Matrix metalloproteinase-10 protects against acute kidney injury by augmenting epidermal growth factor receptor signaling

Matrix metalloproteinase-10 (MMP-10) is a zinc-dependent endopeptidase involved in regulating a wide range of biologic processes, such as apoptosis, cell proliferation, and tissue remodeling. However, the role of MMP-10 in the pathogenesis of acute kidney injury (AKI) is unknown. In this study, we show that MMP-10 was upregulated in the kidneys and predominantly localized in the tubular epithelium in various models of AKI induced by ischemia/reperfusion (IR) or cisplatin. Overexpression of exogenous MMP-10 ameliorated AKI, manifested by decreased serum creatinine, blood urea nitrogen, tubular injury and apoptosis, and increased tubular regeneration. Conversely, knockdown of endogenous MMP-10 expression aggravated kidney injury. Interestingly, alleviation of AKI by MMP-10 in vivo was associated with the activation of epidermal growth factor receptor (EGFR) and its downstream AKT and extracellular signal-regulated kinase-1 and 2 (ERK1/2) signaling. Blockade of EGFR signaling by erlotinib abolished the MMP-10-mediated renal protection after AKI. In vitro, MMP-10 potentiated EGFR activation and protected kidney tubular cells against apoptosis induced by hypoxia/reoxygenation or cisplatin. MMP-10 was colocalized with heparin-binding EGF-like growth factor (HB-EGF) in vivo and activated it by a process of proteolytical cleavage in vitro. These studies identify HB-EGF as a previously unrecognized substrate of MMP-10. Our findings also underscore that MMP-10 can protect against AKI by augmenting EGFR signaling, leading to promotion of tubular cell survival and proliferation after injury.Subject terms: Apoptosis, Cell growth     

Exposure risks to pesticide applicators posed by the use of electric backpack sprayers and stretcher-mounted sprayers in orchards

Abstract

The introduction of the pesticide registration system in pesticide risk assessments has promoted the scientific and safe use of pesticides, and the assessment of occupational exposure risk. In the present study, we performed an experiment in a citrus orchard subject to normal orchard management practices. By measuring the exposure of applicators’ (farmers and technicians) body parts to 45% malathion emulsifiable concentrate during its application using electric backpack sprayers (0.25?KPa) and stretcher-mounted sprayers (1.5?KPa), the unit exposure (UE) was determined. The risks of exposure for pesticide applicators who adopted five different protective measures (A: no personal protective equipment (PPE), i.e., no clothes, no gloves, no caps, and no socks; B: short-sleeved top and shorts; C: short-sleeved top, shorts, and a single pair of gloves; D: short-sleeved top, shorts, a single pair of gloves, and a cap; E: long-sleeved top, long pants, a single pair of gloves, and a cap) were also assessed. The results were as follows: 1) The total levels of exposure for pesticide applicators using electric backpack sprayers and stretcher-mounted sprayers were 3613.63?µg and 5654.28?µg, respectively. When electric backpack sprayers were used, the body parts that had the highest exposure were the head (13.8%), hands (19.9%) and back (14.0%), and when stretcher-mounted sprayers were used, the hands (32.5%) and lower legs (21.1%) had the highest level of exposure; 2) In the absence of PPE, the UE values for farmers who used electric backpack sprayers and farmers who used stretcher-mounted sprayers were significantly different. However, when PPE was used, the difference in UE values between the farmers using the two different types of sprayers was not significant; 3) When protective measure A was adopted, the risk quotient (RQ) values of the farmers and technicians who used electric backpack sprayers for the application of malathion were 1.44 and 0.54, respectively; the corresponding RQ values when protective measure B was adopted were 0.97 and 0.28, respectively. When stretcher-mounted sprayers were used for the application of chlorpyrifos, the RQ value of the farmers who adopted protective measure E was 0.43 while other types of PPE use resulted in RQ values greater than 1. In contrast, the RQ value for technicians was 1.62 when protective measure A was used and 1.02 when protective measure B was adopted, whereas other types of PPE use resulted in RQ values less than 1. Therefore, besides increasing the awareness of personal protection among pesticide applicators, improvement in the management of pesticide use and the enhancement of standard operations are of practical significance for controlling occupational exposure to pesticides.     

Sufficient and necessary conditions for Lyapunov stability of genetic networks with SUM regulatory logic

In this paper, a nonlinear model for genetic regulator networks (GRNs) with SUM regulatory logic is presented. Four sufficient and necessary conditions of global asymptotical stability and global exponential stability for the equilibrium point of the GRNs are proposed, respectively. Specifically, three weak sufficient conditions and corresponding corollaries are derived by using comparing theorem and Dini derivative method. Then, a famous GRN model is used as the example to illustrate the effectiveness of our theoretical results. Comparing to the results in the previous literature, some novel ideas, study methods and interesting results are explored.     

Semaphorin 3A promotes the osteogenic differentiation of rat bone marrow-derived mesenchymal stem cells in inflammatory environments by suppressing the Wnt/β-catenin signaling pathway

Journal of Molecular Histology - After periodontal treatment, the local inflammatory environment surrounding periodontal tissues cannot be entirely eliminated. The means by which alveolar bone...     

Simultaneous Retention of Thermostability and Specific Activity in Chimeric Human Alkaline Phosphatases

Alkaline phosphatases (APs) are a family of dimeric metalloenzymes that has been utilized in many areas due to its ability to hydrolyze a variety of phosphomonoesters. While mammalian APs have higher specific activity than prokaryotic APs, they are generally less thermostable. To cultivate the possibility to confer mammalian APs with higher thermostability as well as high activity, we focused on human AP isozymes. Among the four isozymes of human APs, placental AP (PLAP) retains the highest thermostability, while intestinal AP (IAP) has the highest specific activity. Since the two APs display high homology, a series of chimeric enzymes were made in a secreted form to analyze their properties. Surprisingly, chimeric APs with IAP residues at the N-terminal and PLAP residues at the C-terminal regions showed higher specific activity than PLAP, while keeping thermostability as high as PLAP. Especially, one showed similar specific activity to IAP, while showing slower inactivation than PLAP after incubation at 75 °C. Interestingly, the mutant also showed higher resistance to uncompetitive inhibitors Phe and Leu than their parent enzymes, possibly due to increased hydrophilicity of the active site entrance residues. The obtained chimera will be useful as a novel reporter in various assays including gene hybridization.     

The crosstalk between HIFs and mitochondrial dysfunctions in cancer development

Mitochondria are essential cellular organelles that are involved in regulating cellular energy, metabolism, survival, and proliferation. To some extent, cancer is a genetic and metabolic disease that is closely associated with mitochondrial dysfunction. Hypoxia-inducible factors (HIFs), which are major molecules that respond to hypoxia, play important roles in cancer development by participating in multiple processes, such as metabolism, proliferation, and angiogenesis. The Warburg phenomenon reflects a pseudo-hypoxic state that activates HIF-1α. In addition, a product of the Warburg effect, lactate, also induces HIF-1α. However, Warburg proposed that aerobic glycolysis occurs due to a defect in mitochondria. Moreover, both HIFs and mitochondrial dysfunction can lead to complex reprogramming of energy metabolism, including reduced mitochondrial oxidative metabolism, increased glucose uptake, and enhanced anaerobic glycolysis. Thus, there may be a connection between HIFs and mitochondrial dysfunction. In this review, we systematically discuss the crosstalk between HIFs and mitochondrial dysfunctions in cancer development. Above all, the stability and activity of HIFs are closely influenced by mitochondrial dysfunction related to tricarboxylic acid cycle, electron transport chain components, mitochondrial respiration, and mitochondrial-related proteins. Furthermore, activation of HIFs can lead to mitochondrial dysfunction by affecting multiple mitochondrial functions, including mitochondrial oxidative capacity, biogenesis, apoptosis, fission, and autophagy. In general, the regulation of tumorigenesis and development by HIFs and mitochondrial dysfunction are part of an extensive and cooperative network.Subject terms: Cancer metabolism, Cancer microenvironment