Efficacy of prednisone combined with mycophenolate mofetil for immunoglobulin A nephropathy with moderate-to-severe renal dysfunction.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is a common form of chronic glomerulonephritis. Currently, IgAN is one of the main causes of chronic renal failure in China; its prognosis varies greatly between patients, with renal function at the time of diagnosis and prognosis being strongly correlated. Mycophenolate mofetil (MMF) is a drug with a good immunomodulatory effect and is commonly used clinically. However, its effects in IgAN have not yet been clearly demonstrated. Therefore, herein, we retrospectively compared the effectiveness and safety of prednisone alone or combined with MMF for the treatment of primary IgAN with moderate-to-severe renal impairment. AIM: To evaluate the effectiveness and safety of prednisone and MMF in treating IgAN with moderate-to-severe renal dysfunction. METHODS: Between January 2011 and December 2020, 200 patients with moderate-to-severe IgAN were included in this study, all of whom were admitted to Wuxi People's Hospital affiliated with Nanjing Medical University. All patients underwent a renal puncture biopsy, which revealed primary IgAN with a glomerular filtration rate (GFR) of 30-60 mL/min. The patients were divided into a glucocorticoid therapy group (GTG) and an immunosuppressive therapy group (ITG) according to the different treatment regimens, with 100 patients in each group. Based on general treatments, such as angiotensin-converting enzyme inhibitors/ angiotensin receptor blockers, patients in the GTG were administered prednisone 0.5-0.8 mg/ (kg·d-1) for 4-8 wk, which was reduced by 5 mg every two weeks until the maintenance(30 mg/d) dose was reached and maintained for 12 mo. In the ITG, MMF was administered at 1.0 g/d for 6-12 mo, followed by a maintenance dosage of 0.5 g/d for 12 mo. Age, sex, blood pressure, 24-h urinary egg white measurement, serum creatinine (Scr), blood uric acid, blood albumin, blood potassium (K), hemoglobin, GFR, alanine aminotransferase, total cholesterol (T-CHO), fasting blood glucose, and body mass index were recorded. The 24-h urinary protein, Scr, and GFR levels were recorded 3, 6, 9, and 12 mo after treatment. Follow-up data were also collected. RESULTS: No discernible differences existed between the two groups in terms of age, sex, blood pressure, creatinine, 24-h urinary protein level, GFR, or other biochemical indicators at the time of enrollment. Both regimens significantly reduced the 24-h urinary protein quantitation and stabilized renal function. Nine months after treatment, the 24-h urinary protein and Scr of the ITG decreased more significantly than those of the GTG. By the 12th month of treatment, the 24-h urinary protein and Scr in both groups continued to decrease compared to those by the 9th month. In addition, the overall response rate in the ITG was significantly higher than that in the GTG. The occurrence of side effects did not vary significantly between the two regimens; however, endpoint events were significantly more common in the GTG than in the ITG. The follow-up time for the GTG was noticeably lower than that for the ITG. CONCLUSION: Prednisone combined with MMF was effective for the treatment of IgAN with moderate-to-severe renal dysfunction.

The Antitumour Activity of a Curcumin and Piperine Loaded iRGD-Modified Liposome: In Vitro and In Vivo Evaluation.

Lung cancer is one of the most common cancers around the world, with a high mortality rate. Despite substantial advancements in diagnoses and therapies, the outlook and survival of patients with lung cancer remains dismal due to drug tolerance and malignant reactions. New interventional treatments urgently need to be explored if natural compounds are to be used to reduce toxicity and adverse effects to meet the needs of lung cancer clinical treatment. An internalizing arginine-glycine-aspartic acid (iRGD) modified by a tumour-piercing peptide liposome (iRGD-LP-CUR-PIP) was developed via co-delivery of curcumin (CUR) and piperine (PIP). Its antitumour efficacy was evaluated and validated via in vivo and in vitro experiments. iRGD-LP-CUR-PIP enhanced tumour targeting and cellular internalisation effectively. In vitro, iRGD-LP-CUR-PIP exhibited enhanced cellular uptake, suppression of tumour cell multiplication and invasion and energy-independent cellular uptake. In vivo, iRGD-LP-CUR-PIP showed high antitumour efficacy, mainly in terms of significant tumour volume reduction and increased weight and spleen index. Data showed that iRGD peptide has active tumour targeting and it significantly improves the penetration and cellular internalisation of tumours in the liposomal system. The use of CUR in combination with PIP can exert synergistic antitumour activity. This study provides a targeted therapeutic system based on natural components to improve antitumour efficacy in lung cancer.

Occurrence and potential release of heavy metals in female underwear manufactured in China: Implication for women's health.

Underwear is a potential source of women's exposure to heavy metals owing to its direct contact with the skin, especially the skin of the vagina and vulva, which has a strong absorptive capacity. However, information regarding the prevalence of metals in female underwear, and its potential hazards, remains scarce. In the present study, we examined the concentrations and potential release of Cr, Co, Ni, Cu, As, Cd, Sb, and Pb in brassieres and briefs manufactured in China. We detected higher levels of Pb and moderate levels of other metals, relative to the metal levels reported for other textiles in the literature. Cu, As, Ni and Cd, had higher migration rates (MRs) from the underwear, with medians of 100%, 100%, 30.1%, and 20.7%, respectively. The median MRs of the other metals were in the range 1.07%-15.7%. On the whole, the total and extractable concentrations of these metals differed by item and fabric type. The pollution of raw materials and the use of chemical additives containing metals commonly contributed to the metals in the underwear. On the basis of the exposure estimation, the non-carcinogenic risks posed by the underwear metals were acceptable, but the carcinogenic risks from the metals in 5.18% of brassiere samples exceeded the acceptable level.

Fabrication of PbO2 Electrodes with Different Doses of Er Doping for Sulfonamides Degradation.

In the present study, PbO2 electrodes, doped with different doses of Er (0%, 0.5%, 1%, 2%, and 4%), were fabricated and characterized. Surface morphology characterization by SEM-EDS and XRD showed that Er was successfully doped into the PbO2 catalyst layer and the particle size of Er-PbO2 was reduced significantly. Electrochemical oxidation of sulfamerazine (SMR) in the Er-PbO2 anode system obeyed te pseudo first-order kinetic model with the order of 2% Er-PbO2 > 4% Er-PbO2 > 1% Er-PbO2 > 0.5% Er-PbO2 > 0% PbO2. For 2% Er-PbO2, kSMR was 1.39 h-1, which was only 0.93 h-1 for 0% PbO2. Effects of different operational parameters on SMR degradation in 2% Er-PbO2 anode system were investigated, including the initial pH of the electrolyte and current density. Under the situation of an initial pH of 3, a current density of 30 mA·cm-2, a concentration of SMR 30 mg L-1, and 0.2 M Na2SO4 used as supporting electrolyte, SMR was totally removed in 3 h, and COD mineralization efficiency was achieved 71.3% after 6 h electrolysis. Furthermore, the degradation pathway of SMR was proposed as combining the active sites identification by density functional calculation (DFT) and intermediates detection by LC-MS. Results showed that Er-PbO2 has great potential for antibiotic wastewater treatment in practical applications.

Occurrence and health implications of heavy metals in preschool children's clothing manufactured in four Asian regions.

Clothing may be a potential contributor to body metal burden in children. However, available information on heavy metals in children's clothing is extremely limited and the associated health risks remain poorly understood. This study investigated the concentrations of Pb, Cd, Co, Zn, Cr, As, Cu and Ni in new preschool children's clothing manufactured in four Asian regions. The children's clothing had higher levels of Ni and Cr but lower levels of Pb and Cd in comparison to the concentrations reported in other textile products. The concentrations of Cd were higher in the black clothing than those in the white and color samples. The non-cotton samples contained higher Co concentrations. The Pb concentrations in the samples manufactured in China were significantly higher than those in the other three regions. We estimated the dermal exposure doses for these metals and calculated the associated risks. The results indicated that the health risks from exposure to these metals in the children's clothing were acceptable. However, more research is required to investigate heavy metals and the associated risks in child clothing due to the increasing complexity of their materials and manufacturing processes.

Macrophage­derived exosomal miRNA­155 promotes tubular injury in ischemia­induced acute kidney injury.

Tubule injury is a characteristic pathological feature of acute kidney injury (AKI) and determines the prognosis of kidney disease. However, the exact mechanism of tubule injury remains largely unclear. In the present study, the exact mechanism of tubule injury was investigated. Bilateral renal ischemia/reperfusion (I/R) injury (I/RI) was induced in mice and exosome secretion inhibitor GW4869 and miRNA­155 inhibitor were used. In addition, the exosomal microRNA (miR)­155­mediated cross­talk between macrophage and tubular cells was also investigated. It was determined that tubular injury was observed in an I/R­induced AKI model, which was closely associated with macrophage infiltration. Interestingly, blocking exosome production using GW4869 ameliorated tubular injury in I/R­induced AKI. Mechanistically, once released, activated macrophage­derived exosomal miR­155 was internalized by tubular cells, resulting in increased tubule injury through targeting of suppressor of cytokine signaling­1 (SOCS­1), a negative regulator of NF­κB signaling. In addition, a dual­luciferase reporter assay confirmed that SOCS­1 was the direct target of miR­155 in tubular cells. Notably, injection of these miR­155­enriched exosomes into renal parenchyma resulted in increased tubule injury in vivo. Thus, the present study demonstrated that exosomal miR­155 mediated the communication between activated macrophages and injured tubules, leading to progression of AKI, which not only provide novel insights into the pathophysiology of AKI but also offer a new therapeutic strategy for kidney diseases.

Identification of CCL19 as a Novel Immune-Related Biomarker in Diabetic Nephropathy.

Diabetic nephropathy (DN) is one of the major microvascular complications in diabetic patients and the leading cause of end-stage renal disease (ESRD). Previous studies found that immune-related genes and immune cell infiltration play important roles in the pathogenesis and development of DN. Therefore, this study aimed to explore immune-related biomarkers in DN. In this research, three microarray datasets that included 18 DN and 28 healthy tubule samples were downloaded and integrated as the training set to identify differentially expressed immune-related genes (DEIGs). A total of 63 DEIGs were identified, and most upregulated DEIGs were primarily involved in the inflammatory response and chemokine-mediated signaling pathways. The Microenvironment Cell Populations-counter (MCP-counter) algorithm was then used to estimate the abundance of infiltrated immune and stromal cell populations. According to DEIG, weighted gene coexpression network and protein-protein network analyses, CCL19 was identified as the hub immune-related biomarker. Moreover, the upregulated level of CCL19 was confirmed in other independent datasets as well as in in vitro experiments with high glucose. In summary, this study provides novel insights into the pathogenesis of diabetic nephropathy and identifies CCL19 as a potential critical gene of DN.

The unique molecular mechanism of diabetic nephropathy: a bioinformatics analysis of over 250 microarray datasets.

BACKGROUND/AIMS: Diabetic nephropathy (DN) is one of the main causes of end-stage kidney disease worldwide. Emerging studies have suggested that its pathogenesis is distinct from nondiabetic renal diseases in many aspects. However, it still lacks a comprehensive understanding of the unique molecular mechanism of DN. METHODS: A total of 255 Affymetrix U133 microarray datasets (Affymetrix, Santa Calra, CA, USA) of human glomerular and tubulointerstitial tissues were collected. The 22 215 Affymetrix identifiers shared by the Human Genome U133 Plus 2.0 and U133A Array were extracted to facilitate dataset pooling. Next, a linear model was constructed and the empirical Bayes method was used to select the differentially expressed genes (DEGs) of each kidney disease. Based on these DEG sets, the unique DEGs of DN were identified and further analyzed using gene ontology and pathway enrichment analysis. Finally, the protein-protein interaction networks (PINs) were constructed and hub genes were selected to further refine the results. RESULTS: A total of 129 and 1251 unique DEGs were identified in the diabetic glomerulus (upregulated n = 83 and downregulated n = 203) and the diabetic tubulointerstitium (upregulated n = 399 and downregulated n = 874), respectively. Enrichment analysis revealed that the DEGs in the diabetic glomerulus were significantly associated with the extracellular matrix, cell growth, regulation of blood coagulation, cholesterol homeostasis, intrinsic apoptotic signaling pathway and renal filtration cell differentiation. In the diabetic tubulointerstitium, the significantly enriched biological processes and pathways included metabolism, the advanced glycation end products-receptor for advanced glycation end products signaling pathway in diabetic complications, the epidermal growth factor receptor (EGFR) signaling pathway, the FoxO signaling pathway, autophagy and ferroptosis. By constructing PINs, several nodes, such as AGR2, CSNK2A1, EGFR and HSPD1, were identified as hub genes, which might play key roles in regulating the development of DN. CONCLUSIONS: Our study not only reveals the unique molecular mechanism of DN but also provides a valuable resource for biomarker and therapeutic target discovery. Some of our findings are promising and should be explored in future work.

Evaluation of anemia, malnutrition, mineral, and bone disorder for maintenance hemodialysis patients based on bioelectrical impedance vector analysis (BIVA).

BACKGROUND: ESRD (End-stage renal disease) treatment is a comprehensive medical process and requires numerous serological biochemical tests (SBTs) in diagnosis. To reduce these invasive, expensive, cumbersome, and time-consuming SBTs, there is a need to develop an alternative serological biochemical composition evaluation method. Bioelectrical impedance analysis (BIA) is affected by body's chemical and physical components, which might be correlated with serological biochemical composition and can be potentially used to evaluate biochemical composition in hemodialysis patient treatments. In this work, the relationship of classic and specific bioelectrical impedance vector analysis (BIVA) with major serological biochemical indexes in maintenance hemodialysis (MHD) patients was examined. METHODS: Bioelectrical and biochemical datasets were measured from 280 women and 408 men and formed 3872 effective biochemical-bioelectrical records in total. Statistical analysis was performed. RESULTS: The results show that BIVA vectors have strong relationship with phosphorus, hemoglobin, and PTH in both male and female groups. Strong correlation was also observed between Ca, albumin, CHOL, LDLC, and BIVA vectors in the male group. In the female group, a significant correlation was observed between classic BIVA values and NT-proBNP. SVM models are effective for classifying biochemical indexes. CONCLUSIONS: The obtained correlations and SVM classification models imply that BIVA can be used as a preliminary tool to evaluate and classify the degree of anemia, malnutrition, fluid overload, and mineral and bone disorder (MBD) in MHD patients by reducing the number of SBTs.

Sodium-glucose cotransporter 2 inhibition suppresses HIF-1α-mediated metabolic switch from lipid oxidation to glycolysis in kidney tubule cells of diabetic mice.

Inhibition of sodium-glucose cotransporter 2 (SGLT2) in the proximal tubule of the kidney has emerged as an effective antihyperglycemic treatment. The potential protective role of SGLT2 inhibition on diabetic kidney disease (DKD) and underlying mechanism, however, remains unknown. In this study, metabolic switch was examined using kidney samples from human with diabetes and streptozocin (STZ)-induced experimental mouse model of diabetes treated with or without SGLT2 inhibitor dapagliflozin. Results were further validated using primarily cultured proximal tubule epithelial cells. We found that DKD development and progression to renal fibrosis entailed profound changes in proximal tubule metabolism, characterized by a switch from fatty acid utilization to glycolysis and lipid accumulation, which is associated with the increased expression of HIF-1α. Diabetes-induced tubulointerstitial damage, such as macrophage infiltration and fibrosis, was significantly improved by dapagliflozin. Consistent with the effects of these beneficial interventions, the metabolic disorder was almost completely eliminated by dapagliflozin. The increased level of HIF-1α in renal proximal tubule was nearly nullified by dapagliflozin. Moreover, dapagliflozin protects against glucose-induced metabolic shift in PTCs via inhibiting HIF-1α. It suggests that SGLT2 inhibition is efficient in rectifying the metabolic disorder and may be a novel prevention and treatment strategy for kidney tubule in DKD.

[Effects of radiotherapy upon progression of crescentic glomerulonephritis in rats].

OBJECTIVE: To study the effects of radiotherapy upon progression of crescentic glomerulonephritis in rats. METHODS: Male SD rats were divided into three groups: (1) control (n=12), sham-operation; (2) crescentic glomerulonephritis (n=23), intravenously inject with nephrotoxic serum (NTS); (3) radiotherapy (n=55), a single low-dose irradiation of 0.5 Gy X-ray to both kidneys at Days 6, 13, 20 and 27 after NTS injection, and sacrificed at different time points among control and crescentic glomerulonephritis rats. Radiotherapy rats have received local kidney irradiation at Days 6, 13, 20 and 27 after bolus NTS injection and would be referred to as NTS7dRa1d, NTS14dRa1d, NTS21dRa1d and NTS28dRa1d, respectively. RESULTS: For NTS7dRa1d and NTS14dRa1d rats of radiotherapy, the levels of serum creatinine, glomerular hypercellularity, crescents and global sclerosis were significantly lower at Days 8 (P < 0.05), 15, and 22 post-irradiation as compared with group of crescentic glomerulonephritis of similar time intervals (P < 0.01). The extent of tubulointerstitial damage was also reduced, and radiotherapy associated histological improvements were accompanied by reduced macrophage infiltration in glomeruli and interstitium. The numbers of PCNA- and ED1-positive cells were reduced in the kidneys at Day 1 postirradiation in NTS7dRa1d and NTS14dRa1d rats as compared with group of crescentic glomerulonephritis at similar time intervals (P < 0.05). A larger number of TUNEL-positive cells were noted at Day 1 postirradiation in rats irradiated at Days 6 & 13 after NTS injection as compared with group of crescentic glomerulonephritis at similar time intervals (P < 0.05). With regards to immunostaining for macrophages ED1 and TUNEL, serial sections of irradiated nephritic kidney showed that fewer ED1-positive macrophages were stained for TUNEL. As evaluated expression of active caspases 3 & 7 was noted in irradiated kidneys as compared with the corresponding group of crescentic glomerulonephritis at similar time intervals. Western blot analysis showed marked increase in the expression of active caspase 3 & 7 in irradiated kidneys as compared with NTS injection only the expression of a marked increase in the expression of p53 protein, closely related to radiation-induced apoptosis, was also observed in irradiated kidneys as compared with NTS injection only. CONCLUSION: Radiotherapy inhibits the progression of experimental crescentic glomerulonephritis through inducing apoptosis by a p53-dependent pathway.