemophilic arthropathy.

Hemophilic arthropathy (HA) is a condition caused by recurrent intra-articular bleeding in patients with hemophilia. Pro-inflammatory cytokines play a crucial role in the pathogenesis of HA. Our previous research demonstrated that a novel compound, piperazino-enaminone (JODI), effectively inhibited pro-inflammatory cytokines, including IL-6, MCP-1, MIP-1α, and MIP-1ß, in a mouse model of hemarthrosis. This study aims to enhance the anti-inflammatory effect of JODI by employing nanoparticle delivery systems, which could potentially improve its poor water solubility. Here, we developed liposomes modified with polyethylene glycol (PEG) for the delivery of JODI (JODI-LIP), and found that JODI-LIP exhibited uniform size, morphology, good stability and in vitro release degree. JODI-LIP mitigated cytotoxicity of JODI, and significantly suppressed the production of pro-inflammatory cytokines (TNF-α and IL-1ß) and nitric oxide (NO) release in RAW 264.7 cells stimulated by lipopolysaccharide (LPS), as well as the proliferation of human fibroblast-like synovial (HFLS) cells. In a murine model of HA, JODI-LIP demonstrated superior efficacy in ameliorating joint swelling and synovitis, compared to JODI. Importantly, JODI-LIP markedly reduced pro-inflammatory cytokines (TNF-α, IFN-γ, IL-33, and MCP-1) in injured joints. No hepatic or hematological toxicity was observed in mice treated with JODI-LIP. In summary, our results suggest that JODI-LIP holds promise as a therapeutic intervention for HA by attenuating pro-inflammatory cytokine levels.

Associations between sleep problems and cardiometabolic risk in maintenance hemodialysis patients: A multicenter study.

The incidence of cardiovascular disease is increasing around the world, and it is one of the main causes of death in chronic kidney diseases patients. It is urgent to early identify the factors of cardiometabolic risk. Sleep problems have been recognized as a risk factor for cardiometabolic risk in both healthy people and chronic patients. However, the relationship between sleep problems and cardiometabolic risk has not been clearly explored in hemodialysis patients. This study aimed to investigate the relationship between sleep problems and cardiometabolic risk in 3025 hemodialysis patients by a multicenter study. After adjusting for confounders, binary logistic regression models showed that hemodialysis patients reported sleep duration greater than 7 h were more likely to be with hypertension, hyperglycemia, hypertriglyceridemia, and hypercholesterolemia. Patients reported sleep duration less than 7 h were more likely to be with hypertriglyceridemia and hypercholesterolemia, but the risks of hyperglycemia and Low HDL-cholesterol were decreased. Poor sleep quality was negatively correlated to low HDL cholesterol and hypertriglyceridemia. Moreover, gender-based differences were explained.

Sildenafil increases AAV9 transduction after a systemic administration and enhances AAV9-dystrophin therapeutic effect in mdx mice.

Adeno-associated virus (AAV) vectors have been successfully used to deliver genes for treating rare diseases. However, the systemic administration of high AAV vector doses triggers several adverse effects, including immune response, the asymptomatic elevation of liver transaminase levels, and complement activation. Thus, improving AAV transduction and reducing AAV dosage for treatment is necessary. Recently, we found that a phosphodiesterase-5 inhibitor significantly promoted AAV9 transduction in vitro by regulating the caveolae and macropinocytosis pathways. When AAV9-Gaussian luciferase (AAV9-Gluc) and AAV9-green fluorescent protein (AAV9-GFP) were injected intravenously into mice pre-treated with sildenafil, the expressions of Gluc in the plasma and GFP in muscle tissues significantly increased (P < 0.05). Sildenafil also improved Evans blue permeation in tissues. Additionally, we found that sildenafil promoted Treg proliferation, inhibited B-cell activation, and decreased anti-AAV9 IgG levels (P < 0.05). Furthermore, sildenafil significantly promoted Duchenne muscular dystrophy gene therapy efficacy using AAV9 in mdx mice; it increased micro-dystrophin gene expression, forelimb grip strength, and time spent on the rotarod test, decreased serum creatine kinase levels, and ameliorated histopathology by improving muscle cell morphology and reducing fibrosis (P < 0.05). These results show that sildenafil significantly improved AAV transduction, suppressed the levels of anti-AAV9 IgG, and enhanced the efficacy of gene therapy.

Could long-term dialysis vintage and abnormal calcium, phosphorus and iPTH control accelerate aging among the maintenance hemodialysis population?

OBJECTIVE: Aging is a complex process of physiological dysregulation of the body system and is common in hemodialysis patients. However, limited studies have investigated the links between dialysis vintage, calcium, phosphorus, and iPTH control and aging. The purpose of the current study was to examine these associations. METHODS: During 2020, a cross-sectional study was conducted in 3025 hemodialysis patients from 27 centers in Anhui Province, China. Biological age was calculated by a formula using chronological age and clinical indicators. The absence of the target range for serum phosphorus (0.87-1.45 mmol/L), corrected calcium (2.1-2.5 mmol/L) and iPTH (130-585 pg/mL) were identified as abnormal calcium, phosphorus, and iPTH control. RESULTS: A total of 1131 hemodialysis patients were included, 59.2% of whom were males (669/1131). The mean (standard deviation) of actual age and biological age were 56.07 (12.79) years and 66.94 (25.88), respectively. The median of dialysis vintage was 4.3 years. After adjusting for the confounders, linear regression models showed patients with abnormal calcium, phosphorus, and iPTH control and on hemodialysis for less than 4.3 years (B = 0.211, p = .002) or on hemodialysis for 4.3 years or more (B = 0.302, p < .001), patients with normal calcium, phosphorus, and iPTH control and on hemodialysis for 4.3 years or more (B = 0.087, p = .013) had a higher biological age. CONCLUSION: Our findings support the hypothesis that long-term hemodialysis and abnormal calcium, phosphorus, and iPTH control may accelerate aging in the hemodialysis population. Further studies are warrant to verify the significance of maintaining normal calcium-phosphorus metabolism in aging.

Investigation on maintenance hemodialysis patients with mineral and bone disorder in Anhui province, China.

BACKGROUND: Chronic kidney disease-mineral bone disorder (CKD-MBD) is a common comorbidity in patients with CKD. The study aims to describe the control rates of serum-corrected calcium (Ca), phosphate (P) and intact parathyroid hormone (iPTH) and its risk factors among maintenance hemodialysis (MHD) patients in Anhui Province of China. METHODS: The study was conducted in 27 hemodialysis centers of Anhui Province between January 1st 2020 and December 31th 2020. Chi-square test was used to compare the control rates of serum-corrected Ca, P and iPTH between the present study and DOPPS 4 or Anhui Province in 2014. Binary logistic regression analysis was used to explore the risk factors of the control rates of serum-corrected Ca, P and iPTH. RESULTS: A total of 3 025 MHD patients were recruited in this study, with a mean age of 54.8 (SD: 12.8) years, and 60.1% were males. According to the Chinese Diagnosis and Treatment Guidelines for CKD-MBD, the control rates of serum-corrected Ca, P and iPTH in the present study were 57.9%, 20.0% and 56.0%, respectively. Based on KDOQI guidelines (2003), the control rates of the above indicators were 43.1%, 35.3% and 22.3%, respectively. The control rates of serum-corrected Ca, P and iPTH in this study were lower than those of DOPPS 4 (P < 0.001). Compared to the results of Anhui Province in 2014, the control rate of corrected Ca was higher (P < 0.001) and the control rate of iPTH was lower (P = 0.005). Age, residential area, BMI, dialysis vintage, albumin and hemoglobin levels were factors of serum-corrected Ca, P and iPTH not within target range. CONCLUSION: The control rates of serum-corrected Ca, P and iPTH in MHD patients in Anhui Province are relatively low. Monitoring and management should be strengthened to improve the prognosis of patients undergoing dialysis.

A multi-center study on the association between serum magnesium levels and allostatic load in hemodialysis patients.

Objective: Serum magnesium (Mg2+) levels are associated with insulin resistance, hypertension, lipid abnormalities, and inflammation. However, limited studies have indicated the relationship between Mg2+ and multiple system indexes. The purpose of this study was to investigate the association between Mg2+ and allostatic load (AL) in hemodialysis patients. Methods: A cross-sectional survey was conducted on hemodialysis patients from different centers in Anhui Province, China, between January and December 2020. A total of 3,025 hemodialysis patients were recruited. Their clinical data were measured before hemodialysis. Information was collected by an online self-reported questionnaire and medical record. Serum Mg2+ was divided into three groups by tertiles. A score of AL greater than or equal to 3 was defined as high AL. A binary logistic regression model was applied to examine the relationship between serum Mg2+ and AL. Results: A total of 1,222 patients undergoing hemodialysis were included, 60% of whom were males (733/1,222). The mean (standard deviation) age of patients was 55.90 (12.75). The median level of serum Mg2+ was 1.22 mmol/L. The rate of high AL levels was 23.4%. Serum Mg2+ was negatively correlated with body mass index, fasting blood glucose (Glu), and C-reactive protein and positively correlated with high-density lipoprotein, low-density lipoprotein, total cholesterol, diastolic blood pressure (DBP), and serum phosphorus. After adjusting for gender, anxiety, diabetes, family residence, lipid-lowering agents, antihypertensive medications, albumin, and Glu, the binary logistic regression model showed that patients with lower levels of serum Mg2+ were more likely have high AL (OR for the T1 group of serum Mg2+:1.945, 95% CI: 1.365-2.773, and OR for the T2 group of serum Mg2+:1.556, 95% CI: 1.099-2.201). Conclusion: Our data support the hypothesis that higher serum Mg2+ concentrations may contribute to lower health risk in hemodialysis populations. Further randomized controlled trials and cohort studies are warranted to verify whether Mg2+ supplementation could be part of routine examinations in hemodialysis populations.

Naive haemophilia mice displayed different pattern of cytokine profiles of cytokine profiles changes might be associated with subclinical bleeding.

Subclinical bleeding is a haemorrhage event not clinically detected in haemophilia, and no reliable method is available for predicting subclinical bleeding. We investigated whether haemophilia mice have subclinical haemorrhage and evaluated potential biomarkers including multiple cytokine changes to predict subclinical haemorrhage. Plasma from naïve FVIII-/- and FIX-/- mice and their wild-type counterparts (FVIII WT and FIX WT, respectively) were measured for prothrombin fragment 1 + 2 (F1 + 2) and multiple cytokines. Haemophilia mice with induced hemarthrosis were used as positive clinical bleeding controls. Naive haemophilia mice that displayed higher levels than positive bleeding control were counted. Univariate and multivariate analyses of cytokines were performed. Compared with wild-type mice (FVIII WT 1.1-6.2 vs. FIX WT 2.7-6.7 pmol/l), F1 + 2 widely varied in both haemophilia mouse strains (FVIII-/- 3.7-25.7 vs. FIX-/- 2.7-15.7 pmol/l). Each cytokine varied widely in both naive haemophilia A and B mice, but not significantly, for most cytokines. In comparison to haemophilia mice with hemarthrosis bleeding challenge, naive FVIII-/- mice had elevated pro-inflammatory cytokines and FIX-/- mice had elevated anti-inflammatory cytokines. In addition, interleukin (IL)-4, followed by IL-1, IL-6, TNF-α and MIP-1α in FVIII-/- mice and MIP-1α, followed by IL-1, IL-10 in FVIII-/- mice exhibited significant differences potentially associated with potential subclinical bleeding. Naive haemophilia mice showed elevated pro-inflammatory cytokines with different patterns, represented by pro-inflammatory cytokine elevation in more naïve FVIII-/- mice and more anti-inflammatory cytokines in FIX-/- mice.