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Platelet-derived microvesicles (PMVs), the microvesicles with the highest concentration in the bloodstream, play a key role in the regulation of hemostasis, inflammation, and angiogenesis. PMVs have recently been identified as key factors in the link between platelets and cancer. PMVs bind to both cancer cells and nontransformed cells in the microenvironment of the tumor, and then transfer platelet-derived contents to the target cell. These contents have the potential to either stimulate or modulate the target cell's response. PMVs are encased in a lipid bilayer that contains surface proteins and lipids as well as components found inside the PMV. Each of these components participates in known and potential PMV roles in cancer. The complicated roles played by PMVs in the onset, development, and progression of cancer and cancer-related comorbidities are summarized in this study.

Inadequate trophoblastic invasion is considered as one of hallmarks of preeclampsia (PE), which is characterized by newly onset of hypertension (140/90 mmHg) and proteinuria (300 mg in a 24-h urine) after 20 weeks of gestation. Accumulating evidence has indicated that long noncoding RNAs are aberrantly expressed in PE, whereas detailed mechanisms are unknown. In the present study, we showed that lncRNA Taurine upregulated 1 (TUG1) were downregulated in preeclamptic placenta and in HTR8/SVneo cells under hypoxic conditions, together with reduced enhancer of zeste homolog2 (EZH2) and embryonic ectoderm development (EED) expression, major components of polycomb repressive complex 2 (PRC2), as well as activation of Nodal/ALK7 signalling pathway. Mechanistically, we found that TUG1 bound to PRC2 (EZH2/EED) in HTR8/SVneo cells and weakened TUG1/PRC2 interplay was correlated with upregulation of Nodal expression via decreasing H3K27me3 mark at the promoter region of Nodal gene under hypoxic conditions. And activation of Nodal signalling prohibited trophoblast invasion via reducing MMP2 levels. Overexpression of TUG1 or EZH2 significantly attenuated hypoxia-induced reduction of trophoblastic invasiveness via negative modulating Nodal/ALK7 signalling and rescuing expression of its downstream target MMP2. These investigations might provide some evidence for novel mechanisms responsible for inadequate trophoblastic invasion and might shed some light on identifying future therapeutic targets for PE.

Many governments have imposed methods such as a carbon tax that aim to even out the negative effects of carbon emissions. The taxes levied on different agents lead to different make–buy decisions for production structures and different environmental outcomes. Some original equipment manufacturers (OEMs) outsource remanufacturing to independent remanufacturers (IRs). Thus, a question arises: What are the implications of carbon taxes levied on different agents on remanufacturing outsourcing decisions? To answer this question, we developed two models: (1) acting as common brand owners, OEMs can be taxed for both new and remanufactured products, or (2) acting as different emitters for production and remanufacturing, OEMs are taxed for new products; however, all carbon taxes related to remanufacturing are levied on IRs. Our analysis reveals that, regarding economic performance, firms should undertake a carbon emission tax on their own initiative because this allows the taxpayer to choose more units for its preferred products and leaves its rivals at a huge disadvantage. Moreover, regarding environmental sustainability, carbon emission taxes indeed lead to mitigating the effects of carbon emissions per unit; however, environmental agencies should also pay attention to reducing the total carbon emissions by limiting the volume effects.

Metastasis associated lung adenocarcinoma transcript 1(MALAT1) is a long non‐coding RNA, broadly expressed in mammalian tissues including kidney and up‐regulated in a variety of cancer cells. To date, its functions in podocytes are largely unknown. β‐catenin is a key mediator in the canonical and non‐canonical Wnt signalling pathway; its aberrant expression promotes podocyte malfunction and albuminuria, and contributes to kidney fibrosis. In this study, we found that MALAT1 levels were increased in kidney cortices from C57BL/6 mice with streptozocin (STZ)‐induced diabetic nephropathy, and dynamically regulated in cultured mouse podocytes stimulated with high glucose, which showed a trend from rise to decline. The decline of MALAT1 levels was accompanied with β‐catenin translocation to the nuclei and enhanced expression of serine/arginine splicing factor 1 (SRSF1), a MALAT1 RNA‐binding protein. Further we showed early interference with MALAT1 siRNA partially restored podocytes function and prohibited β‐catenin nuclear accumulation and SRSF1 overexpression. Intriguingly, we showed that β‐catenin was involved in MALAT1 transcription by binding to the promotor region of MALAT1; β‐catenin knock‐down also decreased MALAT1 levels, suggesting a novel feedback regulation between MALAT1 and β‐catenin. Notably, β‐catenin deletion had limited effects on SRSF1 expression, demonstrating β‐catenin might serve as a downstream signal of SRSF1. These findings provided evidence for a pivotal role of MALAT1 in diabetic nephropathy and high glucose‐induced podocyte damage.

Activation of Ras-related C3 botulinum toxin substrate 1 (Rac1) has been implicated in diverse kidney diseases, yet its in vivo significance in diabetic nephropathy (DN) is largely unknown. In the present study, we demonstrated a podocyte-specific Rac1-deficient mouse strain and showed that specific inhibition of Rac1 was able to attenuate diabetic podocyte injury and proteinuria by the blockade of Rac1/PAK1/p38/β-catenin signaling cascade, which reinstated the integrity of podocyte slit diaphragms (SD), rectified the effacement of foot processes (FPs), and prevented the dedifferentiation of podocytes. In vitro, we showed Rac1/PAK1 physically bound to β-catenin and had a direct phosphorylation modification on its C-terminal Ser675, leading to less ubiquitylated β-catenin, namely more stabilized β-catenin, and its nuclear migration under high-glucose conditions; further, p38 activation might be responsible for β-catenin nuclear accumulation via potentiating myocyte-specific enhancer factor 2C (MEF2c) phosphorylation. These findings provided evidence for a potential renoprotective and therapeutic strategy of cell-specific Rac1 deficiency for DN and other proteinuric diseases.

Ras-related C3 botulinum toxin substrate 1 (Rac1), together with its major downstream effector p21-activated kinase 1 (PAK1), has been identified a central role in cellular events such as cell cytoskeletal remodeling that contributed to cell migration and epithelial-mesenchymal transition (EMT). And there are data implicating that podocytes underwent EMT under pathological conditions. However, little is known about mechanisms of podocytes undergoing EMT. To address this, we assessed the cellular changes of podocytes after high glucose stimulation in vitro, detected the effects of Rac1/PAK1 signaling on podocytes in response to the stimuli, and investigated interactions of Rac1/PAK1 axis with β-catenin and Snail under high glucose conditions. We found that in vitro high glucose treatment led to remarkable down-regulation of nephrin and P-cadherin, as well as significant up-regulation of α-SMA and FSP-1, suggesting that in the presence of high glucose, podocytes underwent EMT, during which Rac1/PAK1 signaling was activated. And these were notably ameliorated by Rac1 gene knockdown. Furthermore, β-catenin and Snail nuclear translocation were triggered by Rac1/PAK1 axis, which were both markedly reversed via Rac1 gene knockdown or pretreatment of IPA-3, a PAK1 inhibitor. These findings elaborated that Rac1/PAK1 signaling contributed to high glucose-induced podocyte EMT via promoting β-catenin and Snail transcriptional activities, which could be a potential mechanism involved in podocytes injury in response to stimuli under diabetic conditions.

Focal adhesion kinase (FAK) is a non‐receptor protein tyrosine kinase that regulates cell adhesion, proliferation and differentiation. In the present study, a rat model of high fat diet‐induced hypercholesterolaemia was established to investigate the involvement of FAK in lipid disorder‐related kidney diseases. We showed focal fusion of podocyte foot process that occurred at as early as 4 weeks in rats consuming high fat diet, preceding the onset of proteinuria when aberrant phosphorylation of FAK was found. These abnormalities were ameliorated by dietary intervention of TAE226, a reported inhibitor of FAK. FAK is also an adaptor protein initiating cascades of intracellular signals including c‐Src, Rho GTPase and mitogen‐activated protein kinase (MAPK). P38 MAPK belongs to the latter and is centrally involved in kidney diseases. Our cell culture data revealed oxidized low‐density lipoprotein (ox‐LDL) triggered hyper‐phosphorylation of FAK and p38, ectopic expression of cellular markers (manifested as decreased WT1, podocin and NEPH1, and increased vimentin and mmp9), and re‐arrangement of F‐actin filaments with enhanced cell motility; these mutations were significantly rectified by FAK shRNA. Notably, pre‐treatment of p38 inhibitor did not alter FAK activation, albeit its deletion of p38 hyper‐activity and attenuation of cellular abnormalities, demonstrating that p38 acted as a downstream effector of FAK signalling and ox‐LDL damaged podocytes in a FAK/p38‐dependent manner. This was further identified by animal data that p38 activation was also abrogated by TAE226 treatment in hypercholesterolaemic rats, suggesting that FAK/p38 axis might also be involved in in vivo events. These findings provided a potential early mechanism of hypercholesterolaemia‐related podocyte damage and proteinuria.

Fyn, a member of the Src family of tyrosine kinases, is a key regulator in cytoskeletal remodeling in a variety of cell types. Recent studies have demonstrated that Fyn is responsible for nephrin tyrosine phosphorylation, which will result in polymerization of actin filaments and podocyte damage. Thus detailed involvement of Fyn in podocytes is to be elucidated. In this study, we investigated the potential role of Fyn/ROCK signaling and its interactions with paxillin. Our results presented that high glucose led to filamentous actin (F-actin) rearrangement in podocytes, accompanied by paxillin phosphorylation and increased cell motility, during which Fyn and ROCK were markedly activated. Gene knockdown of Fyn by siRNA showed a reversal effect on high glucose-induced podocyte damage and ROCK activation; however, inhibition of ROCK had no significant effects on Fyn phosphorylation. These observations demonstrate that in vitro Fyn mediates high glucose-induced actin cytoskeleton remodeling of podocytes via promoting ROCK activation and paxillin phosphorylation.

Background Epithelial-mesenchymal transition of tubular epithelial cells, which is characterized by a loss of epithelial cell characteristics and a gain of ECM-producing myofibroblast characteristics, is an essential mechanism that is involved in tubulointerstitial fibrosis, an important component of the renal injury that is associated with diabetic nephropathy. Under diabetic conditions, p38 MAPK activation has been reported in glomeruli and mesangial cells; however, studies on p38 MAPK in TECs are lacking. In this study, the role of p38 MAPK in AP-1 activation and in the EMT in the human proximal tubular epithelial cell line (HK-2) under high glucose concentration conditions is investigated. Methodology/Principal Findings A vector for small interfering RNA that targets p38 MAPK was constructed; the cells were then either transfected with p38 siRNA or pretreated with a chemical inhibitor of AP-1 and incubated with low glucose plus TGF-β1 or high glucose for 48 h. Cells that were not transfected or pretreated and were exposed to low glucose with or without TGF-β1 or high glucose for 48 h were considered to be the controls. We found that high glucose induced an increase in TGF-β1. And high glucose-induced p38 MAPK activation was inhibited by p38 siRNA (P