Towards sustainability: An assessment of an urbanisation bubble in China using a hierarchical - stochastic multicriteria acceptability analysis - Choquet integral method

Urbanisation bubbles have become an increasingly serious problem. Attention has been paid to the speed of urbanisation; however, the issue of quality has been neglected, particularly in the case of China. Therefore, the aim of this research is to evaluate China’s urbanisation bubbles by employing a hierarchical - stochastic multicriteria acceptability analysis (SMAA) - Choquet integral method. In order to highlight regional disparities, we measure the urbanisation bubbles at a provincial level. Our study aggregates the urbanisation bubble indices using the Choquet integral preference model, and considers the interactions between various indicators. Furthermore, robust ordinal regression and SMAA are applied to resolve the robustness issues associated with the entire set of weights assigned to the urbanisation bubble composite indicator. In addition, by employing a multiple criteria hierarchy process, the study aggregates urbanisation bubble indices not only at the comprehensive level, but also at the intermediate levels of the hierarchy. Our findings suggest that the ranking of urbanisation bubbles is positively related to the level of regional development. This study contributes to the evaluation of regional urbanisation and sustainable development

From physiology to pathology: the role of mitochondria in acute kidney injuries and chronic kidney diseases

Background: Renal diseases remain an increasing public health issue affecting millions of people. The kidney is a highly energetic organ that is rich in mitochondria. Numerous studies have demonstrated the important role of mitochondria in maintaining normal kidney function and in the pathogenesis of various renal diseases, including acute kidney injuries (AKI) and chronic kidney diseases (CKD). Summary: Under physiological conditions, fine-tuning mitochondrial energy balance, mitochondrial dynamics (fission and fusion processes), mitophagy, and biogenesis maintain mitochondrial fitness. While under AKI and CKD conditions, disruption of mitochondrial energy metabolism leads to increased oxidative stress. In addition, mitochondrial dynamics shift to excessive mitochondrial fission, mitochondrial autophagy is impaired, and mitochondrial biogenesis is also compromised. These mitochondrial injuries regulate renal cellular functions either directly or indirectly. Mitochondria-targeted approaches, containing genetic (microRNAs) and pharmaceutical methods (mitochondria-targeting antioxidants, mitochondrial permeability pore inhibitors, mitochondrial fission inhibitors, and biogenesis activators) are emerging as important therapeutic strategies for AKI and CKD. Key messages: Mitochondria play a critical role in the pathogenesis of AKI and CKD. This review provides an updated overview of mitochondrial homeostasis under physiological conditions and the involvement of mitochondrial dysfunction in renal diseases. Finally, we summarize the current status of mitochondria-targeted strategies in attenuating renal diseases

Polypyrrole Modified MoS₂ Nanorod Composites as Durable Pseudocapacitive Anode Materials for Sodium-Ion Batteries

As a typical two-dimensional layered metal sulfide, MoS2 has a high theoretical capacity and large layer spacing, which is beneficial for ion transport. Herein, a facile polymerization method is employed to synthesize polypyrrole (PPy) nanotubes, followed by a hydrothermal method to obtain flower-rod-shaped MoS2/PPy (FR-MoS2/PPy) composites. The FR-MoS2/PPy achieves outstanding electrochemical performance as a sodium-ion battery anode. After 60 cycles under 100 mA g−1, the FR-MoS2/PPy can maintain a capacity of 431.9 mAh g−1. As for rate performance, when the current densities range from 0.1 to 2 A g−1, the capacities only reduce from 489.7 to 363.2 mAh g−1. The excellent performance comes from a high specific surface area provided by the unique structure and the synergistic effect between the components. Additionally, the introduction of conductive PPy improves the conductivity of the material and the internal hollow structure relieves the volume expansion. In addition, kinetic calculations show that the composite material has a high sodium-ion transmission rate, and the external pseudocapacitance behavior can also significantly improve its electrochemical performance. This method provides a new idea for the development of advanced high-capacity anode materials for sodium-ion batteries

TP53RK Drives the Progression of Chronic Kidney Disease by Phosphorylating Birc5

Abstract Renal fibrosis is a common characteristic of various chronic kidney diseases (CKDs) driving the loss of renal function. During this pathological process, persistent injury to renal tubular epithelial cells and activation of fibroblasts chiefly determine the extent of renal fibrosis. In this study, the role of tumor protein 53 regulating kinase (TP53RK) in the pathogenesis of renal fibrosis and its underlying mechanisms is investigated. TP53RK is upregulated in fibrotic human and animal kidneys with a positive correlation to kidney dysfunction and fibrotic markers. Interestingly, specific deletion of TP53RK either in renal tubule or in fibroblasts in mice can mitigate renal fibrosis in CKD models. Mechanistic investigations reveal that TP53RK phosphorylates baculoviral IAP repeat containing 5 (Birc5) and facilitates its nuclear translocation; enhanced Birc5 displays a profibrotic effect possibly via activating PI3K/Akt and MAPK pathways. Moreover, pharmacologically inhibiting TP53RK and Birc5 using fusidic acid (an FDA‐approved antibiotic) and YM‐155(currently in clinical phase 2 trials) respectively both ameliorate kidney fibrosis. These findings demonstrate that activated TP53RK/Birc5 signaling in renal tubular cells and fibroblasts alters cellular phenotypes and drives CKD progression. A genetic or pharmacological blockade of this axis serves as a potential strategy for treating CKDs

LONP1 targets HMGCS2 to protect mitochondrial function and attenuate chronic kidney disease

Abstract Mitochondria comprise the central metabolic hub of cells and their imbalance plays a pathogenic role in chronic kidney disease (CKD). Here, we studied Lon protease 1 (LONP1), a major mitochondrial protease, as its role in CKD pathogenesis is unclear. LONP1 expression was decreased in human patients and mice with CKD, and tubular‐specific Lonp1 overexpression mitigated renal injury and mitochondrial dysfunction in two different models of CKD, but these outcomes were aggravated by Lonp1 deletion. These results were confirmed in renal tubular epithelial cells in vitro. Mechanistically, LONP1 downregulation caused mitochondrial accumulation of the LONP1 substrate, 3‐hydroxy‐3‐methylglutaryl‐CoA synthase 2 (HMGCS2), which disrupted mitochondrial function and further accelerated CKD progression. Finally, computer‐aided virtual screening was performed, which identified a novel LONP1 activator. Pharmacologically, the LONP1 activator attenuated renal fibrosis and mitochondrial dysfunction. Collectively, these results imply that LONP1 is a promising therapeutic target for treating CKD

UDP-Glucuronosyltransferase 1A Compromises Intracellular Accumulation and Anti-Cancer Effect of Tanshinone IIA in Human Colon Cancer Cells

<div><p>Background and Purpose</p><p>NAD(P)H: quinone oxidoreductase 1 (NQO1) mediated quinone reduction and subsequent UDP-glucuronosyltransferases (UGTs) catalyzed glucuronidation is the dominant metabolic pathway of tanshinone IIA (TSA), a promising anti-cancer agent. UGTs are positively expressed in various tumor tissues and play an important role in the metabolic elimination of TSA. This study aims to explore the role of UGT1A in determining the intracellular accumulation and the resultant apoptotic effect of TSA.</p><p>Experimental Approach</p><p>We examined TSA intracellular accumulation and glucuronidation in HT29 (UGT1A positive) and HCT116 (UGT1A negative) human colon cancer cell lines. We also examined TSA-mediated reactive oxygen species (ROS) production, cytotoxicity and apoptotic effect in HT29 and HCT116 cells to investigate whether UGT1A levels are directly associated with TSA anti-cancer effect. UGT1A siRNA or propofol, a UGT1A9 competitive inhibitor, was used to inhibit UGT1A expression or UGT1A9 activity.</p><p>Key Results</p><p>Multiple UGT1A isoforms are positively expressed in HT29 but not in HCT116 cells. Cellular S9 fractions prepared from HT29 cells exhibit strong glucuronidation activity towards TSA, which can be inhibited by propofol or UGT1A siRNA interference. TSA intracellular accumulation in HT29 cells is much lower than that in HCT116 cells, which correlates with high expression levels of UGT1A in HT29 cells. Consistently, TSA induces less intracellular ROS, cytotoxicity, and apoptotic effect in HT29 cells than those in HCT116 cells. Pretreatment of HT29 cells with UGT1A siRNA or propofol can decrease TSA glucuronidation and simultaneously improve its intracellular accumulation, as well as enhance TSA anti-cancer effect.</p><p>Conclusions and Implications</p><p>UGT1A can compromise TSA cytotoxicity via reducing its intracellular exposure and switching the NQO1-triggered redox cycle to metabolic elimination. Our study may shed a light in understanding the cellular pharmacokinetic and molecular mechanism by which UGTs determine the chemotherapy effects of drugs that are UGTs’ substrates.</p></div

TSA glucuronidation in HT29 cell S9 fractions.

<p>Enzyme kinetics for the formation of TSA glucuronides (M1 and M2) was examined in (A) cell S9 fractions prepared from HT29 cells pretreated with negative control siRNA, and (B) cell S9 fractions prepared from HT29 cells pretreated with UGT1A siRNA. (C) inhibitory effect of propofol (0–400 µM) on TSA glucuronidation in HT29 cell S9 fractions. Results are presented as mean ± SD of three independent experiments.</p

An NQO1-Initiated and p53-Independent Apoptotic Pathway Determines the Anti-Tumor Effect of Tanshinone IIA against Non-Small Cell Lung Cancer

<div><p>NQO1 is an emerging and promising therapeutic target in cancer therapy. This study was to determine whether the anti-tumor effect of tanshinone IIA (TSA) is NQO1 dependent and to elucidate the underlying apoptotic cell death pathways. NQO1⁺ A549 cells and isogenically matched NQO1 transfected and negative H596 cells were used to test the properties and mechanisms of TSA induced cell death. The in vivo anti-tumor efficacy and the tissue distribution properties of TSA were tested in tumor xenografted nude mice. We observed that TSA induced an excessive generation of ROS, DNA damage, and dramatic apoptotic cell death in NQO1⁺ A549 cells and H596-NQO1 cells, but not in NQO1⁻ H596 cells. Inhibition or silence of NQO1 as well as the antioxidant NAC markedly reversed TSA induced apoptotic effects. TSA treatment significantly retarded the tumor growth of A549 tumor xenografts, which was significantly antagonized by dicoumarol co-treatment in spite of the increased and prolonged TSA accumulations in tumor tissues. TSA activated a ROS triggered, p53 independent and caspase dependent mitochondria apoptotic cell death pathway that is characterized with increased ratio of Bax to Bcl-xl, mitochondrial membrane potential disruption, cytochrome c release, and subsequent caspase activation and PARP-1 cleavage. The results of these findings suggest that TSA is a highly specific NQO1 target agent and is promising in developing as an effective drug in the therapy of NQO1 positive NSCLC.</p> </div

AUC_{0–48 h} and C_max values of TSA and its glucuronides (M1 and M2) in colon cancer cells and in the cell culture medium.

<p>Data are shown as mean ± SD of three independent experiments;</p>*<p>p<0.05 **p<0.01 ***p<0.001, propofol pretreatment (HT29) or UGT1A siRNA pretreatment (HT29) or TSA only (HCT116) group vs TSA only (HT29) group.</p

UGT1A causes the resistance of colon cancer cells to TSA-induced cytotoxicity.

<p>Cells were pretreated with UGT1A siRNA or non-specific siRNA (negative control) for 24 hours, or pretreated with propofol (100 µM)/NAC (5 mM) for 1 hour. Then, Cells were exposed to gradient concentrations of TSA (2.5–80 µM for HT29; 0.5–40 µM for HCT116) for indicated time and MTT assay was performed. (A) HCT116 cells; (B) and (C) HT29 cells. Results are presented as mean ± SD of at least four independent experiments (*P<0.05, **P<0.01, ***P<0.001).</p