Delayed intestinal perforation associated with peritoneal dialysis: A case report of maintaining dialysis after perforation.

Delayed intestinal perforation has various manifestations. For peritonitis with delayed treatment and multi-bacterial peritonitis, we should be alert to the occurrence of this rare complication. Abdominal CT examination and imaging results judgment based on clinical conditions are particularly important for diagnosis. Delayed intestinal perforation of peritoneal dialysis catheter is a rare but serious complication. We reported a 49-year-old patient who had been hospitalized twice within 3 months due to poor drainage of the peritoneal dialysis catheter. During the first hospitalization, peritoneal dialysis-related peritonitis was diagnosed, and a variety of bacterial infections were cultivated. However, at that time, the actual peritoneal dialysis catheter-related intestinal perforation was missed, and he was discharged after anti-infection treatment until a clinical cure was met. After more than 2 months of normal peritoneal dialysis after returning home, the patient again had poor drainage of the peritoneal dialysis catheter, accompanied by the outflow of yellowish-brown sediment. It was found that the peritoneal dialysis catheter had evidence of intestinal perforation. After the removal of the catheter and intestinal repair, he recovered and was discharged from the hospital and received long-term hemodialysis treatment. In the case of delayed intestinal perforation, peritoneal dialysis was maintained normally for more than 2 months, which was an unprecedented situation in previous case reports. In addition, we should be alert to the occurrence of this rare complication, especially when we find the occurrence of polybacterial Peritonitis. Abdominal CT examination and imaging results judgment based on clinical conditions are particularly important for diagnosis.

Architecturally designed sequential-release hydrogels.

Drug synergy has made significant strides in clinical applications in recent decades. However, achieving a platform that enables "single administration, multi-stage release" by emulating the natural physiological processes of the human body poses a formidable challenge in the field of molecular pharmaceutics. Hydrogels, as the novel generation of drug delivery systems, have gained widespread utilization in drug platforms owing to their exceptional biocompatibility and modifiability. Sequential drug delivery hydrogels (SDDHs), which amalgamate the advantages of hydrogel and sequential release platforms, offer a promising solution for effectively navigating the intricate human environment and accomplishing drug sequential release. Inspired by architectural design, this review establishes connections between three pivotal factors in SDDHs construction, namely mechanisms, carrier spatial structure, and stimuli-responsiveness, and three aspects of architectural design, specifically building materials, house structures, and intelligent interactive furniture, aiming at providing insights into recent developments in SDDHs. Furthermore, the dual-drug collocation and cutting-edge hydrogel preparation technologies as well as the prevailing challenges in the field were elucidated.

Downregulation of ARNTL in renal tubules of diabetic db/db mice reduces kidney injury by inhibiting ferroptosis.

BACKGROUND: The prevalence of ferroptosis in diabetic kidney tubules has been documented, yet the underlying mechanism remains elusive. The aim of this study was to ascertain the pivotal gene linked to ferroptosis and establish a novel target for the prevention and management of diabetic kidney disease (DKD). METHODS: Transcriptomics data (GSE184836) from DKD mice (C57BLKS/J) were retrieved from the GEO database and intersected with ferroptosis-related genes from FerrDb. Then, differentially expressed genes associated with ferroptosis in the glomeruli and tubules were screened. Gene ontology analysis and protein-protein interaction network construction were used to identify key genes. Western blotting and real-time quantitative polymerase chain reaction were employed to validate the expression in the same model. Aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL) expression in patients and mice with DKD was assessed using immunohistochemistry staining. ARNTL knockdown in C57BLKS/J mice was established and plasma malonaldehyde, superoxide dismutase, and renal pathology were analyzed. The efficacy of ARNTL knockdown was evaluated using proteomics analysis. Mitochondrial morphology was observed using transmission electron microscopy. RESULTS: ARNTL was screened by bioinformatics analysis and its overexpression verified in patients and mice with DKD. ARNTL knockdown reduced oxidative stress in plasma. Kidney proteomics revealed that ferroptosis was inhibited. The reduction of the classic alteration in mitochondrial morphology associated with ferroptosis was also observed. Gene set enrichment analysis demonstrated that the downregulation of the TGFß pathway coincided with a decrease in collagen protein and TGFß1 levels. CONCLUSIONS: The ferroptosis-associated gene ARNTL is a potential target for treating DKD.

Integrated proteomic and metabolomic profiling of urine of renal anemia patients uncovers the molecular mechanisms of roxadustat.

Roxadustat (FG-4592) is a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) prescribed to patients with low hemoglobin associated with chronic kidney disease. Due to the various HIF-mediated adaptive responses, FG-4592 has attracted significant interest for therapeutic use against various diseases. However, the clinical application of Roxadustat remains limited due to a lack of understanding of its underlying mechanisms. Herein, we performed label-free quantitative liquid chromatography with tandem mass spectrometry (LC-MS-MS) proteomics and un-targeted metabolomics to study the protein and metabolite alterations in the urine of renal anemia patients before and after Roxadustat therapy. The results were validated by parallel reaction monitoring (PRM). A total of 46 proteins (including 15 upregulated and 31 downregulated proteins) and 207 metabolites were significantly altered after Roxadustat treatment in urine samples obtained from renal anemia patients. Then, the altered proteins were further validated by PRM. Finally, proteomics combined with metabolomics analysis revealed that the Ras signalling pathway, cysteine and methionine metabolism, arginine and proline metabolism, and cholesterol metabolism were the main pathways altered by Roxadustat treatment. The multi-omics analysis revealed that Roxadustat could alter the protein expression and reverse the potential metabolic changes to exert hypotensive, lipid metabolic regulation, and renoprotective effects in clinical practice.

Label-free quantitative proteomic analysis of serum exosomes from patients of renal anemia: The Good and the Bad of Roxadustat.

BACKGROUND: Roxadustat is a new oral anti-renal anemia medication that works by stabilizing hypoxia-inducible factor (HIF) which can activate the expression of more than 100 genes in addition to genes related to anemia. However, the more potential molecular targets of roxadustat are not completely clear. Therefore, it is essential to further reveal its molecular targets to guide its clinical applications. METHODS: We performed label-free quantification and LC-MS/MS to study the proteomic alterations in serum exosome of renal anemia patients before and after roxadustat therapy. Results were validated by PRM. RESULTS: A total of 30 proteins were significantly changed after treatment with roxadustat. Among these proteins, 18 proteins were up-regulated (and 12 were down-regulated). The results are statistically significant (P < 0.05). Then, we validated the result by PRM, the results confirmed that TFRC, HSPA8, ITGB3, COL1A2, and YWHAZ were markedly upregulated, while ITIH2 and CFH were significantly downregulated upon treatment with roxadustat. CONCLUSIONS: TFRC and HSPA8 could be an important target of the action of roxadustat, and roxadustat may increase cardiovascular risk through its influence on platelet activation. Our results provide a theoretical basis for its wider clinical application and preventing expected side effects.

pH-Sensitive and Charge-Reversal Polymeric Nanoplatform Enhanced Photothermal/Photodynamic Synergistic Therapy for Breast Cancer.

As reported, breast cancer is one of the most common malignancies in women and has overtaken lung cancer as the most commonly diagnosed cancer worldwide by 2020. Currently, phototherapy is a promising anti-tumor therapy due to its fewer side effects, less invasiveness, and lower cost. However, its application in cancer therapeutics is limited by the incomplete therapeutic effect caused by low drug penetration and monotherapy. Herein, we built a charge-reversal nanoplatform (Ce6-PLGA@PDA-PAH-DMMA NPs), including polydopamine (PDA) and chlorin e6 (Ce6) for enhancing photothermal/photodynamic synergistic therapy. The PAH-DMMA charge-reversal layer enabled Ce6-PLGA@PDA-PAH-DMMA NPs to have long blood circulation at the normal physiological environment and to successfully realize charge reversal under the weakly acidic tumor microenvironment, improving cellular uptake. Besides, in vitro tests demonstrated that Ce6-PLGA@PDA-PAH-DMMA NPs had high photothermal conversion and greater anti-tumor activity than no charge-reversal nanoparticles, which overcame the limited tumor therapeutic efficacy of PTT or photodynamic therapy alone. Overall, the design of pH-responsive and charge-reversal nanoparticles (Ce6-PLGA@PDA-PAH-DMMA NPs) provided a promising approach for synergistic PTT/PDT therapy against breast cancer.

Case Report: Roxadustat in Combination With Rituximab Was Used to Treat EPO-Induced Pure Red Cell Aplasia.

Recombinant human erythropoietin (rHuEPO) is a drug given to patients who have low hemoglobin related to chronic kidney disease or other anemia-related diseases. Some patients who receive rHuEPO repeatedly develop anti-rHuEPO-neutralizing antibodies, leading to the occurrence of pure red cell aplasia (PRCA). PRCA associated with rHuEPO includes severe rHuEPO resistance, blood transfusion dependence, high serum ferritin, severe reticulocytopenia, and presence of anti-rHuEPO antibody. However, the optimal treatment of erythropoietin (EPO)-induced PRCA is unclear. Therapeutic options against it remain a major clinical challenge. Herein we report on 2 male patients with PRCA during rHuEPO treatment, who received a combination therapy of roxadustat plus rituximab but had completely different clinical outcomes. The results obtained in this study show that roxadustat in combination with rituximab could be one of the treatment options for EPO-induced PRCA, but the treatment efficacy can vary from one individual to another. Additionally, we recommend starting reticulocyte monitoring and immunosuppressive agent therapy as early as possible to shorten the course of the disease and improve the outcomes of the patients.

Frontiers in Preparations and Promising Applications of Mesoporous Polydopamine for Cancer Diagnosis and Treatment.

Polydopamine (PDA) is a natural melanin derived from marine mussels that has good biocompatibility, biodegradability, and photothermal conversion ability. As a new coating material, it offers a novel way to modify the surface of various substances. The drug loading capacity and encapsulation efficiency of PDA are greatly improved via the use of mesoporous materials. The abundant pore canals on mesoporous polydopamine (MPDA) exhibit a uniquely large surface area, which provides a structural basis for drug delivery. In this review, we systematically summarized the characteristics and manufacturing process of MPDA, introduced its application in the diagnosis and treatment of cancer, and discussed the existing problems in its development and clinical application. This comprehensive review will facilitate further research on MPDA in the fields of medicine including cancer therapy, materials science, and biology.

Differential expression study of circular RNAs in exosomes from serum and urine in patients with idiopathic membranous nephropathy.

INTRODUCTION: The aim of the study was to further explore the pathogenesis of idiopathic membranous nephropathy (IMN), gene-sequencing was used to analyze the differentially expressed circRNAs in exosomes of patients with IMN, which may lay the foundation for the research of circRNAs as a new class of exosome-based IMN diagnosis biomarkers. MATERIAL AND METHODS: Ten patients with IMN and ten normal controls were recruited as experimental subjects in our study. The exosomes were extracted from the collected serum and urine. Then, pure circRNAs were extracted from the exosomes with a series of enzymatic reactions. Afterwards, the significantly differentially expressed circRNAs were chosen by the method of gene-sequencing. RESULTS: Compared with normal controls, the circRNAs were reduced in the exosomes from serum of patients with IMN, which mostly originated from intron gene regions. Meanwhile, a total of 89 circRNAs were significantly differentially expressed, which were also mostly derived from intron gene regions, including 49 up-regulated and 40 down-regulated genes. However, the species were increased in the exosomes from the urine of patients with IMN compared to normal controls, and they mainly originated from exon gene regions. Simultaneously, 60 circRNAs were significantly differentially expressed, which primarily belonged to intron gene regions, including 54 up-regulated and 6 down-regulated regions. CONCLUSIONS: The significant differential and specific expression of circRNAs in the exosomes from patients with IMN were observed. For example, MUC3A, which originated from chr7:100550808|100551062, could be considered a potential diagnostic biomarker of IMN. Furthermore, these figures may be used as a reference or supplement in the research of the pathogenesis of IMN.

Analysis of differentially expressed microRNA of TNF-α-stimulated mesenchymal stem cells and exosomes from their culture supernatant.

INTRODUCTION: To analyze the microRNA expression of tumor necrosi factor α (TNF-α) stimulated mesenchymal stem cells (MSCs) and exosomes from their culture supernatant. MATERIAL AND METHODS: TNF-α (20 ng/ml) was used to stimulate MSCs, which were then regarded as TNF-α cells (TC), while unstimulated cells were the normal control cells (NCC). MSCs and their culture supernatant were harvested after 48 h. Subsequently, exosomes were isolated from culture supernatants with ExoQuick-TC and were divided into two groups, TNF-α exosomes (TE) and normal control exosomes (NCE). Then, the microRNAs were measured by high-throughput sequencing and the results were differentially analyzed. Finally, the correlation of the target genes corresponding to differently expressed microRNAs was analyzed by gene ontology (GO) and KEGG pathway analysis. RESULTS: High-throughput sequencing showed that the cellular compartment (TC vs. NCC) had 280 microRNAs. miR-146a-5p was a uniquely up-regulated microRNA (p < 0.001) and the most significantly down-regulated microRNA among the 279 microRNAs included was miR-150-5p (p < 0.001). There were 180 differentially expressed microRNAs in the exosome compartment (TE vs. NCE), where miR-146-5p (p < 0.001) was one of 176 upregulated microRNAs and miR-203b-5p (p < 0.001) was one of 4 downregulated microRNAs. Coincidentally, bioinformatics analysis showed that IRAK1 was a critical target gene of miR-146-5p related to the Toll-like receptor (TLR) signaling pathway. CONCLUSIONS: In contrast with the control group, there were significantly differentially expressed microRNAs in both MSCs and exosomes. Interestingly, miR-146a-5p was up-regulated in both comparative groups, and its target gene IRAK1 plays a crucial part in the TLR signaling pathway. These investigations demonstrate a new direction for subsequent inflammation mechanistic studies.

Analysis of microRNA expression profile by small RNA sequencing in Down syndrome fetuses.

Down syndrome (DS) is caused by trisomy of human chromosome 21 (Hsa21) and is associated with numerous deleterious phenotypes, including cognitive impairment, childhood leukemia and immune defects. Five Hsa21­derived microRNAs (i.e., hsa-miR-99a, let-7c, miR-125b-2, miR-155 and miR-802) are involved in variable phenotypes of DS. However, the changes involved in the genome-wide microRNA expression of DS fetuses under the influence of trisomy 21 have yet to be determined. To investigate the expression characteristic of microRNAs during the development of DS fetuses and identify whether another microRNA gene resides in the Hsa21, Illumina high-throughput sequencing technology was employed to comprehensively characterize the microRNA expression profiles of the DS and normal fetal cord blood mononuclear cells (CBMCs). In total, 149 of 395 identified microRNAs were significantly differentially expressed (fold change >2.0 and P<0.001) and 2 of 181 candidate novel microRNAs were identified as residing within the ̔DS critical region̓ of human chromosome 21 (chr21q22.2­22.3). Additionally, 7 of 14 Hsa21-derived microRNAs were detected, although not all seven were overexpressed in DS CBMCs compared with the control. Gene ontology enrichment analyses revealed that a set of abnormally expressed microRNAs were involved in the regulation of transcription, gene expression, cellular biosynthetic process and nucleic acid metabolic process. Significantly, most of the mRNA targets in these categories were associated with immune modulation (i.e., SOD1, MXD4, PBX1, BCLAF1 and FOXO1). Findings of the present study provided a considerable insight into understanding the expression characteristic of microRNAs in the DS fetal CBMCs. To the best of our knowledge, this is the first study to examine genome-wide microRNA expression profiles in the DS fetus. Differentially expressed microRNAs may be involved in hemopoietic abnormalities and the immune defects of DS fetuses and newborns.

The effect of esculentoside A on lupus nephritis-prone BXSB mice.

INTRODUCTION: EsA was reported to have the effect of modulating immune response, cell proliferation and apoptosis as well as anti-inflammatory effects in acute and chronic experimental models. However, the effects of EsA on LN remain poorly understood. To investigate the roles of EsA in LN, the effects of EsA were tested on BXSB mice, a SLE model, in which male SB/Le mice and female C57BL/6 mice were hybridized through recombinant inbred species. MATERIAL AND METHODS: Twenty four BXSB mice were divided into three groups. After 4 weeks, blood samples, urine samples and kidney tissues were collected. Measurement of cytokine levels was carried out using sandwich ELISA reagent kits. Apoptotic scores were obtained with a TUNEL assay. PCNA and Caspase-3 mRNA was detected using the In Situ Hybridization Detection Kit. RESULTS: The results demonstrated that compared with the control group, EsA administration markedly controlled urine protein excretion, improved renal function, alleviated kidney damage and promoted the apoptosis of glomerular intrinsic cells and renal tubular epithelial cells in animals of the treated group (p < 0.05). Meanwhile, EsA reduced the serum IL-6 and TNF-α levels (p < 0.05), inhibited the expression of PCNA and promoted the expression of caspase-3, Fas and FasL in animals of the treated group (p < 0.05). The effects of EsA on BXSB mice were similar to dexamethasone. CONCLUSIONS: All these findings indicated that EsA might play significant roles in the treatment of BXSB mice through modulation of inflammatory cytokines, inhibition of renal cell proliferation and induction of apoptosis. The special targets of EsA in lupus nephritis are worth further exploration.

Human umbilical mesenchymal stem cells attenuate the progression of focal segmental glomerulosclerosis.

Previous studies have suggested the potential of mesenchymal stem cells (MSCs) to repair damaged kidney diseases. However, the effect of human umbilical cord MSCs (HuMSCs) on the progression of focal segmental glomerulosclerosis (FSGS) remains poorly understood. Adriamycin-induced nephropathy is a rodent model of chronic kidney disease that has been studied extensively and has enabled a greater understanding of the processes underlying the progression of FSGS. This study aimed to investigate the role of HuMSCs on the progression of kidney disease using a model of adriamycin-induced nephropathy. Human MSCs were labeled with 5-bromo-2'-deoxyuridine to track their localization to the kidneys after infusion. Clinical parameters and histology suggested amelioration of FSGS in MSC-treated animals at 12 weeks, especially in those that received repeated doses. These results were associated with reduced serum interleukin (IL)-6 and tumor necrosis factor-α, transforming growth factor-ß levels, connective tissue growth factor messenger RNA expression and upregulated serum IL-10 levels. In short, this experiment found that HuMSCs improved kidney fibrosis and modulated the inflammatory response, suggesting that xenogenic transplantation of HuMSCs is a novel approach for improving the progression of FSGS and may be a promising therapeutic intervention in the future.

The effect of mesenchymal stromal cells on doxorubicin-induced nephropathy in rats.

BACKGROUND AIMS: The potential protective effects of mesenchymal stromal cells (MSCs) on some kidney diseases has been reported. However, the effect of MSCs on doxorubicin-induced nephropathy is still poorly understood. METHODS: Rats with doxorubicin-induced kidney injuries were treated with human cord-derived MSCs. Human MSCs were first labeled with 5-bromo-2'-deoxyuridine to track their homing in kidneys after infusion. RESULTS: Alleviation of proteinuria, decreased serum albumin, alleviation of lipid disorders and histologic alterations were found in rats 4 weeks after treatment with MSCs, particularly in rats that were given repeat doses. Decreases in serum levels of interleukin-6, tumor necrosis factor-α and prostaglandin E2 and decreases in messenger RNA levels of kidney tissue cylooxygenase-2 and EP4 were found in MSC-treated rats. MSC-treated rats also displayed an increase in serum interleukin-10 levels. CONCLUSIONS: These results indicate that MSCs ameliorate doxorubicin-induced kidney injuries and inflammation, suggesting a potential clinical treatment for inflammatory kidney diseases.

[Transplantation of human umbilical cord mesenchymal stem cells alleviates the progression of FSGS in rats].

OBJECTIVE: To study the protective effect of human umbilical cord mesenchymal stem cells (HuMSCs) on the progression of focal segmental glomerulosclerosis (FSGS) in rats. METHODS: HuMSCs were incubated by adherent culture. Sprague Dawley rats were randomly assigned to 3 groups: No intervention was applied to the rats of normal control group. Model group and transplant group were injected with adriamycin 4 mg/kg (on day 1) and 3.5 mg/kg (on day 8) via the tail vein, in addition, the transplant group rats were injected with 1 mL HuMSCs suspension (2×10(6);/mL) via the tail vein on day 1, 8, 15 and 22, whereas the model group rats were injected with the same dosage of DMEM in the same way. RESULTS: Transplantation of HuMSCs remarkably alleviated urine protein excretion and hypoalbuminemia, decreased serum cystatin C level and improved kidney damage and inflammatory cell infiltration in renal interstitium. Furthermore, HuMSCs decreased the expressions of TGF-ß1 and connective tissue growth factor (CTGF) mRNA in kidney and reduced the levels of serum IL-6 and TNF-α. CONCLUSION: Transplantation of HuMSCs could alleviate or inhibit the progression of FSGS in rats, of which the mechanism might be related to the regulation the synthesis and release of inflammatory mediators and the inhibition of inflammatory cell infiltration.

Characterization of the Phosphoproteome in SLE Patients.

Protein phosphorylation is a complex regulatory event that is involved in the signaling networks that affect virtually every cellular process. The protein phosphorylation may be a novel source for discovering biomarkers and drug targets. However, a systematic analysis of the phosphoproteome in patients with SLE has not been performed. To clarify the pathogenesis of systemic lupus erythematosus (SLE), we compared phosphoprotein expression in PBMCs from SLE patients and normal subjects using proteomics analyses. Phosphopeptides were enriched using TiO2 from PBMCs isolated from 15 SLE patients and 15 healthy subjects and then analyzed by automated LC-MS/MS analysis. Phosphorylation sites were identified and quantitated by MASCOT and MaxQuant. A total of 1035 phosphorylation sites corresponding to 618 NCBI-annotated genes were identified in SLE patients compared with normal subjects. Differentially expressed proteins, peptides and phosphorylation sites were then subjected to bioinformatics analyses. Gene ontology(GO) and pathway analyses showed that nucleic acid metabolism, cellular component organization, transport and multicellular organismal development pathways made up the largest proportions of the differentially expressed genes. Pathway analyses showed that the mitogen-activated protein kinase (MAPK) signaling pathway and actin cytoskeleton regulators made up the largest proportions of the metabolic pathways. Network analysis showed that rous sarcoma oncogene (SRC), v-rel reticuloendotheliosis viral oncogene homolog A (RELA), histone deacetylase (HDA1C) and protein kinase C, delta (PRKCD) play important roles in the stability of the network. These data suggest that aberrant protein phosphorylation may contribute to SLE pathogenesis.