MiRNA-133a-3p Attenuates Renal Tubular Epithelial Cell Injury via Targeting MALM1 and Suppressing the Notch Signaling Pathway in Diabetic Nephropathy.

Diabetic nephropathy (DN) is a serious microvascular complication of diabetes characterized by structural and functional changes of kidneys. Human renal tubular epithelial (HK-2) cells are important for kidney recovery post injury and usually used for establishment of DN cell models. The study explored the role of microRNA (miR)-133a-3p in DN cell model and animal model. A cell model for DN was established via high glucose (HG) stimulation to HK-2 cells. Cell viability and apoptotic rate were measured by cell counting kit 8 and flow cytometry. Polymerase chain reaction was performed to quantify levels of miR-133a-3p and targets. Luciferase reporter assay was conducted to verify the binding of miR-133a-3p and MAML1. After establishment of a mouse model of DN, levels of renal function indicators were measured by biochemical analysis. Hematoxylin-eosin and periodic acid-schiff staining of kidney samples were performed to analyze histological changes. Western blotting was conducted to quantify levels of apoptotic markers, MAML1, and factors related to Notch signaling. Results showed that HG induced HK-2 cell apoptosis and the reduction of cell viability. MiR-133a-3p was lowly expressed in HG-stimulated HK-2 cells. Overexpressed miR-133a-3p improved HK-2 cell injury by increasing cell viability and hampering apoptosis under HG condition. In addition, miR-133a-3p directly targets MAML1 3'-untranslated region. MAML1 overexpression countervailed the repressive impact of miR-133a-3p on cell apoptosis in the context of HG. Moreover, miR-133a-3p inhibited the activity of Notch pathway by downregulating MAML1. MiR-133a-3p inhibits DN progression in mice, as evidenced by reduced fasting blood glucose level, improved levels of renal function parameters, and alleviation of kidney atrophy. In conclusion, miR-133a-3p improves HG-induced HK-2 cell injury and inhibits DN progression by targeting MAML1 and inactivating Notch signaling.

The mechanism underlying the transitions between stripes, helices, and stacked toroids in the cylindrical shell formed by AB diblock copolymers on a long nanocylinder.

The self-assembly of block copolymers on nanocylinders has attracted a lot of interest due to its potential application in biomedicine and other fields. In this study, the self-assembly phase behavior of AB diblock copolymers on long nanocylinders in soft confinement has been studied by using a simulated annealing method. A square phase diagram of the morphology was constructed by increasing the number of chains of copolymers (cn) and the cylindrical diameter (D). As a result, morphological transitions from striped to helical and axially stacked toroids, as well as reversible transitions, started to appear. By analyzing the chain packing in a fan-shaped region and calculating the mean-square end-to-end distance (DEE2) of the copolymers and number of AB contacts, both types of transitions were found to be driven by the competition between conformational entropy and AB interfacial energy. The number of stripes increased and the helical angle decreased with the increase in cylinder diameter. The chirality of the helix was found to be random.

Machine learning based biomarker discovery for chronic kidney disease-mineral and bone disorder (CKD-MBD).

INTRODUCTION: Chronic kidney disease-mineral and bone disorder (CKD-MBD) is characterized by bone abnormalities, vascular calcification, and some other complications. Although there are diagnostic criteria for CKD-MBD, in situations when conducting target feature examining are unavailable, there is a need to investigate and discover alternative biochemical criteria that are easy to obtain. Moreover, studying the correlations between the newly discovered biomarkers and the existing ones may provide insights into the underlying molecular mechanisms of CKD-MBD. METHODS: We collected a cohort of 116 individuals, consisting of three subtypes of CKD-MBD: calcium abnormality, phosphorus abnormality, and PTH abnormality. To identify the best biomarker panel for discrimination, we conducted six machine learning prediction methods and employed a sequential forward feature selection approach for each subtype. Additionally, we collected a separate prospective cohort of 114 samples to validate the discriminative power of the trained prediction models. RESULTS: Using machine learning under cross validation setting, the feature selection method selected a concise biomarker panel for each CKD-MBD subtype as well as for the general one. Using the consensus of these features, best area under ROC curve reached up to 0.95 for the training dataset and 0.74 for the perspective dataset, respectively. DISCUSSION/CONCLUSION: For the first time, we utilized machine learning methods to analyze biochemical criteria associated with CKD-MBD. Our aim was to identify alternative biomarkers that could serve not only as early detection indicators for CKD-MBD, but also as potential candidates for studying the underlying molecular mechanisms of the condition.

Quantifying the energy-material-pollution nexus in a typical fine chemical industry: A sustainable development-oriented support for collaborative emission reduction.

The fine chemical industry is currently facing challenges in energy saving, material conservation, and pollution reduction due to the dual policy pressure of precise system management and collaborative pollution and carbon reduction. However, the interweaving of materials and energy input-output was not well understood due to the incomplete coverage and the lack of a generic framework. Therefore, a methodology based on the energy-material-pollution (E-M-P) coupling nexus was proposed to quantitatively assess multi-level coupling. According to the selected generic 32 coupling units, two representative glyphosate (PMG) production processes were taken as case studies. Quantification results showed that the solvent element and the material system had a higher priority. Moreover, Process 2 owned a greater optimization potential as the coupling relationship pairs were 2.55 compared to 2.32 for Process 1, and the correlation proportions of material systems reached 69.26 % and 56.92 %, respectively. In addition, assessment results indicated that Process 2 was more environmentally friendly because of the lower ecological indexes (9.7 GPt vs. 15.8 GPt) and weaker carbon footprint (CF) (1.16E+08 vs. 2.32E+08). Combined coupling nexus and environmental assessment organically, methanol had the most optimization potential and was beneficial for the measures such as solvent substitution. This work offered theory and practice guidance with demonstrative value to support the sustainable development of precise system management.

Functional role of microRNA-500a-3P-loaded liposomes in the treatment of cisplatin-induced AKI.

Cisplatin treatment results in acute kidney injury (AKI) by the phosphorylation of mixed lineage kinase domain-like protein (MLKL). The knockout of MLKL, which is a principle mediator of necroptosis, is believed to alleviate the AKI symptoms. The present study was aimed to improve the therapeutic efficacy in AKI. For this purpose, miR-500a-3P was identified as appropriate miRNA therapeutics and loaded in liposome delivery carrier. The authors have showed that the miR-LIP directly controls the expression of RIPK3 and MLKL - a modulator of necroptosis and thereby reduces the severity of kidney injury. The miR-LIP significantly controlled the phosphorylation of MLKL compared to that of CDDP-treated HK2 cells. Similar results are observed with RIPK3. The miR-LIP has also been demonstrated to control the inflammatory response in tubular cells. Western blot analysis further revealed that the phosphorylation of P-65 was mainly responsible for the inflammatory response and miR-LIP significantly decreased the CDDP-induced NF-kB phosphorylation. Overall, the present study explored the molecular mechanism behind the necroptosis in AKI and potential of miRNA in targeting MLKL pathways. Study further highlights the potential advantage of liposome as a delivery carrier for miRNA therapeutics.

Asymmetric construction of quaternary α-nitro amides by palladium-catalyzed C(sp3)-H arylation.

Pd-Catalyzed enantioselective C(sp3)-H arylation of N-(o-Br-aryl) anilides has been disclosed, and quaternary α-nitro amides were constructed with up to 98% ee. The presence of the nitro group on the substrate enables the progress of the reaction and the ready transformation of the product to optically active quaternary amino acid derivatives.

Micro RNA-30b (inhibitor) nanoparticles suppressed the lipopolysaccharide (LPS)-induced acute kidney injury.

The main aim of present study is to evaluate the effect of miR-30b on the function of human proximal tubular epithelial cell line HK-2 cells. For this purpose, miRNA was loaded in an ionically cross-linked polysaccharide nanoparticle. The authors have demonstrated the influence of miR-30b mimic and inhibitor in HK-2 cell killing effect. Lipopolysaccharide (LPS) significantly increased the level of inflammatory cytokines of TNF-α, IL-1ß and level was further increased with the treatment of PAg-miR mimic consistent with the cell viability assay. Interestingly, PAg-miR inhibitor significantly downregulated the expression of inflammatory cytokines and thereby reduced the inflammation in the body. Western blot analysis showed that LPS induced severe apoptosis of HK-2 cells and the apoptosis was further promoted by the PAg-miR (mimic). In contrast, PAg-miR (inhibitor) alleviated the apoptosis of HK-2 cells as indicated in the significantly reduced levels of Bax and c-Caspase-3 proteins. Overall, miR-30b promoted LPS-induced HK-2 cell inflammatory injury by inducing the apoptosis and by releasing inflammatory cytokines, as well as by impairing autophagy process.

Soft Confinement-Induced Morphologies of the Blends of AB Diblock Copolymers and C Homopolymers.

Self-assembly behavior of the blends of AB diblock copolymers and C homopolymers in soft confinement is studied by using a simulated annealing method. Polymer solution droplets in a poor solvent environment realize the soft confinement. Several sequences of soft confinement-induced copolymer aggregates with different shapes and internal structures are predicted as functions of the size of confinement, the number ratio of AB diblock copolymers to C homopolymers, the volume fraction of blocks, the selectivity of confinement's surface, the incompatibility between blocks, and the competition between two block-homopolymer interactions. Simulation results demonstrate that those factors are able to tune the morphology of the aggregates precisely. We anticipate the rules achieved here is helpful to fabrication of polymeric particle with predesigned morphology.

Theoretical simulation of reduction mechanism of graphene oxide in sodium hydroxide solution.

Based on a density functional theory simulation, we proposed a reduction mechanism of graphene oxide (GO) under a sodium hydroxide solution containing anions (OH(-)), cations (Na(+)) and neutral H2O molecules as main components. OH(-) anion can interact with hydroxyl in GO and transfer electrons to the graphene sheet, resulting in negatively charged GO, and these electrons obviously lower the barrier of the ring-opening reaction of epoxy. Na(+) cations can be attracted by the negatively charged GO, and this reaction is equivalent to the one between metallic Na and GO. The opened epoxy is reduced with the assistance of Na(+) cation and water molecule. In such a reduction process, NaOH can be viewed as a catalyst and more defects should be formed because of these diffused epoxies on the negatively charged graphene sheet. Our results may be helpful to understand further the nature of the reduction of GO among various reducing agents.

Highly symmetric patchy multicompartment nanoparticles from the self-assembly of ABC linear terpolymers in C-selective solvents.

Multicompartment micelles, especially those with highly symmetric surfaces such as patchy-like, patchy, and Janus micelles, have tremendous potential as building blocks of hierarchical multifunctional nanomaterials. One of the most versatile and powerful methods to obtain patchy multicompartment micelles is by the solution-state self-assembly of linear triblock copolymers. In this article, we applied the simulated annealing method to study the self-assembly of ABC linear terpolymers in C-selective solvents. Simulations predict a variety of patchy and patchy-like multicompartment micelles with high symmetry and also yield a detailed phase diagram to reveal how to control the patchy multicompartment micelle morphologies precisely. The phase diagram demonstrates that the internal segregated micellar structure depends on the ratio between the volume fractions of the two solvophobic blocks and their incompatibility, whereas the overall micellar shape depends on the copolymer concentration. The relationship between the interfacial energy, stretching energy of chains and the micellar morphology, micellar morphological transition are elucidated by computing the average contact number among the species, the mean square end-to-end distances of the whole terpolymers, the AB blocks in the terpolymers, the AB diblock copolymers, and angle distribution of terpolymers. The anchoring effect of the solvophilic C block on micellar structures is also examined by comparing the morphologies formed from ABC terpolymers and AB diblock copolymers.

Complex micelles from self-assembly of ABA triblock copolymers in B-selective solvents.

We report an extensive simulation study of the self-assembly of amphiphilic ABA triblock copolymers dissolved in solvents selective for the middle B-block. The effects of copolymer composition, copolymer concentration, and A-solvent interactions on the morphologies and morphological transitions of the aggregates are examined systematically. The simulations reveal that a rich variety of aggregates, ranging from spherical and rodlike micelles and vesicles to toroidal and net-cage micelles, can be formed spontaneously from a randomly generated initial state. Phase diagrams are constructed and rich morphological transitions are predicted. Chain packing in different micelles is investigated. The simulation results are compared with previous observations or predictions for related copolymer systems.

Helical vesicles, segmented semivesicles, and noncircular bilayer sheets from solution-state self-assembly of ABC miktoarm star terpolymers.

Multicompartment micelles, especially nanostructured vesicles, offer tremendous potential as delivery vehicles of therapeutic agents and nanoreactors. Solution-state self-assembly of miktoarm star terpolymers provides a versatile and powerful route to obtain multicompartment micelles. Here we report simulations of solution-state self-assembly of ABC star terpolymers composed of a solvophilic A arm and two solvophobic B and C arms. A variety of multicompartment micelles are predicted from the simulations. Phase diagrams for typical star terpolymers are constructed. It is discovered that the overall micelle morphology is largely controlled by the volume fraction of the solvophilic A arms, whereas the internal compartmented and/or segregated structures depend on the ratio between the volume fractions of the two solvophobic arms. The polymer-solvent and polymer-polymer interactions can be used to tune the effective volume fraction of the A-arm and, thereby, induce morphological transitions. For terpolymers with equal or nearly equal length of B and C arms, several previously unknown structures, including vesicles with novel lateral structures (helices or stacked donuts), segmented semivesicles, and elliptic or triangular bilayer sheets, are discovered. When the lengths of B and C arms are not equal, novel micelles such as multicompartment disks and onions are observed.

[Renal protective effects of specific cyclooxygenase-2 inhibitor in rats with subtotal renal ablation].

OBJECTIVE: To investigate the renoprotective effect of specific cyclooxygenase-2 (COX-2) inhibitor rofecoxib and its possible mechanism of retarding progressive renal injury in rats with subtotal renal ablation. METHODS: Rats were randomly divided into six groups: sham, subtotal renal ablation (SNX). SNX treated with rofecoxib (10 mg.kg(-1).d(-1)). SNX treated with indomethacin (2 mg.kg(-1).d(-1)). SNX treated with losartan (100 mg.kg(-1).d(-1)). SNX treated with rofecoxib and losartan. Blood pressure, urinary protein and thromboxane B(2) (TXB(2)) were measured at the 6th week after operation and morphological changes were examined with light microscopy. The mRNA expression of transforming growth factor-beta type I and type II receptors (TbetaRI, TbetaRII) was detected by way of reverse transcription polymerase chain reaction. The expression of plasminogen activator inhibitor type1 (PAI-1), fibronectin (FN) and angiotensin II type 1 receptor was examined utilizing Western blotting or immunohistochemistry. RESULTS: The levels of urinary protein and TXB(2) as well as cortical COX-2 expression in SNX group were significantly increased while COX-1 expression remained undisturbed in comparison with those in sham group. The levels of systolic blood pressure and angiotensin II in renal cortex significantly increased. The expression of TbetaRI and TbetaRII mRNA, PAI-1 and AT1 protein was up-regulated. The glomerulosclerosis index (GSI) and tubular injury index were increased in SNX group. Rofecoxib significantly inhibited the increase in proteinuria and reduced GSI and tubular injury index. The expression of TbetaRI, TbetaRII and PAI-1 was down-regulated by 36.44%, 45.02% and 31.16% respectively, similar to the effect of losartan treatment. Indomethacin significantly decreased proteinuria and slightly reduced GSI. However the tubular injury index was exacerbated. Systolic blood pressure was not significantly blunted in the groups of rofecoxib and indomethacin. There was no significant additive effect of combined therapy with losartan and rofecoxib, though proteinuria was reduced to a lower level. CONCLUSION: Rofecoxib attenuates proteinuria and retards the progressive renal injury in rats with subtotal renal ablation partly by inhibition of COX-2 activity and modulation of activation of renal renin-angiotensin system as well as the down-regulation of transforming growth factor-beta type I and type II receptors and PAI-1.