Coassembly of hypoxia-sensitive macrocyclic amphiphiles and extracellular vesicles for targeted kidney injury imaging and therapy.

BACKGROUND: Hypoxia is a major contributor to global kidney diseases. Targeting hypoxia is a promising therapeutic option against both acute kidney injury and chronic kidney disease; however, an effective strategy that can achieve simultaneous targeted kidney hypoxia imaging and therapy has yet to be established. Herein, we fabricated a unique nano-sized hypoxia-sensitive coassembly (Pc/C5A@EVs) via molecular recognition and self-assembly, which is composed of the macrocyclic amphiphile C5A, the commercial dye sulfonated aluminum phthalocyanine (Pc) and mesenchymal stem cell-excreted extracellular vesicles (MSC-EVs). RESULTS: In murine models of unilateral or bilateral ischemia/reperfusion injury, MSC-EVs protected the Pc/C5A complex from immune metabolism, prolonged the circulation time of the complex, and specifically led Pc/C5A to hypoxic kidneys via surface integrin receptor α4ß1 and αLß2, where Pc/C5A released the near-infrared fluorescence of Pc and achieved enhanced hypoxia-sensitive imaging. Meanwhile, the coassembly significantly recovered kidney function by attenuating cell apoptosis, inhibiting the progression of renal fibrosis and reducing tubulointerstitial inflammation. Mechanistically, the Pc/C5A coassembly induced M1-to-M2 macrophage transition by inhibiting the HIF-1α expression in hypoxic renal tubular epithelial cells (TECs) and downstream NF-κB signaling pathway to exert their regenerative effects. CONCLUSION: This synergetic nanoscale coassembly with great translational potential provides a novel strategy for precise kidney hypoxia diagnosis and efficient kidney injury treatment. Furthermore, our strategy of coassembling exogenous macrocyclic receptors with endogenous cell-derived membranous structures may offer a functional platform to address multiple clinical needs.

Association of plasma neutrophil gelatinase-associated lipocalin with parameters of CKD-MBD in maintenance hemodialysis patients.

INTRODUCTION: Neutrophil gelatinase-associated lipocalin (NGAL) is not only a biomarker of kidney injury but also a bone-derived factor involved in metabolism. We aimed to explore relationships between plasma NGAL and chronic kidney disease-mineral bone disorder (CKD-MBD) parameters in maintenance hemodialysis (MHD) patients. MATERIALS AND METHODS: First, a cross sectional observational study, including 105 MHD patients, was conducted to explore relationships between plasma NGAL levels and CKD-MBD parameters. Second, impact of parathyroidectomy and auto-transplantation (PTX + AT) on plasma NGAL was investigated in 12 MHD patients with severe secondary hyperparathyroidism (SHPT). RESULTS: According to Spearman correlation analysis, plasma NGAL levels were positively correlated with female (r = 0.243, P = 0.012), vintage (r = 0.290, P = 0.003), Klotho (r = 0.234, P = 0.016), calcium(Ca) (r = 0.332, P = 0.001), alkaline phosphatase (ALP) (r = 0.401, P < 0.001) and intact parathyroid hormone (iPTH) (r = 0.256, P = 0.008); while inversely correlated with albumin(Alb) (r = - 0.201, P = 0.039). After adjusting for age, sex, vintage, Alb and all parameters of CKD-MBD(Ca, P, lg(ALP), lg(iPTH), Klotho and fibroblast growth factor 23(FGF23)), lg(NGAL) were positively correlated with Ca (r = 0.481, P < 0.001), P (r = 0.336, P = 0.037), lg(ALP) (r = 0.646, P < 0.001) in Partial correlation analysis; further multiple linear regression analysis showed same positive associations between lg(NGAL) and Ca (ß = 0.330, P = 0.002), P (ß = 0.218, P = 0.037), lg(ALP) (ß = 0.671, P < 0.001). During the 4-7 days after PTX + AT, plasma NGAL decreased from 715.84 (578.73, 988.14) to 688.42 (660.00, 760.26) ng/mL (P = 0.071), Klotho increased from 496.45 (341.73, 848.30) to 1138.25 (593.87, 2009.27) pg/mL (P = 0.099). CONCLUSION: Plasma NGAL levels were positively associated with ALP in MHD patients; and downtrends were shown after PTX + AT in patients with severe SHPT. These findings suggest that NGAL is a participant in CKD-MBD under MHD condition.

Macrocyclic-Amphiphile-Based Self-Assembled Nanoparticles for Ratiometric Delivery of Therapeutic Combinations to Tumors.

Combination chemotherapy refers to the use of multiple drugs to treat cancer. In this therapy, the optimal ratio of the drugs is essential to achieve drug synergism and the desired therapeutic effects. However, most delivery strategies are unable to precisely control the ratio of the drugs during the drug loading and delivery processes, resulting in inefficient synergy and unpredictable efficacy. Herein, a macrocyclic-amphiphile-based self-assembled nanoparticle (MASN) that achieves precise loading and ratiometric delivery of therapeutic combinations is presented. By integrating multiple macrocyclic cavities within a single nanoparticle, the MASN can load multiple drug molecules via the host-guest interaction, and the ratio of the drugs loaded can be predicted with their initial concentrations and characteristic binding affinity. Moreover, MASNs are readily degraded under a hypoxic microenvironment, allowing spontaneous release of the drugs upon reaching tumor tissues. With precise drug loading and controlled release mechanisms, MASNs achieve ratiometric delivery of multiple commercial drugs to tumors, thereby achieving optimal anti-tumor effects. Since the optimal drug ratio of a therapeutic combination can be quickly determined in vitro, MASNs can translate this optimal ratio to the therapeutic benefits in vivo, providing a potential platform for the rapid development of effective combination cancer therapies involving multiple drugs.

Association of hemoglobin with arterial stiffness evaluated by carotid-femoral pulse wave velocity among Chinese adults.

OBJECTIVE: Increased hemoglobin (Hb) levels are known to be associated with increased cardiovascular events and mortalities. Therefore, we assumed that high Hb levels were associated with arterial stiffness. Pulse wave velocity (PWV) is a simple and noninvasive method for measuring arterial stiffness to assess cardiovascular disease in general populations. Accordingly, we conducted a cross-sectional study to explore the association of Hb with PWV. METHODS: A total of 6642 adults aged 54.5 ± 11.2 years undergoing physical examinations were enrolled, 71.7% of whom were males. Arterial stiffness was evaluated by carotid-femoral PWV (cfPWV). Multivariable regression analyses were performed to determine the relationship between Hb and increased cfPWV. RESULTS: In this study, the mean Hb (per 10 g/L increase) was 144.7 ± 13.9 g/L, and the mean cfPWV was 15.1 ± 3.1 m/s. cfPWV was significantly higher in high hemoglobin groups ≥15.4 g/L (Quartile 4) than in the lowest hemoglobin group (Quartile 1 ≤ 13.6 g/L; P < 0.001). Multiple linear regression analysis revealed that Hb positively correlated with cfPWV (ß = 0.16, P < 0.01). Univariate Logistic regression analysis revealed that Hb was associated with increased cfPWV, with an odd ratio (OR) of 1.46 (95% confidence interval [CI], 1.39-1.54). After adjusting for potential confounders, Hb and the highest Hb quartile group were also independently associated with increased cfPWV, with a fully adjusted OR of 1.11 (95% CI, 1.02-1.20) and 1.45 (95% CI, 1.01-2.08), respectively. CONCLUSION: This study demonstrated that Hb levels significantly correlate with increased cfPWV.

Clinical significance of autoantibodies in the assessment and treatment of idiopathic membranous nephropathy.

The present study aimed to explore the correlation between the dynamic serum levels of phospholipase A2 receptor (PLA2R), aldose reductase (AR) and superoxide dismutase 2(SOD2) antibodies with disease activity and treatment response in patients with idiopathic membranous nephropathy (IMN). The present study included 56 patients with IMN who were diagnosed through a renal biopsy and presenting with nephrotic syndrome. The patients were divided into two treatment groups: One treated with cyclophosphamide (CTX) and one with tacrolimus (FK506). Serum was collected prior to treatment, and at 1, 3, 6, 9 and 12 months after the start of the 12-month-long therapy. Samples were tested by ELISA to measure anti-PLA2R, anti-AR and anti-SOD2 antibody titers. In addition, urinary protein excretion, serum albumin (Alb) and other blood biochemical indexes were measured. Theanti-PLA2R antibody positivity rate was 71.43% in the patients prior to treatment. After 12 months of treatment, proteinuria and PLA2R antibody levels were decreased, whereas serum Alb was increased. There was no significant difference of remission rates between the CTX and FK506 groups. In conclusion, the results of the present study indicate that the anti-PLA2R antibody level is correlated with the severity of IMN, whereas anti-AR and anti-SOD2 antibody levels are not. In addition, there was no significant difference between the CTX and FK506 groups in regards to the remission rates of patients with IMN.

Neural Stem Cells Transfected with Reactive Oxygen Species-Responsive Polyplexes for Effective Treatment of Ischemic Stroke.

Neural stem cells (NSCs), capable of ischemia-homing, regeneration, and differentiation, exert strong therapeutic potentials in treating ischemic stroke, but the curative effect is limited in the harsh microenvironment of ischemic regions rich in reactive oxygen species (ROS). Gene transfection to make NSCs overexpress brain-derived neurotrophic factor (BDNF) can enhance their therapeutic efficacy; however, viral vectors must be used because current nonviral vectors are unable to efficiently transfect NSCs. The first polymeric vector, ROS-responsive charge-reversal poly[(2-acryloyl)ethyl(p-boronic acid benzyl)diethylammonium bromide] (B-PDEA), is shown here, that mediates efficient gene transfection of NSCs and greatly enhances their therapeutics in ischemic stroke treatment. The cationic B-PDEA/DNA polyplexes can effectively transfect NSCs; in the cytosol, the B-PDEA is oxidized by intracellular ROS into negatively charged polyacrylic acid, quickly releasing the BDNF plasmids for efficient transcription and secreting a high level of BDNF. After i.v. injection in ischemic stroke mice, the transfected NSCs (BDNF-NSCs) can home to ischemic regions as efficiently as the pristine NSCs but more efficiently produce BDNF, leading to significantly augmented BDNF levels, which in turn enhances the mouse survival rate to 60%, from 0% (nontreated mice) or ≈20% (NSC-treated mice), and enables more rapid and superior functional reconstruction.

Clustering of major cardiovascular risk factors is associated with arterial stiffness in adults.

OBJECTIVE: Cardiovascular disease (CVD) is the leading cause of mortality and morbidity worldwide. Previous studies have indicated that clustering of major CVD risk factors is common. We aimed to explore the association of clustering of CVD risk factors with arterial stiffness in adults. METHODS: A total of 9984 adults were enrolled. We investigated clustering of four major CVD risk factors (defined as two or more of the following: hypertension, diabetes, dyslipidemia, and high body mass index) and their association with arterial stiffness. Arterial stiffness was evaluated using the carotid-femoral pulse wave velocity (cfPWV). RESULTS: In the study group (52.2% men, the mean age was 55.4 ± 10.5 years; only 11.9% of participants were free of any pre-defined CVD risk factors and 61.8% of participants had clustering of CVD risk factors. The cfPWV was significantly higher in the clustered risk factors group than in the no risk factor or the single risk factor groups (16.1 ± 3.1, 13.4 ± 2.2, and 14.3 ± 2.6 m/s, respectively; P < 0.001). Multiple linear regression analysis revealed that age, gender, clustering of CVD risk factors, serum uric acid, and decreased renal function positively correlated with cfPWV. For a categorical outcome, the highest cfPWV quartile (cfPWV ≥ 16.9 m/s) was compared with the lower three quartiles. After adjusting for potential confounders, clustering of CVD risk factors significantly correlated with increased cfPWV compared with that in the no risk factor group, with an odds ratio of 5.76 (95% confidence interval: 4.46-7.44). CONCLUSIONS: Clustering of CVD risk factors significantly correlated with arterial stiffness; this confirms the importance of lifestyle modification to reduce the burden of CVD.

Relationship between occult hepatitis B virus infection and chronic kidney disease in a Chinese population-based cohort.

OBJECTIVE: Previous studies have revealed inconsistent results regarding the association between occult hepatitis B virus (HBV) infection and chronic kidney disease (CKD). Therefore, we conducted a prospective cohort study to evaluate the association between occult HBV infection and CKD. METHODS: A total of 4329 adults, aged 46.2 ± 13.7 years, without CKD at baseline were enrolled while undergoing physical examinations. Occult HBV infection was defined as seropositivity for antibody to HBV core antigen. CKD was defined as decreased estimated glomerular filtration rate (eGFR < 60 ml·min-1·1.73 m-2) or presence of proteinuria ≥1+, assessed using a repeated dipstick method. eGFR was computed using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. RESULTS: The prevalence of occult HBV infection was 8.1% (352/4329). During 5 years of follow-up, 165 patients (3.8%) developed CKD. Univariate Logistic regression analysis showed that occult HBV infection was positively associated with decreased eGFR, with an odds ratio (OR) of 2.15 (95% confidence interval (CI): 1.05-4.11). In contrast, occult HBV infection was not associated with either proteinuria or CKD (P > 0.05). After adjustment for potential confounders in the multivariate Logistic regression analysis, age, hypertension, diabetes, and the highest quartile of uric acid were associated with CKD, with ORs of 1.04 (95% CI: 1.02-1.05), 2.1 (95% CI: 1.46-3.01), 2.02 (95% CI: 1.36-2.99), and 1.86 (95% CI: 1.17-2.95), respectively. However, occult HBV infection was not associated with CKD, with an OR of 1.12 (95% CI: 0.65-1.95). CONCLUSIONS: This study did not find an association between occult HBV infection and CKD. However, high-risk patients infected with HBV should still be targeted for monitoring for the development of CKD.

Effect of calcium carbonate combined with calcitonin on hypercalcemia in hemodialysis patients.

This short-term study assessed the efficacy and safety of calcium carbonate combined with calcitonin in the treatment of hypercalcemia in hemodialysis patients. Patients (n=64) on hemodialysis for chronic kidney disease for more than 6 months were included based on total serum calcium more than 10.5 mg/dL. All patients were randomized (1:1) to receive calcium carbonate combined with calcitonin (Group I) or lanthanum carbonate (Group II) for 12 weeks. Blood levels of calcium, phosphorus and intact parathyroid hormone (iPTH) were measured every month, bone mass density (BMD) and coronary artery calcium scores (CACS) were measured at 3 months. During the study period, serum calcium decreased from 10.72 ± 0.39 to 10.09 ± 0.28 mg/dL (P < 0.05), serum phosphorus decreased from 6.79 ± 1.05 to 5.46 ± 1.18 mg/dL (P < 0.05), and serum iPTH levels in the Group I and Group II were not significantly different from the baseline. There were no significant differences in CACS in either group. There were no significant differences in the BMD values between Group I and baseline. In Group II, the BMD values at the lumbar spine and femoral neck were significantly lower than those before the trial and significantly lower than the corresponding values of Group I (P<0.05). Calcium carbonate combined with calcitonin and lanthanum carbonate were equally effective in the suppression of hypercalcemia in hemodialysis patients. There were no serious treatment-related adverse events in treatment with calcium carbonate combined with calcitonin.

[Spectral study of N2O under pulsed DC discharge].

A new equipment of pulsed DC discharge supersonic molecular beam was set up for producing transient species. Thepulsed DC discharge can be used stably under 10 kV. In data collection using software, it can be utilized as gated integrators and averagers. Using this equipment, the processes of N2O discharge were studied. The emission spectra of N2O+ (A2sigma+ - X2IIi) were obtained. From the intensity of vibrational spectra, the vibrational populations of the N2O+ (A2sigma+ ) states were calculated. Compared with other results, A states of N2O+ depart even more from a Boltzmann distribution.

[Study on visible chemiluminescence from reaction of microwave discharge of CF4/Ar with carbon disulfide].

Using crossed molecular beam-chemiluminescence apparatus, visible chemiluminescence in the region of 300-900 nm was measured from the gas-phase reaction of microwave discharge of CF4 diluted in Ar with carbon disulfide at various pressures. The geometries and frequencies of possible reaction products were respectively investigated at the B3LYP/6-311 + + G (3df, 2pd) and MP2/6-311 + G(d, p) levels. Chemiluminescence spectrum was assigned to emission spectrum of the electronically excited states of F2S2. From the analysis of spectrum and reaction mechanism, it is proposed that carbon disulfur was dissociated by metastable Ar generated from microwave discharge. The electronically excited state of F2S2 was obtained from multistage reactions of the dissociative products with atoms F generated from microwave discharge.