Metformin ameliorates calcium oxalate crystallization and stone formation by activating the Nrf2/HO-1 signaling pathway: Two birds with one stone.

Deposition of calcium oxalate (CaOx) crystals and oxidative stress-induced injury of renal tubular epithelial cell are the primary pathogenic factors of nephrolithiasis. In this study we investigated the beneficial effects of metformin hydrochloride (MH) against nephrolithiasis and explored the underlying molecular mechanism. Our results demonstrated that MH inhibited the formation of CaOx crystals and promoted the transformation of thermodynamically stable CaOx monohydrate (COM) to more unstable CaOx dihydrate (COD). MH treatment effectively ameliorated oxalate-induced oxidative injury and mitochondrial damage in renal tubular cells and reduced CaOx crystal deposition in rat kidneys. MH also attenuated oxidative stress by lowering MDA level and enhancing SOD activity in HK-2 and NRK-52E cells and in a rat model of nephrolithiasis. In both HK-2 and NRK-52E cells, COM exposure significantlylowered the expressions of HO-1 and Nrf2, which was rescued by MH treatment even in the presence of Nrf2 and HO-1 inhibitors. In rats with nephrolithiasis, MH treatment significantly rescued the down-regulation of the mRNA and protein expression of Nrf2 and HO-1 in the kidneys. These results demonstrate that MH can alleviate CaOx crystal deposition and kidney tissue injury in rats with nephrolithiasis by suppressing oxidative stress and activating the Nrf2/HO-1 signaling pathway, suggesting the potential value of MH in the treatment of nephrolithiasis.

Spatial Spillover Effects of Resource Misallocation on the Green Total Factor Productivity in Chinese Agriculture.

Continuous resource misallocation not only results in total factor productivity loss but also leads to ecological degradation. Therefore, in the process of changing from extensive growth to intensive growth, Chinese agriculture should pay attention to the problem of resource misallocation. There is currently a lack of relevant research, especially concerning the spatial spillover effects of resource misallocation at the city level. To fill this gap, we employ a spatial panel model for empirical testing on the basis of measuring agricultural green total factor productivity (GTFP) in 306 cities in China from 1996-2017. We found that there is positive spatial autocorrelation in Chinese agricultural GTFP, but it decreases year by year. Misallocation in land, labor, machinery and fertilizer all directly hinder the local GTFP. The eastern is mainly negatively affected by neighbor resource misallocation, while the central and western are mainly negatively affected by local resource misallocation. Finally, the indirect effect of neighbor resource misallocation on GTFP gradually shifts from inhibiting effect to a facilitating effect with increasing spatial distance. These findings have clear policy implications: Chinese government should strengthen agricultural green technology innovation and diffusion, strengthen environmental regulation and promote the free movement of labor between regions and sectors.

The Chemical Composition Characteristics and Health Risk Assessment of Cooking Fume Condensates from Residential Kitchens in Different Regions of China.

The aim of this study was to explore the similarities and differences of volatile organic pollutants (VOCs) in cooking fumes (COF) of residential buildings in different regions of China, as well as to evaluate their potential health risks. COF condensates were collected from 10 representative cities in China and analyzed by a GC-MS method. Their effects on α-glucosidase, acetylcholinesterase (AchE), and lactate dehydrogenase (LDH) activities were then detected to evaluate potential health risks. A total of 174 kinds of VOCs, including aldehydes, esters, hydrocarbons, alcohols, and carboxylic acid, were identified. There were 59 identical compounds in the northern and southern regions, and 56 common compounds in spicy and non-spicy regions. Health risk assessment results showed that COF condensate could inhibit the activity of α-glucosidase to varying degrees (61.73-129.25%), suggesting that it had a potential risk of causing hypoglycemia. Daily and 3 and 6 month intakes of COF in minors, adults, and the elderly had both activated and inhibited effects on AchE. The activated effect in the southern and spicy areas was higher than that in northern and non-spicy areas, revealing that different regions and dietary habits had different effects on the risk of neurological diseases caused by changes in AchE activity. For minors, adults, and the elderly, COF had different degrees of activation of LDH at different exposure times and regions. Activation in the northern and non-spicy areas was higher than that in southern and spicy areas, suggesting that the health risks caused by changes in LDH activity levels were significantly increased.

Target-responsive subcellular catabolism analysis for early-stage antibody-drug conjugates screening and assessment.

Events including antibody‒antigen affinity, internalization, trafficking and lysosomal proteolysis combinatorially determine the efficiency of antibody-drug conjugate (ADC) catabolism and hence the toxicity. Nevertheless, an approach that conveniently identifies proteins requisite for payload release and the ensuing toxicity for mechanistic studies and quality assessment is lacking. Considering the plethora of ADC candidates under development, we developed a target-responsive subcellular catabolism (TARSC) approach that examines ADC catabolism and probes changes in response to targeted interferences of proteins of interest. We firstly applied TARSC to study the commercial T-DM1 and the biosimilar. We recorded unequivocal catabolic behaviors regardless of the absence and presence of the targeted interferences. Their negligible differences in TARSC profiles agreed with their undifferentiated anti-tumoral efficacy according to further in vitro viability and in vivo tumor growth assays, highlighting TARSC analysis as a useful tool for biosimilarity assessment and functional dissection of proteins requisite for ADC catabolism. Additionally, we employed TARSC to investigate the catabolic behavior of a new trastuzumab-toxin conjugate. Collectively, TARSC can not only characterize ADC catabolism at (sub)cellular level but also comprehensively determine which protein targets affect payload release and therapeutic outcomes. Future use of TARSC is thus anticipated in early-stage screening, quality assessment and mechanistic investigations of ADCs.

Technical Note: Effect of magnetic fields on the microdosimetry of carbon-ion beams.

PURPOSE: To investigate the influence of magnetic fields on the microdosimetry of carbon-ion beams and the scaling effect of tissue equivalent proportional counter (TEPC) defined as the change of energy deposition in a TEPC from that in a microscopic scale region of interest due to the presence of a magnetic field in combination with the TEPC larger physical dimensions. METHODS: Geant4-based Monte Carlo simulations were conducted to calculate the microdosimetric quantities for carbon-ion beams with different initial energies (10-290 MeV/u) under magnetic fields of various strengths (0.5-3 T). The calculations were performed for a 1 µm spherical volume made of tissue, and for spherical TEPCs of 1 and 10 mm in diameter. Then, values of dose-averaged lineal energy (yD ) were acquired for the different scenarios to analyze the effect of magnetic fields on the microdosimetry of carbon-ion beams and the scaling effect of TEPC. RESULTS: The yD values and lineal energy spectra in the 1 µm spherical tissue volume for the scenarios without magnetic field and with magnetic fields of different strengths and directions remained nearly the same for the various energy carbon-ion beams. However, compared with those of the 1 µm spherical tissue volume, an increase of of yD values and an obvious shift of the lineal energy spectra for the TEPCs of 1 and 10 mm in diameter under magnetic fields were found. CONCLUSIONS: The application of magnetic fields under 3 T has no significant influence on the microdosimetric results of carbon-ion beams. However, there is definitely a scaling effect when using TEPC for microdosimetric study, which alters the reading of TEPC in the presence of magnetic fields. Novel methods to correct the reading of TEPC or scaling effect-resistant microdosimetric measurement detectors are urgently needed to perform experimental microdosimetric studies under magnetic fields.

Assessment of microvasculature flow state with a high speed all-optic dual-modal system of optical coherence tomography and photoacoustic imaging.

We propose a high speed all-optic dual-modal system that combines spectral domain optical coherence tomography (SDOCT) and photoacoustic imaging (PAI) to evaluate microvasculature flow states. A homodyne interferometer was used to remotely detect the surface vibration caused by photoacoustic (PA) waves. The PA excitation, PA probing and SDOCT probing beams share the same X-Y galvanometer scanner to perform fast two-dimensional scanning. In addition, we introduced multi-excitation, dual-channel acquisition and sensitivity compensation to improve the imaging speed of the PAI sub-system. The total time for imaging a sample with 256 × 256 pixels is less than 1 minute. The performance of the proposed system was verified by in vivo imaging of the vascular system in a mouse pinna with normal and then blocked blood circulations. The experimental results indicate that the proposed system is capable of revealing different blood flow states (static and moving) and is useful for the study of diseases related to functional blood supply.

Contamination and health risk assessment of PAHs in soils and crops in industrial areas of the Yangtze River Delta region, China.

This is the first investigation into both soil and crop contamination and associated health risks by polycyclic aromatic hydrocarbons (PAHs) in industrial areas of the Yangtze River Delta region (YRDR). Soil and crop samples were collected from farmland surrounded by three typical industries (a steelworks [SW], a petrochemical facility [PF] and a power plant [PP]), and the concentrations and health risks of PAHs in soils and crops were evaluated. The average concentrations of 16 USEPA priority PAHs in surface soil and subsoil were 471.30 µg kg-1 and 341.40 µg kg-1, respectively. The respective average concentrations of 16 PAHs in amaranth, spinach, Chinese chive, and rice tissues were 1710.49, 1176.96, 1218.36 and 352.12 µg kg-1. Based on both the results of a principal component analysis (PCA) and the PAH ratios, the main sources of the PAHs in soils were determined to be the combustion of coal and petroleum. The total values of incremental lifetime cancer risk (ILCR) for males induced by both soils and crops were 2.19 × 10-4, 2.53 × 10-4, and 9.17 × 10-4, and for females were 2.21 × 10-4, 2.50 × 10-4, and 9.68 × 10-4 for childhood, adolescence, and adulthood, respectively. Soils contaminated with PAHs posed a lower risk than crops, but the ILCR values, 4.40 × 10-5 and 3.82 × 10-5 for males and females, was still much higher than the baseline value. The results of this investigation provide novel information for contamination evaluation and human health risk assessment in PAH-contaminated sites.