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.

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.

Skeletal Network Enabling New-Generation Thermoplastic Vulcanizates.

Upcycling of cross-linked rubbers is pressing. The introduction of dynamic covalent bonds into the networks is a popular tactic for recycling thermosetting polymers, but it is very challenging to integrate engineering performance and continuous yet stable reprocessability. Based on traditional rubber formulations, herein, a straightforward strategy is presented for constructing a skeletal network (SN) through interfacial crosslinking and percolation of rubbery granules in a rubber matrix. Rapid exchange reactions involving dynamic interfacial sulfides realize repeated "fragmentation and healing" in the solid-state and consequent reconfiguration of the SN topology of the elastomer, thus endowing the resultant SN elastomer with continuous yet stable re-extrudability. These SN elastomers with hierarchical structures exhibit high gel contents, high resilience, low creep, and reinforcibility competitive to traditional vulcanizates. Specifically, SN elastomers exhibit better overall performance than commercial thermoplastic vulcanizates (TPVs) materials. Overall, a new concept of thermoplastic vulcanizates is proposed, which will promote the sustainable development of rubbers.

Docetaxel suppressed cell proliferation through Smad3/HIF-1α-mediated glycolysis in prostate cancer cells.

BACKGROUND: Tumor glycolysis is a critical event for tumor progression. Docetaxel is widely used as a first-line drug for chemotherapy and shown to have a survival advantage. However, the role of docetaxel in tumor glycolysis remained poorly understood. METHODS: The effect of Docetaxel in tumor glycolysis and proliferation were performed by CCK-8, Western blotting, real-time PCR, glucose, and lactate detection and IHC. ChIP and luciferase assay were used to analyze the mechanism of Docetaxel on Smad3-mediated HIF-1α transactivity. RESULTS: In this study, we showed that docetaxel treatment led to a significant inhibition of cell proliferation in prostate cancer cells through PFKP-mediated glycolysis. Addition of lactate, a production of glycolysis, could reverse the inhibitory effect of docetaxel on cell proliferation. Further analysis has demonstrated that phosphorylation of Smad3 (Ser213) was drastically decreased in response to docetaxel stimulation, leading to reduce Smad3 nuclear translocation. Luciferase and Chromatin immunoprecipitation (ChIP) analysis revealed that docetaxel treatment inhibited the binding of Smad3 to the promoter of the HIF-1α gene, suppressing transcriptional activation of HIF-1α. Moreover, ectopic expression of Smad3 in prostate cancer cells could overcome the decreased HIF-1α expression and its target gene PFKP caused by docetaxel treatment. Most importantly, endogenous Smad3 regulated and interacted with HIF-1α, and this interaction was destroyed in response to docetaxel treatment. What's more, both HIF-1α and PFKP expression were significantly reduced in prostate cancer received docetaxel treatment in vivo. CONCLUSION: These findings extended the essential role of docetaxel and revealed that docetaxel inhibited cell proliferation by targeting Smad3/HIF-1α signaling-mediated tumor Warburg in prostate cancer cells. Video Abstract.

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.

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.

Generic Method to Create Segregated Structures toward Robust, Flexible, Highly Conductive Elastomer Composites.

Electrically and thermally conductive polymer composites are extensively used in our daily life. It is of great significance to fulfill the conductivity requirement while maintaining desirable mechanical performance. An efficient solution to achieve this goal is to construct segregated structures in polymer composites by confining fillers into the interstitial areas among polymer domains. Thus far, it still remains a challenge to create segregated structures in cross-linked polymeric networks. Herein, we report a facile methodology to construct segregated structures in sulfur-cured rubbers using an industrially accessible process toward robust, flexible, highly conductive elastomer composites. Specifically, natural rubber granules (NR-RGs) with reactive di- and polysulfides on the surface are fabricated and then mixed with NR gum, carbon nanotubes (CNTs), and curing additives, followed by compression molding to yield two-phase separate composites. In the composites, CNTs are selectively dispersed in the continuous NR phase due to the volume exclusion effect caused by the separate NR-RG phase, leading to overwhelming electrical conductivity compared to the counterparts with randomly dispersed CNTs. In addition, NR-RGs can serve as novel reinforcement for NR, imparting the composites with remarkably improved modulus and retained stretchability. The simultaneously improved electrical conductivity and mechanical properties are due to the strong interfacial adhesion between the NR matrix and NR-RGs, as the di- and polysulfides on the surface of NR-RGs can participate in the cross-linking reactions of NR gum and enable the establishment of covalent bonding across the interfaces. The universality of this approach in preparing segregated composites with a combination of high conductivities and robust mechanical properties is demonstrated using other diene rubbers as the matrix and boron nitride as the filler.

Engineering Segregated Structures in a Cross-Linked Elastomeric Network Enabled by Dynamic Cross-Link Reshuffling.

Construction of segregated structures in polymer composites is an efficient way to improve the electrical conductivity and reduce the percolation threshold by confining conductive fillers into the interstitial areas between polymer domains. Yet, it remains a great challenge to engineer segregated structures into thermosets as the cross-linked structure prohibits the "sintering" of polymer domains into a coherent material. Thus far, the state of art approaches to create segregated network in cross-linked polymers involve tedious procedures and are limited to latex mixing technology. Here, inspired by solid state plasticity of vitrimers, we present a simple method to create segregated structures in covalently cross-linked networks by compression molding of conductive filler-coated vitrimer granules. Specifically, dynamic boronic ester-cross-linked styrene-butadiene rubber vitrimers was ground into granules and then mechanically mixed with carbon nanotubes (CNTs) to coat CNTs onto vitrimer granules, followed by hot-press molding. During the molding process, the transesterifications of boronic esters enable cross-linked granules to adhere together through molecular bonding, and the high viscosity of granules forces CNTs to selectively localize at their boundary region. As a result, coherently segregated composites with an ultralow percolation threshold, good flexibility, and healing capability are obtained. With this example, we envisage that this work provides a conceptual method to create segregated structures in cross-linked polymers.

Tissue-engineered parathyroid gland and its regulatory secretion of parathyroid hormone.

Parathyroid glands (PTGs) are important endocrine organs being mainly responsible for the secretion of parathyroid hormone (PTH) to regulate the balance of calcium (Ca) /phosphorus (P) ions in the body. Once PTGs get injured or removed, their resulting defect or loss of PTH secretion should disturb the level of Ca/P in blood, thus damaging other related organs (bone, kidney, etc.) and even causing death. Recently, tissue-engineered PTGs (TE-PTGs) have attracted lots of attention as a potential treatment for the related diseases of PTGs caused by hypoparathyroidism and hyperparathyroidism, including tetany, muscle cramp, nephrolithiasis, nephrocalcinosis, and osteoporosis. Although great progress has been made in the establishment of TE-PTGs with an effective strategy to integrate the key factors of cells and biomaterials, its regulatory secretion of PTH to mimic its natural rhythms in the body remains a huge challenge. This review comprehensively describes an overview of PTGs from physiology and pathology to cytobiology and tissue engineering. The state of the arts in TE-PTGs and the feasible strategies to regulate PTH secretion behaviors are highlighted to provide an important foundation for further investigation.

Fluorescence Sensor Array for Discrimination of Urine Proteins and Differentiation Diagnosis of Urinary System Diseases.

Successful discrimination of complex biological samples by sensor array remains a challenging problem. Herein, a three-unit fluorescence sensor array was fabricated using fluorescent molecules, which interact with proteins and generate rich response signals, to realize the discrimination of urinary proteins. As a proof of concept, six urinary proteins were selected as analytes. Results showed 100% accuracy in differentiation and quantitative discrimination of every single protein and their complex mixtures. Moreover, protein profiles of urine samples from healthy people and patients with different urinary diseases, including tubular injury (TI), diabetic nephropathy (DN), and nephropathy (Nep), were well distinguished.

Facile Strategy for the Biomimetic Heterogeneous Design of Elastomers with Mechanical Robustness, Malleability, and Functionality.

It remains challenging to simultaneously realize mechanical robustness, malleability, and functionality in elastomers via facile yet efficient methods. Herein, a simple strategy for the biomimetic heterogeneous design is proposed to achieve mechanically strong, malleable, and functionalized elastomers. We demonstrate the strategy by straightforward mechanical mixing of a highly cross-linked vitrimeric elastomer with a homogeneous gum and subsequent curing, resulting in heterogeneous vitrimeric elastomers (hetero-VEs). The hetero-VEs comprise two phases: a hard phase with dense cross-links and a soft matrix with few cross-links, with excellent interface between the two phases. The hard phases can be deformed upon loading, dissipating energy, which significantly improves the overall mechanical performance of the hetero-VEs. When conductive fillers are incorporated into the soft matrix, due to the volume exclusion effect of the hard phases, the resultant hetero-VEs exhibit high conductivity with a small fraction of fillers. In view of the facile and generic preparation process, this strategy should be a promising way to reinforce and functionalize many vitrimeric elastomer systems.

Catalyst-Free Metathesis of Cyclic Acetals and Spirocyclic Acetal Covalent Adaptable Networks.

Due to the exchangeability of dynamic covalent bonds in the covalent adaptable networks (CANs) at elevated temperature, they possess recyclability while still maintaining many of the superior properties of thermosets. The exploration of dynamic covalent chemistry is of great significance to the expansion of CANs library and hence the sustainable development of thermosets. In this work, we discovered that, in absence of catalyst, the direct metathesis of the cyclic acetals proceeds while the acyclic acetals cannot. The metathesis kinetics of the cyclic acetals were fully revealed with model compounds. For the CANs demonstration, a series of cross-linked spirocyclic acetal polymers with excellent reprocessability, high thermal stability, and high refractivity were prepared via thiol-ene click polymerization. We envisage that the uncovering of the catalyst-free metathesis of cyclic acetals will enrich the dynamic chemistry of acetals and greatly promote the development of acetal-based CANs and their potential applications in optical devices.

Design of next-generation cross-linking structure for elastomers toward green process and a real recycling loop.

Currently adopted cross-linking methods in rubber industry are suffering from variable persistent issues, including the utilization of toxic curing packages, release of volatile organic compounds (VOCs) and difficulties in the recycling of end-of-life materials. It is of great importance to explore a green cross-linking strategy in the area. Herein, we report a new "green" strategy based on hydrolyzable ester cross-links for cross-linking diene-typed elastomers. As a proof of concept, a commercial carboxylated nitrile rubber (XNBR) is efficiently cross-linked by a bio-based agent, epoxidized soybean oil (ESO), without any toxic additives. ESO exhibits an excellent plasticization effect and excellent scorch safety for XNBR. The cross-linking density and mechanical properties of the ESO-cured XNBR can be manipulated in a wide range by changing simply varying the content of ESO. In addition, zinc oxide (ZnO) performs as a catalyst to accelerate the epoxide opening reaction and improve the cross-linking efficiency, serving as reinforcement points to enhance the overall mechanical properties of the ESO-cured XNBR. Furthermore, the end-of-life elastomer materials demonstrate a closed-loop recovery by selectively cleaving the ester bonds, resulting in very high recovery of the mechanical performance of the recycled composites. This strategy provides an unprecedented green avenue to cross-link diene elastomers and a cost-effective approach to further recycle the obtained cross-linked elastomers at high efficiency.

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.

Uniaxial Stretching-Induced Alignment of Carbon Nanotubes in Cross-Linked Elastomer Enabled by Dynamic Cross-Link Reshuffling.

The fascinating properties of carbon nanotubes (CNTs) make them highly promising in fabricating polymer composites. Yet, the property enhancements of polymer/CNTs composites remain far behind the theoretical predictions. A critical issue to resolve this dilemma is to align CNTs in polymer matrices. Thus far, the state of art approaches to create CNT alignment either require complicated preparation processes and specific apparatuses, or is limited to thermoplastic polymers. Here, inspired by the network rearrangement ability of vitrimer in the solid state, we bring forth a facile methodology to align CNT in covalently cross-linked polymers by uniaxially stretching dynamic. Specifically, dynamic boronic ester bond-cross-linked epoxidized natural rubber/CNTs vitrimer composites with randomly dispersed CNTs are prepared, which are able to rearrange the network topologies and release stress at elevated temperatures through boronic ester transesterifications. The alignment of CNTs is performed by the uniaxial stretching of the composites and subsequent cross-link reshuffling at elevated temperatures, which results in anisotropic composites with remarkably enhanced mechanical properties and reduced electrical conductivity along the stretching direction. Furthermore, the mechanical properties of the composites can be readily adjusted by changing the applied strain, relaxation time and temperature due to the modulated CNT alignment degree. With this example, we envisage that this work offers a conceptual and facile approach to align anisotropic fillers in covalently cross-linked polymers.

Integrating Sacrificial Bonds into Dynamic Covalent Networks toward Mechanically Robust and Malleable Elastomers.

Vitrimers are a class of covalently cross-linked polymers that have drawn great attention due to their fascinating properties such as malleability and reprocessability. The state of art approach to improve their mechanical properties is the addition of fillers, which, however, greatly restricts the chain mobility and impedes network topology rearrangement, thereby deteriorating the dynamic properties of vitrimer composites. Here, we demonstrate that the integration of sacrificial bonds into a vitrimeric network can remarkably enhance the overall mechanical properties while facilitating network rearrangement. Specifically, commercially available epoxidized natural rubber is covalently cross-linked with sebacic acid and simultaneously grafted with N-acetylglycine (NAg) through the chemical reaction between epoxy and carboxyl groups, generating exchangeable ß-hydroxyl esters and introducing amide functionalities into the networks. The hydrogen bonds arising from amide functionalities act in a sacrificial and reversible manner, that is, preferentially break prior to the covalent framework and undergo reversible breaking and reforming to dissipate mechanical energy under external load, which leads to a rarely achieved combination of high strength, modulus, and toughness. The topology rearrangement of the cross-linked networks can be accomplished through transesterification reactions at high temperatures, which is accelerated with the increase of grafting NAg amount due to the dissociation of transient hydrogen bonds and increase of the ester concentration in the system.

Elastomer Reinforced with Innate Sulfur-Based Cross-Links as Ligands.

Although the incorporation of sacrificial bonds into an elastomer is an effective way to provide a combination of high strength and high fracture toughness, this method normally involves complicated chemical processes. The coordination between metal ions and polysulfides has been documented. However, the potential of polysulfide structures in vulcanizates as ligands has long been neglected. Using innate sulfur-based cross-links, we show how weak and nonpolar elastomers achieve significant reinforcement without modification of the backbone. By simply soaking vulcanizates into solutions containing metal ions, dual ions are simultaneously introduced into the vulcanizate to generate coordinations with different bond strengths, resulting in an unprecedented high modulus. Overall, this work presents a universal yet high-efficiency reinforcing strategy to prepare high-performance elastomers without additional chemical modifications, which should promote comprehensive research and industrial application of sacrificial bond strategies for elastomers.

Toughening Elastomers Using a Mussel-Inspired Multiphase Design.

It is a challenge to simultaneously achieve high stretchability, high modulus, and recoverability of polymers. Inspired by the multiphase structure of mussel byssus cuticles, we circumvent this dilemma by introducing a deformable microphase-separated granule with rich coordination into a ductile rubber network. The granule can serve as an additional cross-link to improve the modulus, while the sacrificial, reversible coordination can dissociate and reconstruct continuously during stretching to dissipate energy. The elastomer with such a bioinspired multiphase structure exhibits over a 10-fold increase in toughness compared to the original sample. We envision that this work offers a novel yet facile biomimetic route toward high-performance elastomers.